(en)Binding proteins that bind one or more of VEGF, PDGF and/or their receptors, including antibodies, CDR-grafted antibodies, humanized antibodies, binding fragments, fusion proteins, and bispecific or multispecific proteins thereof are disclosed. Also disclosed are methods of making and using the binding proteins.

1.ApplicationNumber: US-201615183725-A
1.PublishNumber: US-2017015742-A1
2.Date Publish: 20170119
3.Inventor: GU JIJIE
BOWLEY DIANA
EATON LUCIA
DONG FENG
BENATUIL LORENZO
GHAYUR TARIQ
CHARI RAVI
RIESER MATTHEW
CLABBERS ANCA

4.Inventor Harmonized: GU JIJIE(US)
BOWLEY DIANA(US)
EATON LUCIA(US)
DONG FENG(US)
BENATUIL LORENZO(US)
GHAYUR TARIQ(US)
CHARI RAVI(US)
RIESER MATTHEW(US)
CLABBERS ANCA(US)

5.Country: US
6.Claims:
(en)Binding proteins that bind one or more of VEGF, PDGF and/or their receptors, including antibodies, CDR-grafted antibodies, humanized antibodies, binding fragments, fusion proteins, and bispecific or multispecific proteins thereof are disclosed. Also disclosed are methods of making and using the binding proteins.

7.Description:
(en)This application claims priority to U.S. Provisional Application Ser. No. 62/175,546, filed Jun. 15, 2015, and U.S. Provisional Application Ser. No. 62/291,964, filed Feb. 5, 2016, each of which is incorporated herein by reference in its entirety.


SEQUENCE LISTING
The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Aug. 5, 2016, is named 12252_0202-00000_SL.txt and is 4,068,254 bytes in size.
FIELD
The invention relates to antibodies and antigen-binding fragments thereof, as well as multivalent and multispecific binding proteins, that bind vascular endothelial growth factor (VEGF) and/or platelet-derived growth factor (PDGF), as well as their receptors, and methods of making, and using the constructs in the diagnosis, prevention, and/or treatment of acute and chronic inflammatory diseases, cancer, and other disorders.
BACKGROUND
Angiogenesis, the formation of new blood vessels from pre-existing vasculature, plays a role in the pathogenesis of many diseases, including ocular diseases such as age-related macular degeneration (AMD) or diabetic macular edema (DME). Vascular endothelial growth factor (VEGF) plays a role in the regulation of normal and abnormal angiogenesis (Ferrara et al, (1997) Endoer. Rev. 18:4-25). Several anti-VEGF agents are provided in the art, e.g., in U.S. Pat. No. 7,169,901, which discloses VEGF antibodies for inhibiting VEGF-induced cell proliferation, and U.S. Pat. No. 7,070,959, which discloses isolated nucleic acid molecules encoding fusion proteins capable of binding VEGF.
Targeting VEGF with currently available therapeutics is not effective in all patients or for all diseases associated with inflammation and/or angiogenesis. A significant population of non-responders present following anti-VEGF monotherapy, and the disease prevalence will only increase as the aging population increases globally.
A currently preferred treatment for wet AMD consists of intravitreal injections of an anti-VEGF agent. However, although anti-VEGF therapy reduces choroidal neovascularization, it does not have an effect on regression of the mature vasculature. Also, current agents do not provide an anti-fibrotic effect, so that once scarring of the retina occurs; visual acuity cannot be recovered. Other limitations of the existing treatments regimens include patient discomfort, the need for repeat injections with inherent complications including endophthalmitis, retinal tear and detachment, intraocular hemorrhage, and cataract formation. There is a substantial time burden on ophthalmologists to provide monthly intravitreal treatment and optical coherence tomography (OCT) measurements on a large volume patients. As a result, there is a significant medical and economic need for an AMD therapeutic with greater efficacy, or that can be delivered less frequently and still achieve optimal efficacy.
Platelet-derived growth factor (PDGF) is a growth factor involved in the regulation of blood vessels from pre-existing vessel tissue. PDGF binds to receptors on pericytes in newly-forming abnormal blood vessels. This may contribute to neovascularization of abnormal blood vessels by providing a protective perictye coating, for example, during ocular disorders such as wet AMD.
Engineered proteins, such as antibodies, fragments, and multispecific binding proteins capable of binding two or more antigens, are known in the art. Such multispecific binding proteins can be generated using cell fusion, chemical conjugation, or recombinant DNA techniques. There are a variety of multispecific binding protein structures known in the art and many structures and methods have distinct disadvantages.
Bispecific antibodies have been produced using quadroma technology. Bispecific antibodies can also be produced by chemical conjugation of two different mAbs. Other approaches include coupling of two parental antibodies with a hetero-bifunctional crosslinker, production of tandem single-chain Fv molecules, diabodies, bispecific diabodies, single-chain diabodies, and di-diabodies. In addition, a multivalent antibody construct comprising two Fab repeats in the heavy chain of an IgG and capable of binding four antigen molecules has been described (see PCT Publication No. WO 01/77342 and Miller et al. (2003) J. Immunol. 170(9):4854-61).
U.S. Pat. No. 7,612,181 (incorporated herein by reference in its entirety) provides a novel family of binding proteins capable of binding two or more antigens with high affinity, which are called dual variable domain binding proteins (DVD-Ig binding protein) or dual variable domain immunoglobulins (DVD-Ig). DVD-Ig molecules are binding proteins that may be used to bind two distinct epitopes on the same molecule or two different molecules simultaneously. DVD-Ig molecules are unique binding proteins comprised of two variable domains fused to N-terminal constant regions. The variable domains may be directly fused to one another or connected via synthetic peptide linkers of assorted length and amino acid composition. DVD-Ig binding proteins may be engineered with intact and functional Fc domains, or otherwise modified constant domains, allowing them to mediate appropriate effector functions and exhibit other desired properties. The DVD-Ig format, due to its flexibility of choice of variable domain pair, orientation of two antigen-binding domains, and the length of the linker that joins them, may provide novel therapeutic modalities.
Accordingly, while VEGF monotherapy has had some success in the art, there remains a need for constructs exhibiting better targeting, efficiency, and/or efficacy in binding to VEGF, as well as improved targeting of other pathways involved in inflammation (such as ocular inflammation), e.g., the PDGF pathway. Improved targeting of either of these molecules, alone or in combination, may lead to improvements in, e.g., preventing, diagnosing, and/or treating disorders such as angiogenic, inflammatory, and/or ocular disorders. Also, while a variety of structures have been provided in the art, with various advantages and disadvantages, new variable domain sequences can further improve the properties of binding proteins targeting VEGF and/or PDGF, or their cognate receptors.
SUMMARY
Disclosed herein are binding proteins capable of binding VEGF and/or PDGF, and/or their cognate receptors. In some embodiments, the binding proteins are antibodies to VEGF and/or PDGF, or antigen-binding fragments thereof. In some embodiments, the binding proteins are bispecific and capable of binding VEGF and PDGF. In some embodiments, the binding proteins comprise one or more sequences from any one of Tables A, 27-30, 38-42, 46-50, or 56-58, or the CDR amino acid residues from those sequences.
In various embodiments, the binding proteins are bispecific or multispecific binding proteins capable of binding one or more of VEGF and/or PDGF, and/or their cognate receptors. In some embodiments, the binding proteins are dual variable domain immunoglobulins (DVD-Igs or DVD-Ig binding proteins) using the binding protein framework disclosed in U.S. Pat. No. 7,612,181 (incorporated herein by reference in its entirety).
In some embodiments, the DVD-Ig binding proteins contain particular first and second polypeptide chains, each comprising first and second variable domains comprising sequences (e.g., sequences selected from those listed in Tables A, 27-30, 38-42, 46-50, or 56-58, or the CDR amino acid residues from those sequences) that form functional binding sites for binding targets such as VEGF and/or PDGF, or their cognate receptors. In some embodiments, the first and second polypeptide chains of the binding protein each independently comprise VD1-(X1)n-VD2-C-X2, wherein VD1 is a first variable domain; VD2 is a second variable domain; C is a constant domain; X1 is a linker; X2 is an Fc region that is either present or absent; n is 0 or 1, and wherein the VD1 domains on the first and second polypeptide chains form a first functional target binding site for VEGF, PDGF, or a cognate receptor, and the VD2 domains on the first and second polypeptide chains form a second functional target binding site for VEGF, PDGF, or a cognate receptor. In some embodiments, (a) the first polypeptide chain of the binding protein comprises VD1-(X1)n-VD2-C-X2, wherein VD1 is a first heavy chain variable domain; VD2 is a second heavy chain variable domain; C is a heavy chain constant domain; X1 is a linker; X2 is an Fc region; and n is 0 or 1 (i.e., X1 and X2 are either present or absent, depending on whether n is independently chosen to be 0 or 1 for each position); and (b) the second polypeptide chain of the binding protein comprises VD1-(X1)n-VD2-C-X2, wherein VD1 is a first light chain variable domain; VD2 is a second light chain variable domain; C is a light chain constant domain; X1 is a linker; X2 is an Fc region; and n is 0 or 1 for X1 and n is 0 for X2 (i.e., the Fc region is absent on the second polypeptide chain); and (c) wherein the VD1 domains on the first and second polypeptide chains form a first functional target binding site for VEGF, PDGF, or a cognate receptor, and the VD2 domains on the first and second polypeptide chains form a second functional target binding site for VEGF, PDGF, or a cognate receptor. In some embodiments, the VD1 position forms a binding site for VEGF and the VD2 position forms a binding site for PDGF. In some embodiments, the CDR and/or variable domains at the VD1 and VD2 positions are antibody variable domains and the constant domains are antibody constant domains. Any of the CDR and/or variable domain and/or first and second polypeptide chain sequences disclosed herein may be incorporated in these DVD-Ig binding protein structures to form binding domains for VEGF and/or PDGF, and/or their cognate receptors.
In some embodiments, both the first and second binding sites of a DVD-Ig construct disclosed herein target VEGF. In some embodiments, both the first and second binding sites target PDGF. In some embodiments, the first binding site targets VEGF and the second binding site targets PDGF. In some embodiments, the first binding site targets PDGF and the second binding site targets VEGF. In some embodiments, an Fc domain is present on one polypeptide chain and absent on the other, or absent on both polypeptide chains. In some embodiments, the sequences of the first and second variable domains on each polypeptide chain (i.e., the VD1 and VD2 positions) are independently selected from the sequences in Table A, 27-30, 38-42, 46-50, or 56-58 to form functional binding sites. In some embodiments, the sequences of the first and second variable domains each contain the three complementarity determining regions (i.e., CDRs 1-3) from the selected sequences listed in Tables A, 27-30, 38-42, 46-50, or 56-58, and are arranged in the same order as shown in the Tables, thereby forming functional binding sites (i.e., the binding domains are capable of binding to their target antigen, VEGF or PDGF). In some embodiments, the paired variable domain sequences on the first and second polypeptide chains (i.e., the VD1 sequence on the first chain paired with the VD1 sequence on the second chain and the VD2 sequence on the first chain paired with the VD2 sequence on the second chain) form functional binding sites for binding targets VEGF and/or PDGF using the sequences in the Tables. In some embodiments, the binding proteins are capable of binding to VEGF and/or PDGF with improved binding affinity and/or neutralization potency, improved in vivo efficacy, improved expression, and/or improved drug-like properties (e.g., thermal stability, storage stability, solubility, etc.).
Also disclosed herein are methods of making and using the claimed binding proteins, e.g., in the detection, inhibition, reduction, prevention, and/or treatment of cancers, tumors, fibrosis, renal disease, inflammation, age-related macular degeneration (AMD), wet AMD, diabetic retinopathy, other angiogenesis-dependent diseases, or angiogenesis-independent diseases characterized by aberrant VEGF and/or PDGF expression or activity.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1A and FIG. 1B are schematic representations of a Dual Variable Domain (DVD) binding protein construct.
FIG. 2A and FIG. 2B show the reactivity of anti-PDGF-BB antibodies and anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules to ECM-associated PDGF-BB.
FIG. 3 illustrates the inhibition of sprouting from a HUVEC/MSC co-culture sprouting assay by anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules.
FIG. 4 is a bar graph showing the area of subretinal neovascularization in Rho/huVEGF transgenic mice.
FIG. 5 is a bar graph showing the area of choroidal neovascularization in Rho/huVEGF transgenic mice.
FIG. 6 is a bar graph comparing choroidal neovascularization in the untreated eye among the different treatment groups.
FIG. 7 is a bar graph showing number of partial, total, and undetached eyes in Tet/opsin/VEGF mice.



DETAILED DESCRIPTION
Vascular endothelial growth factor (VEGF) is a signal protein that regulates physiological angiogenesis during embryogenesis, skeletal growth, and reproductive functions. Aberrant expression of VEGF is implicated in pathological angiogenesis and is associated with tumors, intraocular neovascular disorders, and other diseases. The VEGF family members include VEGF-A, placenta growth factor (PGF), VEGF-B, VEGF-C, and VEGF-D. Multiple isoforms of VEGF-A exist that result from alternative splicing of a single, 8-exon VEGFA gene. The biological effects of VEGF are mediated by various receptors, including two receptor tyrosine kinases, VEGF receptor-1 (VEGFR1) and VEGF receptor-2 (VEGFR2), which differ in their signaling properties. When cells are deficient in oxygen, they produce hypoxia-inducible factor (HIF) which releases VEGF and other mediators triggering a tyrosine kinase pathway leading to angiogenesis (Ferrara et al. (2003) Nat. Med. 9:669-676). In various embodiments, the binding proteins disclosed herein can bind one or more of the VEGF family members, including alternate isoforms, and/or can bind one or more of the cognate VEGF receptors.
Platelet-derived growth factor (PDGF) is a protein that stimulates growth, survival, and motility of mesenchymal cells and certain other cell types. It has significant functions during embryonal development and in the control of blood vessel formation as an adult. PDGF is composed of a dimeric glycoprotein made up of two A (-AA), two B (-BB) chains, or a combination of the two (-AB). There are five different isoforms of PDGF that moderate cellular responses through two receptors, alpha (PDGFRA) and beta (PDGFRB) (Heldin (2013) Cell Commun Sig. 11:97). PDGF plays an important role in driving the proliferation of undifferentiated mesenchyme and some progenitor populations. Overactivity or inappropriate PDGF signaling is associated with the development of certain malignant diseases, as well as non-malignant diseases characterized by excessive cell proliferation and other inflammatory disorders. In various embodiments, the binding proteins disclosed herein can bind one or more of the PDGF isoforms, and/or can bind one or more of the cognate PDGF receptors.
Binding Proteins
Disclosed herein are binding proteins capable of binding one or more of VEGF, PDGF, and their cognate receptors. In some embodiments, the binding protein is an antibody or an antigen-binding fragment thereof. In an embodiment, the binding protein is an antibody, a monoclonal antibody, a murine antibody, a human antibody, a humanized antibody, a bispecific antibody, a chimeric antibody, a Fab, a Fab′, a F(ab′) 2 , an ScFv, an SMIP, an affibody, an avimer, a versabody, a nanobody, a fynomab, a domain antibody, or an antigen binding fragment of any of the foregoing. In an embodiment, the binding protein comprises antibody heavy chain variable domain sequences and antibody light chain variable domain sequences that are capable of binding one or more of VEGF, PDGF, and their cognate receptors. In an embodiment, the binding protein comprises the paired heavy and light chain variable domain sequences of any of the binding sites disclosed in Tables 27-30, 38-42, 46-50, or the CDR sequences from those variable domains. The CDR sequences of the variable domains in the Tables are identified in bold.
In some embodiments, the binding proteins disclosed herein is bispecific or multispecific. The bispecific or multispecific construct may be monovalent or bivalent. Various bispecific or multispecific constructs are known in the art (see e.g., Spiess et al. (2015) Mol. Immunol. 67; 95-106). Bispecific or multispecific constructs include, but are not limited to, an asymmetric bispecific antibody, an asymmetric bispecific IgG4, a CrossMab binding protein, a bispecific antibody, a bispecific binding protein, a multispecific binding protein, a DAF (dual action Fab antibody; two-in-one), a DAF (dual action Fab antibody; four-in-one), a DutaMab, a DT-IgG, a knobs-in-holes binding protein, a Charge pair binding protein, a Fab-arm exchange binding protein, a SEEDbody, a Triomab (Triomab quadroma bispecific or removab bispecific), a LUZ-Y, a Fcab, a κλ-body, an iMab (innovative multimer), and an Orthogonal Fab. In some embodiments, the bispecific or multispecific construct is a DVD-Ig binding protein, an IgG(H)-scFv, an scFv-(H)IgG, an IgG(L)-scFv, an scFv-(L)IgG, an IgG(L, H)-Fv, an IgG(H)-V, a V(H)-IgG, an IgG(L)-V, a V(L)-IgG, a KIH IgG-scFab, a 2scFv-IgG, an IgG-2scFv, an scFv4-Ig, a Zybody, or a DVI-IgG (four-in-one). In some embodiments, the bispecific or multispecific construct also can be a nanobody (or VHH), a bispecific tandem nanobody, a bispecific trivalent tandem nanobody, a nanobody-HSA, a BiTE (bispecific T-cell engager) binding protein, a Diabody, a DART (dual affinity retargeting) binding protein, a TandAb (tetravalent bispecifc tandem antibody), an scDiabody, an scDiabody-CH3, a Diabody-CH3, a Triple Body, a Miniantibody, a Minibody, a TriBi minibody, an scFv-CH3 KIH, a Fab-scFv, an scFv-CH-CL-scFv, a F(ab′)2, a F(ab′)2 scFv2, an scFv-KIH, a Fab-scFv-Fc, a Tetravalent HCAb, an scDiabody-Fc, a Diabody-Fc, a Tandem scFv-Fc, a Fabsc, a bsFc-1/2, a CODV-Ig (cross-over dual variable immunoglobulin), a biclonics antibody or an Intrabody. Bispecific or multispecific constructs also include, for example, a Dock and Lock binding protein, an ImmTAC, an HSAbody, an scDiabody-HSA, a Tandem scFv-Toxin, an IgG-IgG binding protein, a Cov-X-Body, and an scFv1-PEG-scFv2. In some embodiments, the bispecific or multispecific construct is a DVD-Ig binding protein, a CrossMab binding protein, a diabody, a tandem single-chain Fv molecule, a bispecific diabody, a single-chain diabody molecule, or a di-diabody. In some embodiments, the binding protein is a DVD-Ig binding protein. See, e.g., U.S. Pat. No. 7,612,181 (incorporated herein by reference in its entirety). The bispecific or multispecific construct may comprise one or more binding sites for VEGF, PDGF, and/or their receptors. The bispecific or multispecific construct may comprise binding sites only for VEGF, PDGF, and/or their receptors, or may comprise additional binding sites for other antigen targets. The bispecific or multispecific construct may comprise binding sites for more than one epitope on VEGF, PDGF, and/or their receptors, e.g., using different CDR sets or variable domains from those disclosed herein to form binding sites targeting different epitopes.
In various embodiments, the binding protein is capable of binding VEGF, and comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs 1-3 from SEQ ID NO: 18, CDRs 1-3 from SEQ ID NO: 19 and CDRs 1-3 from SEQ ID NO: 20, CDRs 1-3 from SEQ ID NO: 21 and CDRs 1-3 from SEQ ID NO: 22, CDRs 1-3 from SEQ ID NO: 23 and CDRs 1-3 from SEQ ID NO: 24, CDRs 1-3 from SEQ ID NO: 25 and CDRs 1-3 from SEQ ID NO: 26, CDRs 1-3 from SEQ ID NO: 27 and CDRs 1-3 from SEQ ID NO: 28, CDRs 1-3 from SEQ ID NO: 29 and CDRs 1-3 from SEQ ID NO: 30, CDRs 1-3 from SEQ ID NO: 31 and CDRs 1-3 from SEQ ID NO: 32, CDRs 1-3 from SEQ ID NO: 33 and CDRs 1-3 from SEQ ID NO: 34, CDRs 1-3 from SEQ ID NO: 35 and CDRs 1-3 from SEQ ID NO: 36, CDRs 1-3 from SEQ ID NO: 37 and CDRs 1-3 from SEQ ID NO: 38, CDRs 1-3 from SEQ ID NO: 39 and CDRs 1-3 from SEQ ID NO: 40, CDRs 1-3 from SEQ ID NO: 41 and CDRs 1-3 from SEQ ID NO: 42, or CDRs 1-3 from SEQ ID NO: 43 and CDRs 1-3 from SEQ ID NO: 44. In an embodiment, the binding protein is capable of binding VEGF, and comprises SEQ ID NO: 17 and SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20, SEQ ID NO: 21 and SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24, SEQ ID NO: 25 and SEQ ID NO: 26, SEQ ID NO: 27 and SEQ ID NO: 28, SEQ ID NO: 29 and SEQ ID NO: 30, SEQ ID NO: 31 and SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34, SEQ ID NO: 35 and SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38, SEQ ID NO: 39 and SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, or SEQ ID NO: 43 and SEQ ID NO: 44. Any of said binding proteins capable of binding VEGF may also be capable of binding PDGF, and may comprise any of the PDGF binding sequences as described herein.
In various embodiments, the binding protein is capable of binding PDGF, and comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs 1-3 from SEQ ID NO: 2, CDRs 1-3 from SEQ ID NO: 3 and CDRs 1-3 from SEQ ID NO: 4, CDRs 1-3 from SEQ ID NO: 5 and CDRs 1-3 from SEQ ID NO: 6, CDRs 1-3 from SEQ ID NO: 7 and CDRs 1-3 from SEQ ID NO: 8, CDRs 1-3 from SEQ ID NO: 9 and CDRs 1-3 from SEQ ID NO: 10, CDRs 1-3 from SEQ ID NO: 11 and CDRs 1-3 from SEQ ID NO: 12, CDRs 1-3 from SEQ ID NO: 13 and CDRs 1-3 from SEQ ID NO: 14, CDRs 1-3 from SEQ ID NO: 15 and CDRs 1-3 from SEQ ID NO: 16, or CDRs 1-3 from SEQ ID NO: 211 and CDRs 1-3 from SEQ ID NO: 212. In an embodiment, the binding protein is capable of binding PDGF, and comprises SEQ ID NO: 1 and SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16, or SEQ ID NO: 211 and SEQ ID NO: 212. Any of said binding proteins capable of binding PDGF may also be capable of binding VEGF, and may comprise any of the VEGF binding sequences as described herein.
In an embodiment, the binding protein is a bispecific or multispecific antibody capable of binding one or more of VEGF, PDGF, and their cognate receptors, or another multispecific construct capable of binding the targets. In certain embodiments, the treatment is with bispecific antibodies that have been produced by quadroma technology (Milstein and Cuello (1983) Nature 305(5934): 537-40), by chemical conjugation of two different monoclonal antibodies (Staerz et al. (1985) Nature 314(6012): 628-31), or by knob-into-hole or similar approaches which introduces mutations in the Fc region (Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90(14): 6444-6448). In some embodiments, the multispecific binding protein is a dual variable domain immunoglobulin (DVD-Ig), e.g., as disclosed in U.S. Pat. No. 7,612,181 (incorporated herein by reference in their entirety). In an embodiment, the DVD-Ig binding protein comprises one or more binding sites comprising the paired heavy and light chain variable domain sequences of any of the binding sites disclosed in Tables 27-30, 38-42, 46-50, or 56-58, or the CDR sequences from those variable domains. For instance, a binding site for VEGF can comprise a paired set of heavy and light chain variable domain sequences from any one of Tables 27 or 38-42, or the CDR regions from those sequences, while the PDGF can comprise the paired heavy and light chain variable domain sequences in Tables 28 or 46-50, or the CDR regions from those sequences. The CDR regions of some of these sequences are shown in Table A and in Table 57.
In some embodiments, a multispecific binding protein disclosed herein is capable of binding VEGF and PDGF, and allows for fewer injections or a lower concentration of active agent, as compared to combination antibody therapy.
In some embodiments, the DVD-Ig binding protein comprises first and second polypeptide chains, each independently comprising VD1-(X1)n-VD2-C-X2, wherein: VD1 is a first variable domain; VD2 is a second variable domain; C is a constant domain; X1 is a linker; X2 is an Fc region that is either present or absent; n is independently 0 or 1 on the first and second chains, and wherein the VD1 domains on the first and second polypeptide chains form a first functional target binding site and the VD2 domains on the first and second polypeptide chains form a second functional target binding site. In some embodiments, the binding protein is capable of binding one or more of VEGF, PDGF, and their cognate receptors, e.g., using a paired set of sequences from any one of Tables 27-30, 38-42, 46-50, or 56-58. In some embodiments, the binding protein comprises VD1 sequences on the first and second polypeptide chains (i.e., a VD1 sequence on the first chain paired with a VD1 sequence on the second chain) that together form a binding domain capable of binding a target selected from VEGF, PDGF, and their cognate receptors. In some embodiments, the binding protein is capable of binding VEGF at both the VD1 and VD2 positions. In some embodiments, the binding protein is capable of binding PDGF at both the VD1 and VD2 positions. In some embodiments, the binding protein is capable of binding VEGF at the VD1 position and PDGF at the VD2 position. In some embodiments, the binding protein is capable of binding PDGF at the VD1 position and VEGF at the VD2 position.
When a binding protein comprises the CDRs from a sequence selected from any one of Tables 27-30, 38-42, 46-50, or 56-58, the CDRs are arranged in the order specified by the sequence in the Table and separated by suitable framework sequences to form a functional binding site. The paired sequences selected from the Tables that form a functional binding site for a target (e.g., a binding site for VEGF and/or PDGF), or the CDRs from those sequences, may be placed in either the VD1 or VD2 positions on the first and second polypeptide chains to form a binding site at either the VD1 or VD2 domain.
The binding proteins disclosed herein comprise VD1 and VD2 binding domains that are capable of binding to first and second target antigens. As used herein, a VD1 domain or a VD2 domain, or a VD1 position or VD2 position, may refer to either the variable domain sequence on one polypeptide chain (e.g., a VD1 heavy chain sequence) or to the variable domain sequences on both the first and second polypeptide chain (e.g., a VD1 heavy chain sequence and a VD1 light chain sequence) that together form the functional binding site, as indicated by the context in which it is discussed.
In some embodiments, a DVD-Ig binding protein can comprise two first and two second polypeptide chains forming four functional binding sites on two arms of the construct. An example of a four chain structure having two arms, each arm comprising a first and second polypeptide chain and two functional binding sites, is shown in FIG. 1 .
In an embodiment, the DVD-Ig binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs 1-3 from SEQ ID NO: 18, CDRs 1-3 from SEQ ID NO: 19 and CDRs 1-3 from SEQ ID NO: 20, CDRs 1-3 from SEQ ID NO: 21 and CDRs 1-3 from SEQ ID NO: 22, CDRs 1-3 from SEQ ID NO: 23 and CDRs 1-3 from SEQ ID NO: 24, CDRs 1-3 from SEQ ID NO: 25 and CDRs 1-3 from SEQ ID NO: 26, CDRs 1-3 from SEQ ID NO: 27 and CDRs 1-3 from SEQ ID NO: 28, CDRs 1-3 from SEQ ID NO: 29 and CDRs 1-3 from SEQ ID NO: 30, CDRs 1-3 from SEQ ID NO: 31 and CDRs 1-3 from SEQ ID NO: 32, CDRs 1-3 from SEQ ID NO: 33 and CDRs 1-3 from SEQ ID NO: 34, CDRs 1-3 from SEQ ID NO: 35 and CDRs 1-3 from SEQ ID NO: 36, CDRs 1-3 from SEQ ID NO: 37 and CDRs 1-3 from SEQ ID NO: 38, CDRs 1-3 from SEQ ID NO: 39 and CDRs 1-3 from SEQ ID NO: 40, CDRs 1-3 from SEQ ID NO: 41 and CDRs 1-3 from SEQ ID NO: 42, or CDRs 1-3 from SEQ ID NO: 43 and CDRs 1-3 from SEQ ID NO: 44. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 17 and SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20, SEQ ID NO: 21 and SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24, SEQ ID NO: 25 and SEQ ID NO: 26, SEQ ID NO: 27 and SEQ ID NO: 28, SEQ ID NO: 29 and SEQ ID NO: 30, SEQ ID NO: 31 and SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34, SEQ ID NO: 35 and SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38, SEQ ID NO: 39 and SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, or SEQ ID NO: 43 and SEQ ID NO: 44.
In an embodiment, a DVD-Ig binding protein is disclosed that is capable of binding VEGF and PDGF, wherein the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs 1-3 from SEQ ID NO: 2, CDRs 1-3 from SEQ ID NO: 3 and CDRs 1-3 from SEQ ID NO: 4, CDRs 1-3 from SEQ ID NO: 5 and CDRs 1-3 from SEQ ID NO: 6, CDRs 1-3 from SEQ ID NO: 7 and CDRs 1-3 from SEQ ID NO: 8, CDRs 1-3 from SEQ ID NO: 9 and CDRs 1-3 from SEQ ID NO: 10, CDRs 1-3 from SEQ ID NO: 11 and CDRs 1-3 from SEQ ID NO: 12, CDRs 1-3 from SEQ ID NO: 13 and CDRs 1-3 from SEQ ID NO: 14, CDRs 1-3 from SEQ ID NO: 15 and CDRs 1-3 from SEQ ID NO: 16, or CDRs 1-3 from SEQ ID NO: 211 and CDRs 1-3 from SEQ ID NO: 212. In an embodiment, the binding site for PDGF comprises SEQ ID NO: 1 and SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16, or SEQ ID NO: 211 and SEQ ID NO: 212.
In an embodiment, the DVD-Ig binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs 1-3 from SEQ ID NO: 18, CDRs 1-3 from SEQ ID NO: 19 and CDRs 1-3 from SEQ ID NO: 20, CDRs 1-3 from SEQ ID NO: 21 and CDRs 1-3 from SEQ ID NO: 22, CDRs 1-3 from SEQ ID NO: 23 and CDRs 1-3 from SEQ ID NO: 24, CDRs 1-3 from SEQ ID NO: 25 and CDRs 1-3 from SEQ ID NO: 26, CDRs 1-3 from SEQ ID NO: 27 and CDRs 1-3 from SEQ ID NO: 28, CDRs 1-3 from SEQ ID NO: 29 and CDRs 1-3 from SEQ ID NO: 30, CDRs 1-3 from SEQ ID NO: 31 and CDRs 1-3 from SEQ ID NO: 32, CDRs 1-3 from SEQ ID NO: 33 and CDRs 1-3 from SEQ ID NO: 34, CDRs 1-3 from SEQ ID NO: 35 and CDRs 1-3 from SEQ ID NO: 36, CDRs 1-3 from SEQ ID NO: 37 and CDRs 1-3 from SEQ ID NO: 38, CDRs 1-3 from SEQ ID NO: 39 and CDRs 1-3 from SEQ ID NO: 40, CDRs 1-3 from SEQ ID NO: 41 and CDRs 1-3 from SEQ ID NO: 42, or CDRs 1-3 from SEQ ID NO: 43 and CDRs 1-3 from SEQ ID NO: 44; and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs 1-3 from SEQ ID NO: 2, CDRs 1-3 from SEQ ID NO: 3 and CDRs 1-3 from SEQ ID NO: 4, CDRs 1-3 from SEQ ID NO: 5 and CDRs 1-3 from SEQ ID NO: 6, CDRs 1-3 from SEQ ID NO: 7 and CDRs 1-3 from SEQ ID NO: 8, CDRs 1-3 from SEQ ID NO: 9 and CDRs 1-3 from SEQ ID NO: 10, CDRs 1-3 from SEQ ID NO: 11 and CDRs 1-3 from SEQ ID NO: 12, CDRs 1-3 from SEQ ID NO: 13 and CDRs 1-3 from SEQ ID NO: 14, CDRs 1-3 from SEQ ID NO: 15 and CDRs 1-3 from SEQ ID NO: 16, or CDRs 1-3 from SEQ ID NO: 211 and CDRs 1-3 from SEQ ID NO: 212. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 17 and SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20, SEQ ID NO: 21 and SEQ ID NO: 22, SEQ ID NO: 23 and SEQ ID NO: 24, SEQ ID NO: 25 and SEQ ID NO: 26, SEQ ID NO: 27 and SEQ ID NO: 28, SEQ ID NO: 29 and SEQ ID NO: 30, SEQ ID NO: 31 and SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34, SEQ ID NO: 35 and SEQ ID NO: 36, SEQ ID NO: 37 and SEQ ID NO: 38, SEQ ID NO: 39 and SEQ ID NO: 40, SEQ ID NO: 41 and SEQ ID NO: 42, or SEQ ID NO: 43 and SEQ ID NO: 44; and the binding site for PDGF comprises SEQ ID NO: 1 and SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16, or SEQ ID NO: 211 and SEQ ID NO: 212.
In various embodiments, the DVD-Ig binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 35 and CDRs-1-3 from SEQ ID NO: 36, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 15 and CDRs-1-3 from SEQ ID NO: 16. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 35 and SEQ ID NO: 36, and the binding site for PDGF comprises SEQ ID NO: 15 and SEQ ID NO: 16. In any of these embodiments, the binding site for VEGF may be the outer binding domain or VD1 position as described herein, and the binding site for PDGF may be the inner domain or VD2 position as described herein. In various embodiments, any of the DVD-Ig binding proteins disclosed herein can comprise one or more of the X1 linkers shown in Table 55. In an embodiment, the X1 linker on the heavy chain is a GS-H10 linker and the X1 linker on the light chain is a GS-L10(dR) linker. In an embodiment, the X1 linker on the heavy chain is a GS-H10 linker and the X1 linker on the light chain is a GS-L10 linker. In an embodiment, the X1 linker on the heavy chain is an HG-short linker and the X1 linker on the light chain is an LK-long linker.
In various embodiments, any of the antibodies, binding proteins, or DVD-Ig binding proteins disclosed herein can comprise a human IgG (e.g., an IgG1) heavy chain constant region on the first polypeptide chain comprising substitutions of leucines at positions 234 and 235 with alanines, and optionally also (or alternatively) a substitution of histidine at position 435 with alanine, wherein the amino acid positions are numbered using EU index numbering. In various embodiments, the antibody, binding protein, or DVD-Ig binding protein can also comprise a human kappa or lambda light chain constant region on the second polypeptide chain. In an embodiment, the light chain comprises a wild-type human kappa light chain constant region sequence.
In an embodiment, the DVD-Ig binding protein is capable of binding VEGF and PDGF, and comprises PR-1610561 (comprising SEQ ID NOs: 131 and 132). In an embodiment, the binding protein comprises a heavy chain constant region on the first polypeptide chain comprising a human IgG1 heavy chain sequence modified by one or more amino acid changes, wherein the changes comprise substitution of leucines at positions 234 and 235 with alanines, and optionally also comprising a substitution of histidine at position 435 with alanine, wherein the amino acid positions are numbered using EU index numbering; and a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence. In an embodiment, the binding protein comprises an IgG1 constant region with substitution of leucines at positions 234 and 235 with alanines, and a substitution of histidine at position 435 with alanine, wherein the amino acid positions are numbered using EU index numbering; and a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence. In some embodiments, the L234A, L235A, and H435 mutations are present in a DVD-Ig binding protein comprising PR-1610561 (comprising SEQ ID NOs: 131 and 132). In some embodiments, the binding protein carrying the constant region mutations has increased ocular duration over an antibody, but is rapidly cleared from systemic circulation (e.g., by altering FcRn recognition), as compared to an antibody or as compared to the same binding protein lacking the constant region mutations. In some embodiments, the high ocular duration allows for less frequent administration and/or fewer overall injections while achieving a comparable or improved efficacy as compared to administration of a combination of anti-VEGF and anti-PDGF antibodies or as compared to administration of the binding protein lacking the constant region mutations. In some embodiments, the binding protein carrying the constant region mutations has decreased ADCC and CDC effector functions mediated by binding to extracellular matrix-associated VEGF-A and/or PDGF-BB, as compared to administration of the binding protein lacking the constant region mutations. In some embodiments, the binding protein carrying the constant region mutations does not bind to one or more Fc-gamma receptors. In some embodiments, systemic levels of the binding protein in a patient drops below detectable levels after less than 20, 25, 30, 35, or 40 hours following administration at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg/kg, or more (or any concentration in between) in an intravenous bolus dose.
In an embodiment, the DVD-Ig binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs-1-3 from SEQ ID NO: 18, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs-1-3 from SEQ ID NO: 2. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 17 and SEQ ID NO: 18, and the binding site for PDGF comprises SEQ ID NO: 1 and SEQ ID NO: 2. In an embodiment, the DVD-Ig binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 39 and CDRs-1-3 from SEQ ID NO: 40, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 15 and CDRs-1-3 from SEQ ID NO: 16. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 39 and SEQ ID NO: 40, and the binding site for PDGF comprises SEQ ID NO: 15 and SEQ ID NO: 16. In any of these embodiments, the binding site for VEGF may be the outer binding domain or VD1 sequence as described herein, and the binding site for PDGF may be the inner domain or VD2 sequence as described herein. In various embodiments, the binding proteins can comprise one or more of the X1 linkers shown in Table 55. In an embodiment, the X1 linker on the heavy chain is a GS-H10 linker and the X1 linker on the light chain is a GS-L10(dR) linker. In an embodiment, the X1 linker on the heavy chain is a GS-H10 linker and the X1 linker on the light chain is a GS-L10 linker. In an embodiment, the X1 linker on the heavy chain is an HG-short linker and the X1 linker on the light chain is an LK-long linker. In an embodiment, the binding protein is capable of binding VEGF and PDGF, and comprises PR-1572102 (comprising SEQ ID NOs: 88 and 89) or PR-1572105 (comprising SEQ ID NOs: 94 and 95) or PR1611292 (comprising SEQ ID NOs: 141 and 142). In an embodiment, the binding protein comprises a heavy chain constant region on the first polypeptide chain comprising a human IgG1 heavy chain sequence modified by one or more amino acid changes, wherein the changes comprise substitution of leucines at positions 234 and 235 with alanines, and optionally also comprising a substitution of histidine at position 435 with alanine, wherein the amino acid positions are numbered using EU index numbering; and a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence.
In an embodiment, the DVD-Ig binding protein comprises the first and second polypeptide chains of any of the DVD-Ig binding proteins disclosed in Tables 56-58. The CDR sequences of the variable domains in Tables 56-58 are in bold and the linker sequences are italicized.
In an embodiment, the DVD-Ig binding protein comprises the first and second polypeptide chains of PR-1563988 (comprising SEQ ID NOs: 45 and 46), PR-1563990 (comprising SEQ ID NOs: 47 and 48), PR-1563998 (comprising SEQ ID NOs: 49 and 50), PR-1564009 (comprising SEQ ID NOs: 51 and 52), PR-1564010 (comprising SEQ ID NOs: 53 and 54), PR-1564011 (comprising SEQ ID NOs: 55 and 56), PR-1564012 (comprising SEQ ID NOs: 57 and 58), PR-1564013 (comprising SEQ ID NOs: 59 and 60), PR-1565031 (comprising SEQ ID NOs: 76 and 77), PR-1565032 (comprising SEQ ID NOs: 78 and 79), PR-1565035 (comprising SEQ ID NOs: 80 and 81), PR-1572102 (comprising SEQ ID NOs: 88 and 89), PR-1572103 (comprising SEQ ID NOs: 90 and 91), PR-1572104 (comprising SEQ ID NOs: 92 and 93), PR-1572105 (comprising SEQ ID NOs: 94 and 95), PR-1572106 (comprising SEQ ID NOs: 96 and 97), PR-1575832 (comprising SEQ ID NOs: 99 and 100), PR-1575834 (comprising SEQ ID NOs: 101 and 102), PR-1575835 (comprising SEQ ID NOs: 103 and 104), PR-1577165 (comprising SEQ ID NOs: 105 and 106), PR-1577166 (comprising SEQ ID NOs: 107 and 108), PR-1577547 (comprising SEQ ID NOs: 109 and 110), PR-1577548 (comprising SEQ ID NOs: 111 and 112), PR-1577550 (comprising SEQ ID NOs: 113 and 114), PR-1578137 (comprising SEQ ID NOs: 116 and 117), PR-1610560 (comprising SEQ ID NOs: 129 and 130), PR-1610561 (comprising SEQ ID NOs: 131 and 132), PR-1610562 (comprising SEQ ID NOs: 133 and 134), PR-1610563 (comprising SEQ ID NOs: 135 and 136), PR-1611291 (comprising SEQ ID NOs: 139 and 140), PR-1611292 (comprising SEQ ID NOs: 141 and 142), PR-1612489 (comprising SEQ ID NOs: 161 and 162), PR-1612491 (comprising SEQ ID NOs: 163 and 164), PR-1612492 (comprising SEQ ID NOs: 165 and 166), PR-1612495 (comprising SEQ ID NOs: 171 and 172), PR-1612496 (comprising SEQ ID NOs: 173 and 174), PR-1612499 (comprising SEQ ID NOs: 177 and 178), PR-1612500 (comprising SEQ ID NOs: 179 and 180), PR-1612501 (comprising SEQ ID NOs: 181 and 182), PR-1612502 (comprising SEQ ID NOs: 183 and 184), PR-1613183 (comprising SEQ ID NOs: 185 and 186), PR-1613184 (comprising SEQ ID NOs: 187 and 188), PR-1613185 (comprising SEQ ID NOs: 189 and 190), PR-1613190 (comprising SEQ ID NOs: 199 and 200), PR-1565040 (comprising SEQ ID NOs: 3844 and 3845), PR-1565042 (comprising SEQ ID NOs: 3837 and 3838), PR-1565044 (comprising SEQ ID NOs: 213 and 214), PR-1565051 (comprising SEQ ID NOs: 215 and 216), PR-1565083 (comprising SEQ ID NOs: 217 and 218), PR-1565084 (comprising SEQ ID NOs: 219 and 220), PR-1565085 (comprising SEQ ID NOs: 221 and 222), PR-1565086 (comprising SEQ ID NOs: 223 and 224), PR-1571821 (comprising SEQ ID NOs: 225 and 226), PR-1571823 (comprising SEQ ID NOs: 227 and 228), PR-1575521 (comprising SEQ ID NOs: 229 and 230), PR-1571824 (comprising SEQ ID NOs: 231 and 232), PR-1571825 (comprising SEQ ID NOs: 233 and 234), PR-1571826 (comprising SEQ ID NOs: 235 and 236), PR-1571827 (comprising SEQ ID NOs: 237 and 238), PR-1571828 (comprising SEQ ID NOs: 239 and 240), PR-1571830 (comprising SEQ ID NOs: 241 and 242), PR-1571831 (comprising SEQ ID NOs: 243 and 244), PR-1571832 (comprising SEQ ID NOs: 245 and 246), PR-1571836 (comprising SEQ ID NOs: 247 and 248), PR-1577053 (comprising SEQ ID NOs: 249 and 250), or PR-1577056 (comprising SEQ ID NOs: 251 and 252.
In some embodiments, a binding protein, including a DVD-Ig binding protein, antibody, or fragment thereof, is capable of binding VEGF and/or PDGF and has at least about 80%, 90%, 95%, or 99% homology to CDRs 1-3 or to the full variable domains of any of the sequences in Tables 27, 28, 38-42, or 46-50. As used herein, the term percent (%) homology defines the percentage of residues in the amino acid sequence variant that are identical after aligning the sequences and introducing gaps and other spacing, e.g., using the BLAST alignment software.
In an embodiment, the binding protein has an on rate constant (K on ) to one or more targets of at least about 10 2 M −1 s −1 ; at least about 10 3 M −1 s −1 ; at least about 10 4 M −1 s −1 ; at least about 10 5 M −1 s −1 ; or at least about 10 6 M −1 s −1 , as measured by surface plasmon resonance. In an embodiment, the binding protein has an on rate constant (K on ) to one or more targets from about 10 2 M −1 s −1 to about 10 3 M −1 s −1 ; from about 10 3 M −1 s −1 to about 10 4 M −1 s −1 ; from about 10 4 M −1 s −1 to about 10 5 M −1 s −1 ; or from about 10 5 M −1 s −1 to about 10 6 M −1 s −1 , as measured by surface plasmon resonance.
In an embodiment, the binding protein has an off rate constant (K off ) for one or more targets of at most about 10 −3 s −1 ; at most about 10 −4 s −1 ; at most about 10 −5 s −1 ; or at most about 10 −6 s −1 , as measured by surface plasmon resonance. In an embodiment, the binding protein has an off rate constant (K off ) to one or more targets of about 10 −3 s −1 to about 10 −4 s −1 ; of about 10 −4 s −1 to about 10 −5 s −1 ; or of about 10 −5 s −1 to about 10 −6 s −1 , as measured by surface plasmon resonance.
In an embodiment, the binding protein has a dissociation constant (K d ) to one or more targets of at most about 10 −7 M; at most about 10 −8 M; at most about 10 −9 M; at most about 10 −10 M; at most about 10 −11 M; at most about 10 −12 M; or at most 10 −13 M. In an embodiment, the binding protein has a dissociation constant (K d ) to its targets of about 10 −7 M to about 10 −8 M; of about 10 −8 M to about 10 −9 M; of about 10 −9 M to about 10 −10 M; of about 10 −10 M to about 10 −11 M; of about 10 −11 M to about 10 −12 M; or of about 10 −12 to M about 10 −13 M.
In an embodiment, the binding protein is a conjugate further comprising an agent. In an embodiment, the agent is an immunoadhesion molecule, an imaging agent, a therapeutic agent, or a cytotoxic agent. In an embodiment, the imaging agent is a radiolabel, an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, or biotin. In another embodiment, the radiolabel is 3 H, 14 C, 35 S, 90 Y, 99 Tc, 111 In, 125 I, 131 I, 177 Lu, 166 Ho, or 153 Sm. In yet another embodiment, the therapeutic or cytotoxic agent is an anti-metabolite, an alkylating agent, an antibiotic, a growth factor, a cytokine, an anti-angiogenic agent, an anti-mitotic agent, an anthracycline, toxin, or an apoptotic agent, or an immunosuppressive agent.
In an embodiment, the binding protein is a crystallized binding protein and exists as a crystal. In an embodiment, the crystal is a carrier-free pharmaceutical controlled release crystal. In another embodiment, the crystallized binding protein has a greater half-life in vivo than the soluble counterpart of the binding protein. In yet another embodiment, the crystallized binding protein retains biological activity.
In certain embodiments, a binding protein disclosed herein can compete for binding to VEGF, PDGF, and/or a cognate receptor with any of the antibodies, binding proteins, or bispecific antibodies disclosed herein. In certain embodiments, a binding protein disclosed herein can compete for binding with an antibody, binding protein, or bispecific antibody comprising CDRs and/or variable domains selected from those identified in Tables 27, 28, 38-42, or 46-50. In certain embodiments, a binding protein disclosed herein can compete for binding with PR-1610561 (comprising SEQ ID NOs: 131 and 132) or a binding protein comprising the CDRs and/or variable domains of PR-1610561. In certain embodiments, a binding protein disclosed herein can compete for binding with PR-1572102 (comprising SEQ ID NOs: 88 and 89) or PR-1572105 (comprising SEQ ID NOs: 94 and 95) or PR1611292 (comprising SEQ ID NOs: 141 and 142).
According to certain embodiments, a binding protein disclosed herein can bind to the same epitope of VEGF, PDGF, and/or a cognate receptor as any of the antibodies, binding proteins, or bispecific antibodies disclosed herein. In certain embodiments, a binding protein disclosed herein can bind to the same epitope of VEGF, PDGF, and/or a cognate receptor bound by an antibody, binding protein, or bispecific antibody comprising CDRs and/or variable domains selected from those identified in Tables 27, 28, 38-42, or 46-50. In certain embodiments, a binding protein disclosed herein can bind to the same epitope as PR-1610561 (comprising SEQ ID NOs: 131 and 132) or a binding protein comprising the CDRs and/or variable domains of PR-1610561. In certain embodiments, a binding protein disclosed herein binds to the same epitope as PR-1572102 (comprising SEQ ID NOs: 88 and 89) or PR-1572105 (comprising SEQ ID NOs: 94 and 95) or PR1611292 (comprising SEQ ID NOs: 141 and 142).
In certain embodiments, competitive binding can be evaluated using a cross-blocking assay, such as the assay described in ANTIBODIES, A LABORATORY MANUAL, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1 st edition 1988, 2 nd edition 2014). In some embodiments, competitive binding is identified when a test antibody or binding protein reduces binding of a reference antibody or binding protein (e.g., a binding protein comprising CDRs and/or variable domains selected from those identified in Tables 27, 28, 38-42, or 46-50) to VEGF, PDGF, and/or a cognate receptor by at least about 50% in the cross-blocking assay (e.g., 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%, or more, or any percentage in between), and/or vice versa. In some embodiments, competitive binding can be due to shared or similar (e.g., partially overlapping) epitopes, or due to steric hindrance where antibodies or binding proteins bind at nearby epitopes. See, e.g., Tzartos, Methods in Molecular Biology, vol. 66, Epitope Mapping Protocols, pages 55-66, Humana Press Inc. (1998). In some embodiments, competitive binding can be used to sort groups of binding proteins that share similar epitopes, e.g., those that compete for binding can be “binned” as a group of binding proteins that have overlapping or nearby epitopes, while those that do not compete are placed in a separate group of binding proteins that do not have overlapping or nearby epitopes
In an embodiment, the binding protein described herein is glycosylated. For example, the glycosylation pattern may be a human glycosylation pattern.
In various embodiments, a pharmaceutical composition comprising a binding protein disclosed herein and a pharmaceutically acceptable carrier is provided. In a further embodiment, the pharmaceutical composition comprises at least one additional agent such as a therapeutic agent for treating a disorder or a diagnostic agent. For example, the additional agent may be a therapeutic agent, an imaging agent, a cytotoxic agent, an angiogenesis inhibitor (including but not limited to an anti-VEGF antibody or a VEGF-trap), a kinase inhibitor (including but not limited to a KDR and a TIE-2 inhibitor), a co-stimulation molecule blocker (including but not limited to anti-B7.1, anti-B7.2, CTLA4-Ig, anti-CD20), an adhesion molecule blocker (including but not limited to an anti-LFA-1 antibody, an anti-E/L selectin antibody, a small molecule inhibitor), an anti-cytokine antibody or functional fragment thereof (including but not limited to an anti-IL-18, an anti-TNF, and an anti-IL-6/cytokine receptor antibody), methotrexate, cyclosporin, rapamycin, FK506, a detectable label or reporter, a TNF antagonist, an antirheumatic, a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial, an antipsoriatic, a corticosteriod, an anabolic steroid, an erythropoietin, an immunoglobulin, an immunosuppressive, a growth hormone, a hormone replacement drug, a radiopharmaceutical, an antidepressant, an antipsychotic, a stimulant, an asthma medication, a beta agonist, an inhaled steroid, an epinephrine or analog, a cytokine, or a cytokine antagonist.
In various embodiments, a binding protein disclosed herein binds to VEGF and comprises CDRs and/or variable domains selected from those identified in Tables A, 2.4.1-2.4.9, 27, and 38-42. In some embodiments, the binding protein comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of the CDR sets listed in Tables A, 2.4.1-2.4.9, 27, and 38-42. In some embodiments, the binding protein comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 2.4.1-2.4.9, 27, and 38-42. In some embodiments, the binding protein is a bispecific or multispecific binding protein, comprising CDRs and/or variable domains selected from Tables A, 2.4.1-2.4.9, 27, and 38-42. The binding protein may further comprise heavy and light chain constant domains selected from Table 3. In some embodiments, the binding protein is also capable of binding to PDGF.
In some embodiments, a binding protein disclosed herein binds to PDGF and comprises CDRs and/or variable domains selected from those identified in Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding protein comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of the CDR sets listed in Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding protein comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding protein is a bispecific or multispecific binding protein, comprising CDRs and/or variable domains selected from Tables A, 1.4.1-1.4.7, 28, and 46-50. The binding protein may further comprise heavy and light chain constant domains selected from Table 3. In some embodiments, the binding protein is also capable of binding to VEGF.
In some embodiments, a binding protein disclosed herein binds to VEGF and PDGF, wherein the binding site for VEGF comprises CDRs and/or variable domains selected from those identified in Tables A, 2.4.1-2.4.9, 27, and 38-42 and the binding site for PDGF comprises CDRs and/or variable domains selected from those identified in Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding sites for VEGF and PDGF comprises CDRs and/or variable domains selected from any of the variable domains listed in Tables 56-59, 95, and 96. In some embodiments, binding proteins disclosed herein comprise binding sites for VEGF and PDGF comprising the paired CDRs and/or variable domains from any one of the bispecific binding proteins selected from Tables 56-59, 95, and 96. In some embodiments, the binding proteins are DVD-Ig binding proteins, or any of the other bispecific or multispecific formats disclosed herein. The binding protein described herein may further comprise one or more linkers between the VEGF and PDGF binding sites, wherein the linkers comprise sequences that are selected from Table 55. The binding protein described herein may also comprise heavy and light chain constant domains selected from Table 3.
In some embodiments, a binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs-1-3 from SEQ ID NO: 18, and the binding site for PDGF comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 35 and CDRs-1-3 from SEQ ID NO: 36, and the binding site for PDGF comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 39 and CDRs-1-3 from SEQ ID NO: 40, and the binding site for PDGF comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding site for VEGF comprises SEQ ID NO: 17 and SEQ ID NO: 18, and the binding site for PDGF comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding site for VEGF comprises SEQ ID NO: 35 and SEQ ID NO: 36, and the binding site for PDGF comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 1.4.1-1.4.7, 28, and 46-50. In some embodiments, the binding site for VEGF comprises SEQ ID NO: 39 and SEQ ID NO: 40, and the binding site for PDGF comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 1.4.1-1.4.7, 28, and 46-50. The binding protein described herein may further comprise one or more linkers between the VEGF and PDGF binding sites, wherein the linkers comprise sequences that are selected from Table 55. The binding protein described herein may also comprise heavy and light chain constant domains selected from Table 3.
In some embodiments, a binding protein is capable of binding VEGF and PDGF, wherein the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs-1-3 from SEQ ID NO: 2, and the binding site for VEGF comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of Tables A, 2.4.1-2.4.9, 27, and 38-42. In some embodiments, the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 15 and CDRs-1-3 from SEQ ID NO: 16, and the binding site for VEGF comprises a CDR set of heavy chain CDRs 1-3 and paired light chain CDRs 1-3 selected from any of Tables A, 2.4.1-2.4.9, 27, and 38-42. In some embodiments, the binding site for PDGF comprises SEQ ID NO: 1 and SEQ ID NO: 2, and the binding site for VEGF comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 2.4.1-2.4.9, 27, and 38-42. In some embodiments, the binding site for PDGF comprises SEQ ID NO: 15 and SEQ ID NO: 16, and the binding site for VEGF comprises a heavy chain variable domain and paired light chain variable domain selected from any of the variable domains listed in Tables A, 2.4.1-2.4.9, 27, and 38-42. The binding protein described herein may further comprise one or more linkers between the VEGF and PDGF binding sites, wherein the linkers comprise sequences that are selected from Table 55. The binding protein described herein may also comprise heavy and light chain constant domains selected from Table 3.
In some embodiments, a binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs-1-3 from SEQ ID NO: 18, and the binding site PDGF comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs-1-3 from SEQ ID NO: 2. In some embodiments, the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 35 and CDRs-1-3 from SEQ ID NO: 36, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 15 and CDRs-1-3 from SEQ ID NO: 16. In some embodiments, the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 39 and CDRs-1-3 from SEQ ID NO: 40, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 15 and CDRs-1-3 from SEQ ID NO: 16. The binding protein described herein may further comprise one or more linkers between the VEGF and PDGF binding sites, wherein the linkers comprise sequences that are selected from Table 55. The binding protein described herein may also comprise heavy and light chain constant domains selected from Table 3.
In some embodiments, a binding protein is capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises SEQ ID NO: 17 and SEQ ID NO: 18, and the binding site PDGF comprises SEQ ID NO: 1 and SEQ ID NO: 2. In some embodiments, the binding site for VEGF comprises SEQ ID NO: 35 and SEQ ID NO: 36, and the binding site for PDGF comprises SEQ ID NO: 15 and SEQ ID NO: 16. In some embodiments, the binding site for VEGF comprises SEQ ID NO: 39 and SEQ ID NO: 40, and the binding site for PDGF comprises SEQ ID NO: 15 and SEQ ID NO: 16. The binding protein described herein may further comprise one or more linkers between the VEGF and PDGF binding sites, wherein the linkers comprise sequences that are selected from Table 55. The binding protein described herein may also comprise heavy and light chain constant domains selected from Table 3.
In some embodiments, the binding protein is a DVD-Ig binding protein, capable of binding VEGF and PDGF. In some embodiment, the heavy chain of the binding protein comprises a DVD-Ig heavy chain variable domain and paired DVD-Ig light chain variable domain selected from Tables 56-59, 95, and 96. In some embodiments, the binding protein comprises DVD-Ig heavy and light chain variable domains of SEQ ID NO: 131 and SEQ ID NO: 132. In some embodiments, the binding protein comprises DVD-Ig heavy and light chain variable domains of SEQ ID NO: 88 and SEQ ID NO: 89. In some embodiments, the binding protein comprises DVD-Ig heavy and light chain variable domains of SEQ ID NO: 94 and SEQ ID NO: 95. In some embodiments, the binding protein comprises DVD-Ig heavy and light chain variable domains of SEQ ID NO: 141 and SEQ ID NO: 142. The DVD-Ig binding protein described herein may further comprise heavy and light chain constant domains selected from Table 3.
In certain embodiments, a binding protein disclosed herein is a DVD-Ig binding protein, comprising first and second polypeptide chains of SEQ ID NO: 131 and SEQ ID NO: 132. In some embodiments, the DVD-Ig binding protein comprises first and second polypeptide chains of SEQ ID NO: 88 and SEQ ID NO: 89. In some embodiments, the DVD-Ig binding protein comprises first and second polypeptide chains of SEQ ID NO: 94 and SEQ ID NO: 95. In some embodiments, the DVD-Ig binding protein comprises first and second polypeptide chains of SEQ ID NO: 141 and SEQ ID NO: 142.
Binding Protein Properties
The development and production of a binding protein for use as a human therapeutic agent, e.g., as an anti-inflammatory agent or oncologic agent, may require more than the identification of a binding protein capable of binding to a desired target or targets. The binding proteins disclosed herein exhibit favorable properties in one or more of the following categories (a) the binding kinetics (on-rate, off-rate and affinity) for both the inner and outer antigen-binding domains, (b) potencies in various biochemical and cellular bioassays, (c) in vivo efficacies in relevant tumor models, (d) pharmacokinetic and pharmacodynamics properties, (e) manufacturability, including protein expression level in selected cell lines, scalability, post-translational modification, physicochemical properties such as monomer percentage, solubility, and stability (intrinsic, freeze/thaw, storage stability, etc.), (f) formulation properties, (g) potential immunogenicity risk, (h) toxicological properties, and (i) binding mode and valency. Binding mode and valency may affect binding properties and cellular potencies of a molecule.
The binding proteins disclosed herein exhibit favorable properties in some or each of the categories listed above, including surprisingly high binding affinity at both the VD1 and VD2 positions.
In some embodiments a binding protein or binding proteins disclosed herein targeting VEGF and PDGF serve to both reduce choroidal neovascularization and increase regression of mature vasculature, e.g., in ocular conditions such as AMD. In some embodiments a binding protein or binding proteins disclosed herein targeting VEGF and PDGF neutralize VEGF and PDGF simultaneously. In some embodiments, the binding protein exhibits one or more of high potency to VEGF and/or PDGF, extended ocular duration, and rapid clearance from systemic circulation. In some embodiments, the binding protein is a bispecific and allows for a single injection of an agent to both targets (VEGF and PDGDF), reducing injection volume/frequency while still retaining the drug-like products of a traditional antibody.
In some embodiments, the disclosed binding protein exhibits superior in vivo efficacy (e.g., in a preclinical model of choroidal neovascularization or AMD) as compared to existing treatments for AMD (e.g., Elyea™ and/or Lucentis™). In some embodiments, the disclosed binding protein is a DVD-Ig binding protein and exhibits a high ocular duration. In some embodiments, the DVD-Ig binding protein may be, e.g., 150-200 kDa in weight or greater, and may provide for a longer ocular duration as compared to lower weight agents such as monoclonal antibodies. In some embodiments, the binding protein disclosed herein is a DVD-Ig binding protein and has an ocular half life of at least about 4 days, or at least about 4. 6 days, or at least about 5 days, or at least about 6 days, or at least about 6.5 days, or more. In some embodiments, the DVD-Ig ocular half life is greater than the half-life of an antibody or other construct having a smaller size, while retaining a more rapid systemic clearance similar to that of the antibody. In some embodiments, the DVD-Ig binding protein has an ocular half life of at least about 4 (or at least about 4.6) days after intravitreoius administration at 0.25 mg.
In some embodiments, the disclosed binding proteins are DVD-Ig binding proteins and exhibit improved drug-like properties, including one or more of high thermostability (e.g., a T onset of greater than 50°, 55°, 60°, 61°, 62°, 63°, 64°, or 65° C.), a solubility of at least about 70, 72, 74, 76, 78, or 80 mg/ml, a viscosity at room temperature and at a concentration of 100 mg/ml of about 7.2 centipoise, an effective storage stability in a universal buffer, and/or high freeze-thaw stability. In some embodiments, the DVD-Ig binding protein does not exhibit a significant change in monomer percentage at low concentration after storage at 5° C. or 40° C. for 10, 15, 20, 21, 22, 23, 24, 25, or more days, and/or does not exhibit a significant increase in aggregation at 50-150 mg/ml (or 100+/−10 mg/ml) after 1, 2, 3, 4, 5, or more freeze/thaw cycles.
In certain embodiments, a binding protein exhibiting particularly favorable properties in some or each of the categories listed above is a DVD-Ig binding protein capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 35 and CDRs-1-3 from SEQ ID NO: 36, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 15 and CDRs-1-3 from SEQ ID NO: 16. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 35 and SEQ ID NO: 36, and the binding site for PDGF comprises SEQ ID NO: 15 and SEQ ID NO: 16. In an embodiment, the binding protein is capable of binding VEGF and PDGF, and comprises PR-1610561 (comprising SEQ ID NOs: 131 and 132). In an embodiment, the binding protein comprises a heavy chain constant region on the first polypeptide chain comprising a human IgG1 heavy chain sequence modified by one or more amino acid changes, wherein the changes comprise substitution of leucines at positions 234 and 235 with alanines, and optionally also comprising a substitution of histidine at position 435 with alanine, wherein the amino acid positions are numbered using EU index numbering; and a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence
In certain embodiments, a binding protein exhibiting particularly favorable properties in some or each of the categories listed above is a DVD-Ig binding protein capable of binding VEGF and PDGF, wherein the binding site for VEGF comprises CDRs 1-3 from SEQ ID NO: 17 and CDRs-1-3 from SEQ ID NO: 18, and the binding site for PDGF comprises CDRs 1-3 from SEQ ID NO: 1 and CDRs-1-3 from SEQ ID NO: 2. In an embodiment, the binding site for VEGF comprises SEQ ID NO: 17 and SEQ ID NO: 18, and the binding site for PDGF comprises SEQ ID NO: 1 and SEQ ID NO: 2. In an embodiment, the binding protein is capable of binding VEGF and PDGF, and comprises PR-1572102 (comprising SEQ ID NOs: 88 and 89) or PR-1572105 (comprising SEQ ID NOs: 94 and 95) or PR1611292 (comprising SEQ ID NOs: 141 and 142). In an embodiment, the binding protein comprises a heavy chain constant region on the first polypeptide chain comprising a human IgG1 heavy chain sequence modified by one or more amino acid changes, wherein the changes comprise substitution of leucines at positions 234 and 235 with alanines, and optionally also comprising a substitution of histidine at position 435 with alanine, wherein the amino acid positions are numbered using EU index numbering; and a light chain constant region on the second polypeptide chain comprising a human kappa light chain constant region sequence.
For instance, in some embodiments, the binding protein disclosed herein (e.g., PR-1610561, PR-1572102, PR-1572105, or PR1611292) may exhibit one or more of the following features: enhanced in vivo efficacy in human VEGF transgenic mice, enhanced potency (as measured, e.g., via BIACORE, ELISA, or co-culture sprouting assay), improved expression (e.g., in HEK293 or CHO cells), and improved drug-like properties (e.g., thermal stability, storage stability, solubility, physicochemical properties, and/or pharmacokinetics) as compared to another binding protein or combination of binding proteins targeting VEGF and PDGF.
Preparation of Binding Proteins
In another aspect, the disclosure provides a method of making a binding protein that binds PDGF, VEGF, and/or either or both cognate receptors. In an embodiment, the method of making a binding protein comprises the steps of a) obtaining a first parent antibody, or antigen binding portion thereof, that binds PDGF, VEGF, or a cognate receptor; b) obtaining a second parent antibody, or antigen binding portion thereof, that binds PDGF, VEGF, or a cognate receptor; c) determining the sequences of the variable domains of the parent antibodies or antigen binding portions thereof; d) preparing construct(s) encoding any of the binding proteins described herein using those variable domain sequences; and e) expressing the polypeptide chains, such that a binding protein that binds PDGF, VEGF, and/or either or both cognate receptors is generated.
In any of the embodiments herein, the VD1 heavy chain variable domain, if present, and light chain variable domain, if present, can be from a first parent antibody or antigen binding portion thereof; the VD2 heavy chain variable domain, if present, and light chain variable domain, if present, can be from a second parent antibody or antigen binding portion thereof. The first and second parent antibodies can be the same or different.
In one embodiment, the first parent antibody or antigen binding portion thereof, binds a first antigen, and the second parent antibody or antigen binding portion thereof, binds a second antigen. In an embodiment, the first and second antigens are the same antigen. In another embodiment, the parent antibodies bind different epitopes on the same antigen. In another embodiment, the first and second antigens are different antigens. In another embodiment, the first parent antibody or antigen binding portion thereof, binds the first antigen with a potency different from the potency with which the second parent antibody or antigen binding portion thereof, binds the second antigen. In yet another embodiment, the first parent antibody or antigen binding portion thereof, binds the first antigen with an affinity different from the affinity with which the second parent antibody or antigen binding portion thereof, binds the second antigen.
In another embodiment, the first parent antibody or antigen binding portion thereof, and the second parent antibody or antigen binding portion thereof, are a human antibody, CDR grafted antibody, humanized antibody, and/or affinity matured antibody. The “parent antibody”, which provides at least one antigen binding specificity of the multivalent and or multispecific binding protein, may be one that is internalized (and/or catabolized) by a cell expressing an antigen to which the antibody binds; and/or may be an agonist, cell death-inducing, and/or apoptosis-inducing antibody, and the multivalent and or multispecific binding protein as described herein may display improvement(s) in one or more of these properties. Moreover, the parent antibody may lack any one or more of these properties, but may acquire one or more of them when constructed as a multivalent binding protein as described herein. For example, different Fc mutants may prevent FcR, FcR-gamma, complement, or C′ binding, or extend half-life.
In various embodiments, an isolated nucleic acid encoding any one of the binding proteins disclosed herein is also provided. Also provided is a composition comprising one or more nucleic acids wherein said one or more nucleic acids encode a nucleic acid encoding any one of the binding proteins disclosed herein. For example, the composition may comprise a nucleic acid that encodes a first polypeptide and a nucleic acid that encodes a second polypeptide, wherein said first and second polypeptide together form a binding protein as described herein. A further embodiment provides a vector (e.g., an expression vector) comprising the isolated nucleic acid disclosed herein. Also provided is a vector (e.g. an expression vector) that comprises one or more nucleic acids that encode a binding protein as described herein. Also provided is a composition comprising one or more vectors that encode a binding protein as described herein. For example, the composition may comprise a vector that encodes a first polypeptide and a vector that encodes a second polypeptide, wherein said first and second polypeptide together form a binding protein as described herein. In some embodiments, the vector is pcDNA; pTT (Durocher et al. (2002) Nucleic Acids Res. 30(2):e9; pTT3 (pTT with additional multiple cloning site; pEFBOS (Mizushima and Nagata (1990) Nucleic Acids Res. 18:17); pBV; pJV; pcDNA3.1 TOPO; pEF6 TOPO; pBOS; pHybE; or pBJ. In an embodiment, the vector is a vector disclosed in U.S. Pat. No. 8,187,836.
In another aspect, a host cell is transformed with the vector disclosed herein. In an embodiment, the host cell is a prokaryotic cell, for example, E. coli . In another embodiment, the host cell is a eukaryotic cell, for example, a protist cell, an animal cell, a plant cell, or a fungal cell. In an embodiment, the host cell is a mammalian cell including, but not limited to, CHO, COS, NSO, SP2, PER.C6, or a fungal cell, such as Saccharomyces cerevisiae , or an insect cell, such as Sf9. In an embodiment, two or more binding proteins, e.g., with different specificities, are produced in a single recombinant host cell. For example, the expression of a mixture of antibodies has been called Oligoclonics™ (Merus B.V., The Netherlands) disclosed in U.S. Pat. Nos. 7,262,028 and 7,429,486.
In various embodiments, a binding proteins disclosed herein can be prepared by culturing any one of the host cells disclosed herein in a culture medium under conditions sufficient to produce the binding protein.
One embodiment provides a composition for the release of a binding protein wherein the composition comprises a crystallized binding protein, an ingredient, and at least one polymeric carrier. In an embodiment, the polymeric carrier is poly (acrylic acid), a poly (cyanoacrylate), a poly (amino acid), a poly (anhydride), a poly (depsipeptide), a poly (ester), poly (lactic acid), poly (lactic-co-glycolic acid) or PLGA, poly (b-hydroxybutyrate), poly (caprolactone), poly (dioxanone), poly (ethylene glycol), poly ((hydroxypropyl) methacrylamide, poly [(organo)phosphazene], a poly (ortho ester), poly (vinyl alcohol), poly (vinylpyrrolidone), a maleic anhydride-alkyl vinyl ether copolymer, a pluronic polyol, albumin, alginate, cellulose, a cellulose derivative, collagen, fibrin, gelatin, hyaluronic acid, an oligosaccharide, a glycaminoglycan, a sulfated polysaccharide, or blends and copolymers thereof. In an embodiment, the ingredient is albumin, sucrose, trehalose, lactitol, gelatin, hydroxypropyl-β-cyclodextrin, methoxypolyethylene glycol, or polyethylene glycol.
The binding proteins provided herein, such as DVD-Ig binding proteins, may be produced by any of a number of techniques known in the art. For example, expression from host cells, wherein expression vector(s) encoding the DVD-Ig heavy and DVD-Ig light chains is (are) transfected into a host cell by standard techniques. Although it is possible to express the DVD-Ig binding proteins provided herein in either prokaryotic or eukaryotic host cells, DVD-Ig binding proteins are preferably expressed in eukaryotic cells, for example, mammalian host cells.
In an exemplary system for recombinant expression of DVD-Ig proteins, a recombinant expression vector encoding both the DVD-Ig heavy chain and the DVD-Ig light chain is introduced into dhfr-CHO cells by calcium phosphate-mediated transfection. Within the recombinant expression vector, the DVD-Ig heavy and light chain sequences are each operatively linked to CMV enhancer/AdMLP promoter regulatory elements to drive high levels of transcription of the genes. The recombinant expression vector also carries a DHFR gene, which allows for selection of CHO cells that have been transfected with the vector using methotrexate selection/amplification. The selected transformant host cells are cultured to allow for expression of the DVD-Ig heavy and light chains and intact DVD-Ig protein is recovered from the culture medium. Standard molecular biology techniques may be used to prepare the recombinant expression vector, transfect the host cells, select for transformants, culture the host cells and recover the DVD-Ig protein from the culture medium. In some embodiments, a method of synthesizing a DVD-Ig binding protein by culturing a host cell provided herein in a suitable culture medium until a DVD-Ig binding protein is synthesized is also provided. The method may further comprise isolating the DVD-Ig protein from the culture medium.
A feature of a DVD-Ig binding protein is that it can be produced and purified in a similar way to a conventional antibody. The design of the full length DVD-Ig binding protein heavy and light chains provided herein leads to assemble primarily to the desired dual-specific multivalent full length binding proteins. In an embodiment, 50%-75% of the binding protein produced by this method is a dual specific tetravalent binding protein (e.g., a DVD-Ig binding protein). In another embodiment, 75%-90% of the binding protein produced by this method is a dual specific tetravalent binding protein. In another embodiment, 90%-95% of the binding protein produced is a dual specific tetravalent binding protein. In some embodiments, at least 50%, at least 75% and at least 90% of the assembled, and expressed dual variable domain immunoglobulin molecules are the desired dual-specific tetravalent protein.
In various embodiments, the disclosure provides methods of expressing a dual variable domain light chain and a dual variable domain heavy chain in a single cell leading to a primary product of a dual-specific tetravalent full length binding protein, where the primary product is more than 50%, such as more than 75% and more than 90%, of all assembled protein, comprising a dual variable domain light chain and a dual variable domain heavy chain.
Therapeutic and Diagnostic Uses
Also disclosed herein, in various embodiments, are methods for diagnosing and treating a mammal (e.g., a human) comprising the step of administering to the mammal, or a sample taken from the mammal, an effective amount of a composition disclosed herein. A binding protein as described herein may be used in a method for therapy or diagnosis.
Given their ability to bind VEGF, PLGF, and/or their cognate receptors, in some embodiments, the binding proteins provided herein can be used to detect one or more of those antigens (e.g., in a biological sample, such as serum or plasma), using a conventional immunoassay, such as an enzyme linked immunosorbent assays (ELISA), a radioimmunoassay (RIA), or tissue immunohistochemistry. The binding protein is directly or indirectly labeled with a detectable substance to facilitate detection of the bound or unbound antibody. Suitable detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin. An example of a luminescent material is luminol and examples of suitable radioactive materials include 3 H, 14 C, 35 S, 90 Y, 99 Tc, 111 In, 125 I, 131 I, 177 Lu, 166 Ho, and 153 Sm.
In some embodiments, a method is disclosed for treating a human subject suffering from a disorder in which the target, or targets, capable of being bound by the binding proteins disclosed herein is/are detrimental, comprising administering to the human subject a binding protein disclosed herein such that the activity of the target, or targets, in the human subject is inhibited and one or more symptoms is alleviated or treatment is achieved is provided. In various embodiments, treatment comprises reducing, improving, or ameliorating one or more symptom of a disorder. Treatment includes but does not necessarily require curing (i.e., completely eliminating) a disorder or a symptom of a disorder.
The binding proteins provided herein can be used to treat humans suffering from diseases such as, for example, those associated with increased angiogenesis and/or inflammation (e.g., ocular inflammation). In an embodiment, the binding proteins provided herein or antigen-binding portions thereof, are used to treat an autoimmune disorder, asthma, ocular inflammation, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), insulin dependent diabetes mellitus, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus (SLE), multiple sclerosis, sepsis, a neurodegenerative disease, or an oncological disorder. In an embodiment, a binding protein disclosed herein is used to treat an eye disorder (e.g., an angiogenic eye disorder). In an embodiment, the eye disorder is a macular degeneration, such as wet macular degeneration, dry macular degeneration, age related macular degeneration (AMD), exudative AMD, dry eye, glaucoma, diabetic retinopathy, diabetic macular edema, central retinal vein occlusion, corneal neovascularization, iris neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), choroidal neovascularization, optic disc neovascularization, retinal neovascularization, vitreal neovascularization, pannus, pterygium, macular edema, diabetic macular edema (DME), vascular retinopathy, retinal degeneration, uveitis, keratoconjunctivitis sicca, blepharitis, keratitis or another inflammatory disease of the eye.
In an embodiment, the binding proteins provided herein are capable of neutralizing the activity of their antigen targets both in vitro and in vivo. Accordingly, such binding proteins can be used to inhibit antigen activity, e.g., in a cell culture containing the antigens, in human subjects or in other mammalian subjects having the antigens with which a binding protein provided herein cross-reacts. In another embodiment, a method for reducing antigen activity in a subject suffering from a disease or disorder in which the antigen activity is detrimental is provided. A binding protein provided herein may be administered to a human subject for therapeutic purposes. In some embodiments, the binding protein (e.g., the DVD-Ig binding protein) is administered to a patient, e.g., a patient suffering from wet AMD, and can have one or more effects selected from regressing mature vasculature (e.g., via VEGF binding), reducing choroidal neovascularization (e.g., via VEGF binding), allowing access to blood vessels by stripping off pericytes (e.g., via PDGF binding), and/or providing anti-fibrotic effects to reduce visual loss from scarring (e.g., via PDGF binding). In some embodiments, the binding protein is multispecific for VEGF and PDGF, and is administered at a reduced number of injections and/or a reduced injection frequency, as compared to a combination antibody therapy.
The term “a disorder in which antigen activity is detrimental” encompasses diseases and other disorders in which the presence of the antigen in a subject suffering from the disorder has been shown to be or is suspected of being either responsible for the pathophysiology of the disorder or a factor that contributes to a worsening of the disorder. Accordingly, a disorder in which antigen activity is detrimental is a disorder in which reduction of antigen activity is expected to alleviate the symptoms and/or progression of the disorder. Such disorders may be evidenced, for example, by an increase in the concentration of the antigen in a biological fluid of a subject suffering from the disorder (e.g., an increase in the concentration of antigen in serum, plasma, synovial fluid, etc., of the subject). Non-limiting examples of disorders that can be treated with the binding proteins provided herein include those disorders discussed below and in the section pertaining to pharmaceutical compositions comprising the binding proteins.
Binding proteins disclosed herein, such as the DVD-Ig binding proteins, can be employed in some embodiments for tissue-specific delivery (target a tissue marker and a disease mediator for enhanced local PK thus higher efficacy and/or lower toxicity), including intracellular delivery (targeting an internalizing receptor and an intracellular molecule), delivering through a biological barrier, such as to the inside of the eye or brain (e.g., targeting transferrin receptor and a CNS disease mediator for crossing the blood-brain barrier). The binding proteins may also serve as carrier proteins to deliver an antigen to a specific location via binding to a non-neutralizing epitope of that antigen and also to increase the half-life of the antigen. Furthermore, the binding protein may be designed to either be physically linked to medical devices implanted into patients or target these medical devices (see Burke et al. (2006) Advanced Drug Deliv. Rev. 58(3): 437-446; Hildebrand et al. (2006) Surface and Coatings Technol. 200(22-23): 6318-6324; Drug/device combinations for local drug therapies and infection prophylaxis, Wu (2006) Biomaterials 27(11):2450-2467; Mediation of the cytokine network in the implantation of orthopedic devices, Marques (2005) Biodegradable Systems in Tissue Engineer. Regen. Med. 377-397).
In an embodiment, diseases that can be treated or diagnosed with the compositions and methods disclosed herein include, but are not limited to, primary and metastatic cancers, including carcinomas of breast, colon, rectum, lung, oropharynx, hypopharynx, esophagus, stomach, pancreas, liver, gallbladder and bile ducts, small intestine, urinary tract (including kidney, bladder and urothelium), female genital tract (including cervix, uterus, and ovaries as well as choriocarcinoma and gestational trophoblastic disease), male genital tract (including prostate, seminal vesicles, testes and germ cell tumors), endocrine glands (including the thyroid, adrenal, and pituitary glands), and skin, as well as hemangiomas, melanomas, sarcomas (including those arising from bone and soft tissues as well as Kaposi's sarcoma), tumors of the brain, nerves, eyes, and meninges (including astrocytomas, gliomas, glioblastomas, retinoblastomas, neuromas, neuroblastomas, Schwannomas, and meningiomas), solid tumors arising from hematopoietic malignancies such as leukemias, and lymphomas (both Hodgkin's and non-Hodgkin's lymphomas).
Another embodiment provides for the use of the binding protein in the treatment of a disease or disorder, wherein the disorder is arthritis, osteoarthritis, juvenile chronic arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis scleroderma, graft versus host disease, organ transplant rejection, acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlein purpurea, microscopic vasculitis of the kidneys, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acute transverse myelitis, Huntington's chorea, Parkinson's disease, Alzheimer's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignancies, heart failure, myocardial infarction, Addison's disease, sporadic poly glandular deficiency type I and polyglandular deficiency type II, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthopathy, arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative colitic arthropathy, enteropathic synovitis, chlamydia, yersinia and salmonella associated arthropathy, spondyloarthopathy, atheromatous disease/arteriosclerosis, atopic allergy, autoimmune bullous disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune haemolytic anaemia, Coombs positive haemolytic anaemia, acquired pernicious anaemia, juvenile pernicious anaemia, myalgic encephalitis/Royal Free Disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, Acquired Immunodeficiency Syndrome, Acquired Immunodeficiency Related Diseases, Hepatitis B, Hepatitis C, common varied immunodeficiency (common variable hypogammaglobulinaemia), dilated cardiomyopathy, female infertility, ovarian failure, premature ovarian failure, fibrotic lung disease, cryptogenic fibrosing alveolitis, post-inflammatory interstitial lung disease, interstitial pneumonitis, connective tissue disease associated interstitial lung disease, mixed connective tissue disease associated lung disease, systemic sclerosis associated interstitial lung disease, rheumatoid arthritis associated interstitial lung disease, systemic lupus erythematosus associated lung disease, dermatomyositis/polymyositis associated lung disease, Sjögren's disease associated lung disease, ankylosing spondylitis associated lung disease, vasculitic diffuse lung disease, haemosiderosis associated lung disease, drug-induced interstitial lung disease, fibrosis, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, postinfectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune mediated hypoglycaemia, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthrosis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leucopaenia, autoimmune neutropaenia, renal disease NOS, glomerulonephritides, microscopic vasulitis of the kidneys, lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestation of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjörgren's syndrome, Takayasu's disease/arteritis, autoimmune thrombocytopaenia, idiopathic thrombocytopaenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxoedema, phacogenic uveitis, primary vasculitis, vitiligo acute liver disease, chronic liver diseases, alcoholic cirrhosis, alcohol-induced liver injury, cholestasis, idiosyncratic liver disease, Drug-Induced hepatitis, Non-alcoholic Steatohepatitis, allergy and asthma, group B streptococci (GBS) infection, mental disorders (e.g., depression and schizophrenia), Th2 Type and Th1 Type mediated diseases, acute and chronic pain (different forms of pain), and cancers such as lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma) abetalipoproteinemia, Acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infection, acute pancreatitis, acute renal failure, adenocarcinomas, aerial ectopic beats, AIDS dementia complex, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allograft rejection, alpha-1-antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horn cell degeneration, anti cd3 therapy, antiphospholipid syndrome, anti-receptor hypersensitivity reactions, aordic and peripheral aneuryisms, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, atrial fibrillation (sustained or paroxysmal), atrial flutter, atrioventricular block, B cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, bundle branch block, Burkitt's lymphoma, burns, cardiac arrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation response, cartilage transplant rejection, cerebellar cortical degenerations, cerebellar disorders, chaotic or multifocal atrial tachycardia, chemotherapy associated disorders, chronic myelocytic leukemia (CML), chronic alcoholism, chronic inflammatory pathologies, chronic lymphocytic leukemia (CLL), chronic obstructive pulmonary disease (COPD), chronic salicylate intoxication, colorectal carcinoma, congestive heart failure, conjunctivitis, contact dermatitis, cor pulmonale, coronary artery disease, Creutzfeldt-Jakob disease, culture negative sepsis, cystic fibrosis, cytokine therapy associated disorders, Dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatitis, dermatologic conditions, diabetes, diabetes mellitus, diabetic ateriosclerotic disease, Diffuse Lewy body disease, dilated congestive cardiomyopathy, disorders of the basal ganglia, Down's Syndrome in middle age, drug-induced movement disorders induced by drugs which block CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, epiglottitis, epstein-barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial hematophagocytic lymphohistiocytosis, fetal thymus implant rejection, Friedreich's ataxia, functional peripheral arterial disorders, fungal sepsis, gas gangrene, gastric ulcer, graft rejection of any organ or tissue, gram negative sepsis, gram positive sepsis, granulomas due to intracellular organisms, hairy cell leukemia, Hallerrorden-Spatz disease, hashimoto's thyroiditis, hay fever, heart transplant rejection, hemachromatosis, hemodialysis, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage, hepatitis A, His bundle arryhthmias, HIV infection/HIV neuropathy, Hodgkin's disease, hyperkinetic movement disorders, hypersensitity reactions, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorders, hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison's disease, idiopathic pulmonary fibrosis, antibody mediated cytotoxicity, Asthenia, infantile spinal muscular atrophy, inflammation of the aorta, influenza a, ionizing radiation exposure, iridocyclitis/uveitis/optic neuritis, ischemia-reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, kidney transplant rejection, legionella, leishmaniasis, leprosy, lesions of the corticospinal system, lipedema, liver transplant rejection, lymphederma, malaria, malignamt Lymphoma, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, metabolic/idiopathic, migraine headache, mitochondrial multi.system disorder, mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, multiple systems degenerations (Mencel Dejerine-Thomas Shy-Drager and Machado-Joseph), myasthenia gravis, mycobacterium avium intracellulare, mycobacterium tuberculosis, myelodyplastic syndrome, myocardial ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, neurodegenerative diseases, neurogenic I muscular atrophies, neutropenic fever, non-hodgkins lymphoma, occlusion of the abdominal aorta and its branches, occlusive arterial disorders, okt3 therapy, orchitis/epidydimitis, orchitis/vasectomy reversal procedures, organomegaly, osteoporosis, pancreas transplant rejection, pancreatic carcinoma, paraneoplastic syndrome/hypercalcemia of malignancy, parathyroid transplant rejection, pelvic inflammatory disease, perennial rhinitis, pericardial disease, peripheral atherlosclerotic disease, peripheral vascular disorders, peritonitis, pernicious anemia, pneumocystis carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), post perfusion syndrome, post pump syndrome, post-MI cardiotomy syndrome, preeclampsia, Progressive supranucleo Palsy, primary pulmonary hypertension, radiation therapy, Raynaud's phenomenon and disease, Raynoud's disease, Refsum's disease, regular narrow QRS tachycardia, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, sarcomas, scleroderma, senile chorea, Senile Dementia of Lewy body type, seronegative arthropathies, shock, sickle cell anemia, skin allograft rejection, skin changes syndrome, small bowel transplant rejection, solid tumors, specific arrythmias, spinal ataxia, spinocerebellar degenerations, streptococcal myositis, structural lesions of the cerebellum, Subacute sclerosing panencephalitis, Syncope, syphilis of the cardiovascular system, systemic anaphalaxis, systemic inflammatory response syndrome, systemic onset juvenile rheumatoid arthritis, T-cell or FAB ALL, Telangiectasia, thromboangitis obliterans, thrombocytopenia, toxicity, transplants, trauma/hemorrhage, type III hypersensitivity reactions, type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria, valvular heart diseases, varicose veins, vasculitis, venous diseases, venous thrombosis, ventricular fibrillation, viral and fungal infections, vital encephalitis/aseptic meningitis, vital-associated hemaphagocytic syndrome, Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection of any organ or tissue, acute coronary syndromes, acute idiopathic polyneuritis, acute inflammatory demyelinating polyradiculoneuropathy, acute ischemia, adult Still's disease, anaphylaxis, anti-phospholipid antibody syndrome, aplastic anemia, atopic eczema, atopic dermatitis, autoimmune dermatitis, autoimmune disorder associated with streptococcus infection, autoimmune enteropathy, autoimmune hearing loss, autoimmune lymphoproliferative syndrome (ALPS), autoimmune myocarditis, autoimmune premature ovarian failure, blepharitis, bronchiectasis, bullous pemphigoid, cardiovascular disease, catastrophic antiphospholipid syndrome, celiac disease, cervical spondylosis, chronic ischemia, cicatricial pemphigoid, clinically isolated syndrome (cis) with risk for multiple sclerosis, childhood onset psychiatric disorder, dacryocystitis, dermatomyositis, diabetic retinopathy, disk herniation, disk prolaps, drug induced immune hemolytic anemia, endometriosis, endophthalmitis, episcleritis, erythema multiforme, erythema multiforme major, gestational pemphigoid, Guillain-Barré syndrome (GBS), hay fever, Hughes syndrome, idiopathic Parkinson's disease, idiopathic interstitial pneumonia, IgE-mediated allergy, immune hemolytic anemia, inclusion body myositis, infectious ocular inflammatory disease, inflammatory demyelinating disease, inflammatory heart disease, inflammatory kidney disease, IPF/UIP, iritis, keratitis, keratoconjunctivitis sicca, Kussmaul disease or Kussmaul-Meier disease, Landry's paralysis, Langerhan's cell histiocytosis, livedo reticularis, macular degeneration, microscopic polyangiitis, morbus bechterev, motor neuron disorders, mucous membrane pemphigoid, multiple organ failure, myelodysplastic syndrome, myocarditis, nerve root disorders, neuropathy, non-A non-B hepatitis, optic neuritis, osteolysis, ovarian cancer, pauciarticular JRA, peripheral artery occlusive disease (PAOD), peripheral vascular disease (PVD), peripheral artery, disease (PAD), phlebitis, polyarteritis nodosa (or periarteritis nodosa), polychondritis, polymyalgia rheumatica, poliosis, polyarticular JRA, polyendocrine deficiency syndrome, polymyositis, post-pump syndrome, primary Parkinsonism, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma), prostatitis, pure red cell aplasia, primary adrenal insufficiency, recurrent neuromyelitis optica, restenosis, rheumatic heart disease, sapho (synovitis, acne, pustulosis, hyperostosis, and osteitis), scleroderma, secondary amyloidosis, shock lung, scleritis, sciatica, secondary adrenal insufficiency, silicone associated connective tissue disease, sneddon-wilkinson dermatosis, spondilitis ankylosans, Stevens-Johnson syndrome (SJS), systemic inflammatory response syndrome, temporal arteritis, toxoplasmic retinitis, toxic epidermal necrolysis, transverse myelitis, TRAPS (tumor necrosis factor receptor, type 1 allergic reaction, type II diabetes, usual interstitial pneumonia (UIP), vernal conjunctivitis, viral retinitis, Vogt-Koyanagi-Harada syndrome (VKH syndrome), wet macular degeneration, wound healing, fibrosis, renal disease, wet macular degeneration, wound healing, age related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema, central retinal vein occlusion, corneal neovascularization, exudative AMD, iris neovascularization, neovascular glaucoma, post-surgical fibrosis in glaucoma, proliferative vitreoretinopathy (PVR), choroidal neovascularization, optic disc neovascularization, retinal neovascularization, vitreal neovascularization, pannus, pterygium, macular edema, diabetic macular edema (DME), vascular retinopathy, retinal degeneration, uveitis, or an inflammatory disease of the eye.
In some embodiments, any one of the binding proteins disclosed herein can be used to treat a disorder listed above. In certain embodiments, the binding protein used to treat any of the disorders discussed herein is one or more of the binding proteins listed in Tables 27-30, 38-42, 46-50, or 55-58. In certain embodiments, the binding protein used to treat any of the disorders discussed herein is one or more of the binding proteins listed in Tables 56-58. In certain embodiments, the binding protein is PR-1572102, PR-1572105, PR-1610561, or PR1611292.
In some embodiments, a binding protein (e.g., PR-1572102, PR-1572105, PR1611292, or PR-1610561) may be used to treat wet AMD that is non-responsive to anti-VEGF monotherapy. For instance, a binding protein targeting VEGF and PDGF (e.g., PR-1572102, PR-1572105, or PR-1610561) may lead to better regression of angiogenesis, thereby providing for a more effective treatment (this does not necessarily mean, however, that such a binding protein would have a reduced administration frequency; whether that is the case is presently unknown). The dual inhibition of both VEGF and PDGF may provide for certain improved treatment outcomes, as compared to anti-VEGF monotherapy.
In another aspect, methods of treating a patient suffering from a disorder are disclosed, comprising the step of administering any one of the binding proteins disclosed herein before, concurrently, or after the administration of a second agent, are provided. In an embodiment, the second agent is an imaging agent, cytotoxic agent, angiogenesis inhibitor, kinase inhibitor, co-stimulation molecule blocker, adhesion molecule blocker, anti-cytokine antibody or functional fragment thereof, methotrexate, cyclosporin, rapamycin, FK506, detectable label or reporter, TNF antagonist, antirheumatic, muscle relaxant, narcotic, non-steroid anti-inflammatory drug (NSAID), analgesic, anesthetic, sedative, local anesthetic, neuromuscular blocker, antimicrobial, antipsoriatic, corticosteriod, anabolic steroid, erythropoietin, immunization, immunoglobulin, immunosuppressive, growth hormone, hormone replacement drug, radiopharmaceutical, antidepressant, antipsychotic, stimulant, asthma medication, beta agonist, inhaled steroid, epinephrine or analog, cytokine, or cytokine antagonist.
Also disclosed, in various embodiments, are anti-idiotype antibodies to the binding proteins disclosed herein. An anti-idiotype antibody includes any protein or peptide-containing molecule that comprises at least a portion of an immunoglobulin molecule such as, but not limited to, at least one complementarily determining region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework region, or any portion thereof, that can be incorporated into a binding protein provided herein.
Also disclosed herein, in various embodiments, are methods of determining the presence, amount or concentration of VEGF and/or PDGF, or fragment thereof, in a test sample. In some embodiments, the methods comprise assaying the test sample for the antigen, or fragment thereof, by an immunoassay. The immunoassay (i) employs at least one binding protein and at least one detectable label and (ii) comprises comparing a signal generated by the detectable label as a direct or indirect indication of the presence, amount or concentration of the antigen, or fragment thereof, in the test sample to a signal generated as a direct or indirect indication of the presence, amount or concentration of the antigen, or fragment thereof, in a control or a calibrator. The calibrator is optionally part of a series of calibrators in which each of the calibrators differs from the other calibrators in the series by the concentration of the antigen, or fragment thereof. The method can comprise (i) contacting the test sample with at least one capture agent, which binds to an epitope on the antigen, or fragment thereof, so as to form a capture agent/antigen, or fragment thereof, complex, (ii) contacting the capture agent/antigen, or fragment thereof, complex with at least one detection agent, which comprises a detectable label and binds to an epitope on the antigen, or fragment thereof, that is not bound by the capture agent, to form a capture agent/antigen, or fragment thereof/detection agent complex, and (iii) determining the presence, amount or concentration of the antigen, or fragment thereof, in the test sample based on the signal generated by the detectable label in the capture agent/antigen, or fragment thereof/detection agent complex formed in (ii), wherein at least one capture agent and/or at least one detection agent is the at least one binding protein.
Alternatively, the method may comprise (i) contacting the test sample with at least one capture agent, which binds to an epitope on the antigen, or fragment thereof, so as to form a capture agent/antigen, or fragment thereof, complex, and simultaneously or sequentially, in either order, contacting the test sample with detectably labeled antigen, or fragment thereof, which can compete with any antigen, or fragment thereof, in the test sample for binding to the at least one capture agent, wherein any antigen, or fragment thereof, present in the test sample and the detectably labeled antigen compete with each other to form a capture agent/antigen, or fragment thereof, complex and a capture agent/detectably labeled antigen, or fragment thereof, complex, respectively, and (ii) determining the presence, amount or concentration of the antigen, or fragment thereof, in the test sample based on the signal generated by the detectable label in the capture agent/detectably labeled antigen, or fragment thereof, complex formed in (ii), wherein at least one capture agent is the at least one binding protein and wherein the signal generated by the detectable label in the capture agent/detectably labeled antigen, or fragment thereof, complex is inversely proportional to the amount or concentration of antigen, or fragment thereof, in the test sample.
In some embodiments, the test sample is from a patient, in which case the method can further comprise diagnosing, prognosticating, or assessing the efficacy of therapeutic/prophylactic treatment of the patient. If the method further comprises assessing the efficacy of therapeutic/prophylactic treatment of the patient, the method optionally further comprises modifying the therapeutic/prophylactic treatment of the patient as needed to improve efficacy. The method can be adapted for use in an automated system or a semi-automated system. Accordingly, the methods described herein also can be used to determine whether or not a subject has or is at risk of developing a given disease, disorder or condition. Specifically, such a method can comprise the steps of: (a) determining the concentration or amount in a test sample from a subject of analyte, or fragment thereof, (e.g., using the methods described herein, or methods known in the art); and (b) comparing the concentration or amount of analyte, or fragment thereof, determined in step (a) with a predetermined level, wherein, if the concentration or amount of analyte determined in step (a) is favorable with respect to a predetermined level, then the subject is determined not to have or be at risk for a given disease, disorder or condition. However, if the concentration or amount of analyte determined in step (a) is unfavorable with respect to the predetermined level, then the subject is determined to have or be at risk for a given disease, disorder or condition.
Additionally, in various embodiments, provided herein are methods of monitoring the progression of disease in a subject. In some embodiments, the method can comprise the steps of: (a) determining the concentration or amount in a test sample from a subject of analyte; (b) determining the concentration or amount in a later test sample from the subject of analyte; and (c) comparing the concentration or amount of analyte as determined in step (b) with the concentration or amount of analyte determined in step (a), wherein if the concentration or amount determined in step (b) is unchanged or is unfavorable when compared to the concentration or amount of analyte determined in step (a), then the disease in the subject is determined to have continued, progressed or worsened. By comparison, if the concentration or amount of analyte as determined in step (b) is favorable when compared to the concentration or amount of analyte as determined in step (a), then the disease in the subject is determined to have discontinued, regressed or improved.
Optionally, the method further comprises comparing the concentration or amount of analyte as determined in step (b), for example, with a predetermined level. Further, optionally the method comprises treating the subject with one or more pharmaceutical compositions for a period of time if the comparison shows that the concentration or amount of analyte as determined in step (b), for example, is unfavorably altered with respect to the predetermined level.
Also provided, in various embodiments, are kits for assaying a test sample for VEGF and/or PDGF, or fragment thereof. The kit may comprise at least one component for assaying the test sample for an antigen, or fragment thereof, and instructions for assaying the test sample for an antigen, or fragment thereof, wherein the at least one component includes at least one composition comprising the binding protein disclosed herein, wherein the binding protein is optionally detectably labeled.
Unless otherwise defined herein, scientific and technical terms used herein have the meanings that are commonly understood by those of ordinary skill in the art. In the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. The use of “or” means “and/or” unless stated otherwise. The use of the term “including”, as well as other forms, such as “includes” and “included”, is not limiting. Any range disclosed herein is intended to encompass the endpoints of that range unless stated otherwise.
Generally, nomenclatures used in connection with cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those known and commonly used in the art. The methods and techniques provided herein are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. Enzymatic reactions and purification techniques are performed according to manufacturer's specifications, as commonly accomplished in the art or as described herein. The nomenclatures used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.
That the disclosure may be more readily understood, select terms are defined below.
The term “antibody” refers to an immunoglobulin (Ig) molecule, which is may comprise four polypeptide chains, two heavy (H) chains and two light (L) chains, or it may comprise a functional fragment, mutant, variant, or derivative thereof, that retains the epitope binding features of an Ig molecule. Such fragment, mutant, variant, or derivative antibody formats are known in the art. In an embodiment of a full-length antibody, each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (CH). In the case of an IgG molecule, the CH comprises three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The CL is comprised of a single CL domain. The VH and VL can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). Generally, each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. CDR regions may be determined by standard methods, e.g., those of Kabat et al. Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), or subclass.
The term “bispecific antibody” refers to an antibody that binds one antigen (or epitope) on one of its two binding arms (one pair of HC/LC), and binds a different antigen (or epitope) on its second binding arm (a different pair of HC/LC). A bispecific antibody is a type of bispecific binding protein. A bispecific antibody may have two distinct antigen binding arms (in both specificity and CDR sequences), and may be monovalent for each antigen to which it binds. Bispecific antibodies include those generated by quadroma technology (Milstein and Cuello (1983) Nature 305(5934): 537-40), by chemical conjugation of two different monoclonal antibodies (Staerz et al. (1985) Nature 314(6012): 628-31), or by knob-into-hole or similar approaches which introduces mutations in the Fc region (Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90(14): 6444-6448).
The term “affinity matured” refers to an antibody or binding protein with one or more alterations in one or more CDR or framework (FR) regions thereof, which may result in an improvement in the affinity for an antigen, compared to a parent antibody or binding protein which does not possess those alteration(s). Exemplary affinity matured antibodies or binding protein will have nanomolar or even picomolar affinities for the target antigen. Affinity matured antibodies or binding protein may be produced by procedures known in the art, e.g., Marks et al. (1992) BioTechnology 10:779-783 describes affinity maturation by VH and VL domain shuffling. Random mutagenesis of CDR and/or framework residues is described by Barbas et al. (1994) Proc. Nat. Acad. Sci. USA 91:3809-3813; Schier et al. (1995) Gene 169:147-155; Yelton et al. (1995) J. Immunol. 155:1994-2004; Jackson et al. (1995) J. Immunol. 154(7):3310-9; Hawkins et al. (1992) J. Mol. Biol. 226:889-896 and mutation at selective mutagenesis positions, contact or hypermutation positions with an activity enhancing amino acid residue as described in U.S. Pat. No. 6,914,128.
The term “CDR-grafted” refers to an antibody or binding protein that comprises heavy and light chain variable region sequences in which the sequences of one or more of the CDR regions of VH and/or VL are replaced with CDR sequences of another antibody or binding protein. For example, the two antibodies or binding protein can be from different species, such as antibodies or binding protein having murine heavy and light chain variable regions in which one or more of the murine CDRs has been replaced with human CDR sequences.
The term “humanized” refers to an antibody or binding protein from a non-human species that has been altered to be more “human-like”, i.e., more similar to human germline sequences. One type of humanized antibody or binding protein is a CDR-grafted antibody or binding protein, in which non-human CDR sequences are introduced into human VH and VL sequences to replace the corresponding human CDR sequences. A humanized antibody or binding protein also encompasses a variant, derivative, analog or fragment of an antibody or binding protein that comprises framework region (FR) sequences having substantially (e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or at least 99% identity to) the amino acid sequence of a human antibody and at least one CDR having substantially the amino acid sequence of a non-human antibody. A humanized antibody or binding protein may comprise substantially all of at least one variable domain (Fab, Fab′, F(ab′) 2, FabC, Fv) in which the sequence of all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin (i.e., donor antibody) and the sequence of all or substantially all of the FR regions are those of a human immunoglobulin. The humanized antibody or binding protein also may include the CH1, hinge, CH2, CH3, and/or CH4 regions of the heavy chain. In an embodiment, a humanized antibody or binding protein may also comprise at least a portion of a human immunoglobulin Fc region. In some embodiments, a humanized antibody or binding protein only contains a humanized light chain. In some embodiments, a humanized antibody or binding protein only contains a humanized heavy chain. In some embodiments, a humanized antibody or binding protein only contains a humanized variable domain of a light chain and/or humanized variable domain of a heavy chain. In some embodiments, a humanized antibody or binding protein contains a humanized light chain as well as at least a variable domain of a heavy chain. In some embodiments, a humanized antibody or binding protein contains a humanized heavy chain as well as at least a variable domain of a light chain
The term “anti-idiotypic antibody” refers to an antibody raised against the amino acid sequence of the antigen combining site of another antibody. Anti-idiotypic antibodies may be administered to enhance an immune response against an antigen.
The term “biological activity” refers to any one or more biological properties of a molecule (whether present naturally as found in vivo, or provided or enabled by recombinant means). Biological properties include, but are not limited to, binding a receptor, inducing cell proliferation, inhibiting cell growth, inducing other cytokines, inducing apoptosis, and enzymatic activity.
The term “neutralizing” refers to counteracting the biological activity of an antigen when a binding protein specifically binds to the antigen. In an embodiment, a neutralizing binding protein binds to an antigen (e.g., VEGF and/or PDGF or their receptors) and reduces the antigen's biological activity by at least about 20%, about 40%, about 60%, about 80%, about 85%, about 90%, about 95%, or about 100% (or any percentage in between).
The term “specificity” refers to the ability of a binding protein to selectively bind an antigen.
The term “affinity” refers to the strength of the interaction between a binding protein and an antigen, and is determined by the sequence of the CDRs of the binding protein as well as by the nature of the antigen, such as its size, shape, and/or charge. Binding proteins may be selected for affinities that provide desired therapeutic end-points while minimizing negative side-effects. Affinity may be measured using methods known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
The term “potency” refers to the ability of a binding protein to achieve a desired effect, and is a measurement of its therapeutic efficacy. Potency may be assessed using methods known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
The term “cross-reactivity” refers to the ability of a binding protein to bind a target other than that against which it was raised. Generally, a binding protein will bind its target tissue(s)/antigen(s) with an appropriately high affinity, but will display an appropriately low affinity for non-target normal tissues. Methods of assessing cross-reactivity are known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
The term “biological function” refers the specific in vitro or in vivo actions of a binding protein. Binding proteins may target several classes of antigens and achieve desired therapeutic outcomes through multiple mechanisms of action. Binding proteins may target soluble proteins, cell surface antigens, as well as extracellular protein deposits. Binding proteins may agonize, antagonize, or neutralize the activity of their targets. Binding proteins may assist in the clearance of the targets to which they bind, or may result in cytotoxicity when bound to cells. Portions of two or more antibodies may be incorporated into a multivalent format to achieve distinct functions in a single binding protein molecule. The in vitro assays and in vivo models used to assess biological function are known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
A “stable” binding protein refers to one in which the binding protein retains some level of its physical stability, chemical stability and/or biological activity upon storage. Methods of stabilizing binding proteins and assessing their stability at various temperatures are known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
The term “solubility” refers to the ability of a protein to remain dispersed within an aqueous solution. The solubility of a protein in an aqueous formulation depends upon the proper distribution of hydrophobic and hydrophilic amino acid residues, and therefore, solubility can correlate with the production of correctly folded proteins. A person skilled in the art will be able to detect an increase or decrease in solubility of a binding protein using routine HPLC techniques and methods known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
Binding proteins may be produced using a variety of host cells or may be produced in vitro, and the relative yield per effort determines the “production efficiency.” Factors influencing production efficiency include, but are not limited to, host cell type (prokaryotic or eukaryotic), choice of expression vector, choice of nucleotide sequence, and methods employed. The materials and methods used in binding protein production, as well as the measurement of production efficiency, are known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
The term “immunogenicity” means the ability of a substance to induce an immune response. Administration of a therapeutic binding protein may result in a certain incidence of an immune response. Potential elements that might induce immunogenicity in a multivalent format may be analyzed during selection of the parental antibodies, and steps to reduce such risk can be taken to optimize the parental antibodies prior to incorporating their sequences into a multivalent binding protein format. Methods of reducing the immunogenicity of antibodies and binding proteins are known to one skilled in the art (U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
The terms “label” and “detectable label” refer to a moiety attached to a member of a specific binding pair, such as an antibody/binding protein or its analyte to render a reaction (e.g., binding) between the members of the specific binding pair, detectable. The labeled member of the specific binding pair is referred to as “detectably labeled.” Thus, the term “labeled binding protein” refers to a protein with a label incorporated that provides for the identification of the binding protein. In an embodiment, the label is a detectable marker that can produce a signal that is detectable by visual or instrumental means, e.g., incorporation of a radiolabeled amino acid or attachment to a polypeptide of biotinyl moieties that can be detected by marked avidin (e.g., streptavidin containing a fluorescent marker or enzymatic activity that can be detected by optical or colorimetric methods). Examples of labels for polypeptides include, but are not limited to, the following: radioisotopes or radionuclides (e.g., 3 H, 14 C, 35 S, 90 Y, 99 Tc, 111 In, 125 I, 131 I, 177 Lu, 166 Ho, or 153 Sm); chromogens, fluorescent labels (e.g., FITC, rhodamine, lanthanide phosphors), enzymatic labels (e.g., horseradish peroxidase, luciferase, alkaline phosphatase); chemiluminescent markers; biotinyl groups; predetermined polypeptide epitopes recognized by a secondary reporter (e.g., leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags); and magnetic agents, such as gadolinium chelates. Representative examples of labels commonly employed for immunoassays include moieties that produce light, e.g., acridinium compounds, and moieties that produce fluorescence, e.g., fluorescein. In this regard, the moiety itself may not be detectably labeled but may become detectable upon reaction with yet another moiety.
The term “conjugate” refers to a binding protein that is chemically linked to a second chemical moiety, such as a therapeutic or cytotoxic agent. The term “agent” includes a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials. In an embodiment, the therapeutic or cytotoxic agents include, but are not limited to, pertussis toxin, taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. When employed in the context of an immunoassay, the conjugate antibody may be a detectably labeled antibody used as the detection antibody.
The terms “crystal” and “crystallized” refer to a binding protein (e.g., an antibody), or antigen binding portion thereof, that exists in the form of a crystal. Crystals are one form of the solid state of matter, which is distinct from other forms such as the amorphous solid state or the liquid crystalline state. Crystals are composed of regular, repeating, three-dimensional arrays of atoms, ions, molecules (e.g., proteins such as antibodies), or molecular assemblies (e.g., antigen/antibody complexes). These three-dimensional arrays are arranged according to specific mathematical relationships that are well-understood in the field. The fundamental unit, or building block, that is repeated in a crystal is called the asymmetric unit. Repetition of the asymmetric unit in an arrangement that conforms to a given, well-defined crystallographic symmetry provides the “unit cell” of the crystal. Repetition of the unit cell by regular translations in all three dimensions provides the crystal. (See Giege and Ducruix (1999) C RYSTALLIZATION OF N UCLEIC A CIDS AND P ROTEINS, A P RACTICAL A PPROACH , 2nd ed., pp. 20 1-16, Oxford University Press, NY, N.Y.).
The term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked One type of vector is a “plasmid,” which refers to a circular double stranded DNA loop into which additional DNA segments may be ligated. Another type of vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome. Other vectors include RNA vectors. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Certain vectors are capable of directing the expression of genes to which they are operatively linked Such vectors are referred to herein as “recombinant expression vectors” (or simply, “expression vectors”). In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, “plasmid” and “vector” may be used interchangeably as the plasmid is the most commonly used form of vector. However, other forms of expression vectors are also included, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions. A group of pHybE vectors (e.g., U.S. Pat. No. 8,187,836) may be used for parental antibody and DVD-binding protein cloning. V1, derived from pJP183; pHybE-hCg1,z,non-a V2; and pJP184, may be used for cloning of antibody and DVD heavy chains with a wild type constant region or modified constant region (e.g., a L234, L235, H435A modified IgG1 constant region). V2, derived from pJP191 (with or without modifications to the Kozak site); pHybE-hCk V3, may be used for cloning of antibody and DVD light chains with a kappa constant region. V3, derived from pJP192; pHybE-hCl V2, may be used for cloning of antibody and DVD light chains with a lambda constant region. V4, built with a lambda signal peptide and a kappa constant region, may be used for cloning of DVD light chains with a lambda-kappa hybrid V domain. V5, built with a kappa signal peptide and a lambda constant region, may be used for cloning of DVD light chains with a kappa-lambda hybrid V domain. V7, derived from pJP183; pHybE-hCg1,z,non-a V2, may be used for cloning of antibody and DVD heavy chains with a (234,235 AA) mutant constant region.
The terms “recombinant host cell” or “host cell” refer to a cell into which exogenous, e.g., recombinant, DNA has been introduced. Such terms refer not only to the particular subject cell, but to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term “host cell” as used herein. In an embodiment, host cells include prokaryotic and eukaryotic cells. In an embodiment, eukaryotic cells include protist, fungal, plant and animal cells. In another embodiment, host cells include but are not limited to the prokaryotic cell line E. coli ; mammalian cell lines CHO, HEK 293, COS, NSO, SP2 and PER.C6; the insect cell line Sf9; and the fungal cell Saccharomyces cerevisiae.
The term “transfection” encompasses a variety of techniques commonly used for the introduction of exogenous nucleic acid (e.g., DNA) into a host cell, e.g., electroporation, calcium-phosphate precipitation, DEAE-dextran transfection and the like.
The term “cytokine” refers to a protein released by one cell population that acts on another cell population as an intercellular mediator. The term “cytokine” includes proteins from natural sources or from recombinant cell culture and biologically active equivalents of the native sequence cytokines.
The term “biological sample” refers to a quantity of a substance from a living thing or formerly living thing Such substances include, but are not limited to, blood, plasma, serum, urine, amniotic fluid, synovial fluid, endothelial cells, leukocytes, monocytes, other cells, organs, tissues, bone marrow, lymph nodes and spleen.
The term “component” refers to an element of a composition. In relation to a diagnostic kit, for example, a component may be a capture antibody, a detection or conjugate antibody, a control, a calibrator, a series of calibrators, a sensitivity panel, a container, a buffer, a diluent, a salt, an enzyme, a co-factor for an enzyme, a detection reagent, a pretreatment reagent/solution, a substrate (e.g., as a solution), a stop solution, and the like that can be included in a kit for assay of a test sample. Thus, a “component” can include a polypeptide or other analyte as above, that is immobilized on a solid support, such as by binding to an anti-analyte (e.g., anti-polypeptide) antibody. Some components can be in solution or lyophilized for reconstitution for use in an assay.
“Control” refers to a composition known to not analyte (“negative control”) or to contain analyte (“positive control”). A positive control can comprise a known concentration of analyte. A “positive control” can be used to establish assay performance characteristics and is a useful indicator of the integrity of reagents (e.g., analytes).
“Predetermined cutoff” and “predetermined level” refer generally to an assay cutoff value that is used to assess diagnostic/prognostic/therapeutic efficacy results by comparing the assay results against the predetermined cutoff/level, where the predetermined cutoff/level already has been linked or associated with various clinical parameters (e.g., severity of disease, progression/nonprogression/improvement, etc.). While the present disclosure may provide exemplary predetermined levels, it is well-known that cutoff values may vary depending on the nature of the immunoassay (e.g., antibodies employed, etc.). It further is well within the ordinary skill of one in the art to adapt the disclosure herein for other immunoassays to obtain immunoassay-specific cutoff values for those other immunoassays based on this disclosure. Whereas the precise value of the predetermined cutoff/level may vary between assays, correlations as described herein (if any) may be generally applicable.
“Pretreatment reagent,” e.g., lysis, precipitation and/or solubilization reagent, as used in a diagnostic assay as described herein refers to one that lyses any cells and/or solubilizes any analyte that is/are present in a test sample. Pretreatment is not necessary for all samples, as described further herein. Among other things, solubilizing the analyte (e.g., polypeptide of interest) may entail release of the analyte from any endogenous binding proteins present in the sample. A pretreatment reagent may be homogeneous (not requiring a separation step) or heterogeneous (requiring a separation step). With use of a heterogeneous pretreatment reagent there is removal of any precipitated analyte binding proteins from the test sample prior to proceeding to the next step of the assay.
“Quality control reagents” in the context of immunoassays and kits described herein, include, but are not limited to, calibrators, controls, and sensitivity panels. A “calibrator” or “standard” typically is used (e.g., one or more, such as a plurality) in order to establish calibration (standard) curves for interpolation of the concentration of an analyte, such as an antibody or an analyte. Alternatively, a single calibrator, which is near a predetermined positive/negative cutoff, can be used. Multiple calibrators (i.e., more than one calibrator or a varying amount of calibrator(s)) can be used in conjunction so as to comprise a “sensitivity panel.”
The term “specific binding partner” refers to a member of a specific binding pair. A specific binding pair comprises two different molecules that specifically bind to each other through chemical or physical means. Therefore, in addition to antigen and antibody specific binding, other specific binding pairs can include biotin and avidin (or streptavidin), carbohydrates and lectins, complementary nucleotide sequences, effector and receptor molecules, cofactors and enzymes, enzyme inhibitors and enzymes, and the like. Furthermore, specific binding pairs can include members that are analogs of the original specific binding members, for example, an analyte-analog. Immunoreactive specific binding members include antigens, antigen fragments, and antibodies, including monoclonal and polyclonal antibodies as well as complexes, fragments, and variants (including fragments of variants) thereof, whether isolated or recombinantly produced.
The term “Fc region” refers to the C-terminal region of an immunoglobulin heavy chain, which may be generated by papain digestion of an intact antibody or binding protein. The Fc region may be a native sequence Fc region or a variant Fc region. The Fc region of an immunoglobulin generally comprises two constant domains, a CH2 domain and a CH3 domain, and optionally comprises a CH4 domain. Replacements of amino acid residues in the Fc portion to alter effector function are known in the art (e.g., U.S. Pat. Nos. 5,648,260 and 5,624,821). The Fc region mediates several important effector functions, e.g., cytokine induction, antibody dependent cell mediated cytotoxicity (ADCC), phagocytosis, complement dependent cytotoxicity (CDC), and half-life/clearance rate of antibody or binding protein and antigen-antibody or antigen-binding protein complexes. In some cases these effector functions are desirable for a therapeutic immunoglobulin but in other cases might be unnecessary or even deleterious, depending on the therapeutic objectives.
The term “antigen-binding portion” of a binding protein refers to one or more fragments of a binding protein that retain the ability to specifically bind to an antigen. The antigen-binding function of a binding protein may be performed by fragments of a full-length binding protein, including bispecific, dual specific, or multi-specific formats; for instance, binding to two or more different antigens. Examples of binding fragments encompassed within the term “antigen-binding portion” of an binding protein include (i) an Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) an F(ab′) 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of a single arm of an antibody or binding protein, (v) a dAb fragment, which comprises a single variable domain; and (vi) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they may be joined, e.g., using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv). Such single chain antibodies or binding proteins are also intended to be encompassed within the term “antigen-binding portion” of an antibody or binding protein. Other forms of single chain antibodies, such as diabodies are also encompassed. In addition, single chain antibodies or binding protein also include “linear” antibodies or binding protein comprising a pair of tandem Fv segments (VH-CH1-VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen binding regions.
The term “multivalent binding protein” refers to a binding protein comprising two or more antigen binding sites. In an embodiment, the multivalent binding protein is engineered to have three or more antigen binding sites, and may not be a naturally occurring antibody. The term “multispecific binding protein” refers to a binding protein capable of binding two or more related or unrelated targets. In an embodiment, the dual variable domain (DVD) binding proteins provided herein comprise two or more antigen binding sites and are tetravalent or multivalent binding proteins.
The term “linker” refers to an amino acid residue or a polypeptide comprising two or more amino acid residues joined by peptide bonds that are used to link two polypeptides (e.g., two VH or two VL domains) Such linker polypeptides are well known in the art (see, e.g., Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak et al. (1994) Structure 2:1121-1123). A number of suitable linkers for use in the binding proteins described herein are set out in Table 55. In some embodiments, the X1 linker on the heavy chain is a GS-H10 linker and the X1 linker on the light chain is a GS-L10(dR) linker. In some embodiments, the X1 linker on the heavy chain is a GS-H10 linker and the X1 linker on the light chain is a GS-L10 linker. In some embodiments, the X1 linker on the heavy chain is an HG-short linker and the X1 linker on the light chain is an LK-long linker.
The terms “Kabat numbering”, “Kabat definitions” and “Kabat labeling” are used interchangeably herein. These terms, which are recognized in the art, refer to a system of numbering amino acid residues which are more variable (i.e., hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody or binding protein, or an antigen binding portion thereof (Kabat et al. (1971) Ann. NY Acad. Sci. 190:382-391 and, Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242). For the heavy chain variable region, the hypervariable region ranges from amino acid positions 31 to 35 for CDR1, amino acid positions 50 to 65 for CDR2, and amino acid positions 95 to 102 for CDR3. For the light chain variable region, the hypervariable region ranges from amino acid positions 24 to 34 for CDR1, amino acid positions 50 to 56 for CDR2, and amino acid positions 89 to 97 for CDR3. In some embodiments, the CDR sequences, framework sequences, and or constant region sequences are identified using Kabat numbering.
The term “CDR” refers to a complementarity determining region within an immunoglobulin variable region sequence. There are three CDRs in each of the variable regions of the heavy chain and the light chain, which are designated CDR1, CDR2 and CDR3, for each of the heavy and light chain variable regions. The term “CDR set” refers to a group of three CDRs that occur in a single variable region capable of binding the antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat (Kabat et al. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody or binding protein, but also provides precise residue boundaries defining the three CDRs in each heavy or light chain sequence. These CDRs may be referred to as Kabat CDRs. Chothia and coworkers (Chothia and Lesk (1987) J. Mol. Biol. 196:901-917; Chothia et al. (1989) Nature 342:877-883) found that certain sub-portions within Kabat CDRs adopt nearly identical peptide backbone conformations, despite having great diversity at the level of amino acid sequence. These sub-portions were designated as L1, L2 and L3 or H1, H2 and H3 where the “L” and the “H” designates the light chain and the heavy chain regions, respectively. These regions may be referred to as Chothia CDRs, which have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs overlapping with the Kabat CDRs have been described by Padlan (1995) FASEB J. 9:133-139 and MacCallum (1996) J. Mol. Biol. 262(5):732-45). Still other CDR boundary definitions may not strictly follow one of the herein systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. The methods used herein may utilize CDRs defined according to any of these systems, although certain embodiments use Kabat or Chothia defined CDRs.
The term “epitope” refers to a region of an antigen that is specifically bound by a binding protein disclosed herein. In certain embodiments, epitope determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl, and, in certain embodiments, may have specific three dimensional structural characteristics, and/or specific charge characteristics. An antigen or fragment can contain more than one epitope. An epitope may be determined by obtaining an X-ray crystal structure of an antibody:antigen complex and determining which residues on the antigen (e.g., VEGF or PDGF or a receptor) are within a specified distance of residues on the antibody of interest, wherein the specified distance is, 5 Å or less, e.g., 5 Å, 4 Å, 3 Å, 2 Å, 1 Å or less, or any distance in between. In some embodiments, the epitope is defined as a stretch of 8 or more contiguous amino acid residues along the antigen sequence in which at least 50%, 70% or 85% of the residues are within the specified distance of the antibody or binding protein in the X-ray crystal structure.
In certain embodiments, a binding protein specifically binds an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and/or macromolecules. Binding proteins that bind to the same or similar epitopes will likely cross-compete (one prevents the binding or modulating effect of the other). Cross-competition, however, can occur even without partial or complete epitope overlap, e.g., if epitopes are adjacent in three-dimensional space and/or due to steric hindrance.
The term “pharmacokinetic(s)” refers to the process by which a drug is absorbed, distributed, metabolized, and excreted by an organism. To generate a multivalent binding protein molecule with a desired pharmacokinetic profile, parent monoclonal antibodies with similarly desired pharmacokinetic profiles are selected. The PK profiles of the selected parental monoclonal antibodies can be easily determined in rodents using methods known to one skilled in the art (see, e.g., U.S. Pat. No. 7,612,181).
The term “bioavailability” refers to the degree and rate at which a drug is absorbed into a living system or is made available at the site of physiological activity. Bioavailability can be a function of several of the previously described properties, including stability, solubility, immunogenicity and pharmacokinetics, and can be assessed using methods known to one skilled in the art (see, e.g., U.S. Pat. No. 7,612,181).
The term “surface plasmon resonance” refers to an optical phenomenon that allows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIAcore® system (BIAcore International AB, a GE Healthcare company, Uppsala, Sweden and Piscataway, N.J.). For further descriptions, see Jönsson et al. (1993) Ann. Biol. Clin. 51:19-26. The term “K on ” refers to the on rate constant for association of a binding protein (e.g., an antibody or DVD-Ig) to the antigen to form the, e.g., DVD-Ig/antigen complex. The term “K on ” also refers to “association rate constant”, or “ka”, as is used interchangeably herein. This value indicating the binding rate of a binding protein to its target antigen or the rate of complex formation between a binding protein, e.g., an antibody, and antigen also is shown by the equation below:
Antibody (“Ab”)+Antigen (“Ag”)→Ab-Ag

The term “K off ” refers to the off rate constant for dissociation, or “dissociation rate constant”, of a binding protein (e.g., an antibody or DVD-Ig) from the, e.g., DVD-Ig/antigen complex as is known in the art. This value indicates the dissociation rate of a binding protein, e.g., an antibody, from its target antigen or separation of Ab-Ag complex over time into free antibody and antigen as shown by the equation below:
Ab+Ag←Ab-Ag

The terms “K d ” and “equilibrium dissociation constant” may refer to the value obtained in a titration measurement at equilibrium, or by dividing the dissociation rate constant (K off ) by the association rate constant (K on ). The association rate constant, the dissociation rate constant and the equilibrium dissociation constant, are used to represent the binding affinity of a binding protein (e.g., an antibody or DVD-Ig) to an antigen. Methods for determining association and dissociation rate constants are well known in the art. Using fluorescence-based techniques offers high sensitivity and the ability to examine samples in physiological buffers at equilibrium. Other experimental approaches and instruments such as a BIAcore® (biomolecular interaction analysis) assay, can be used (e.g., instrument available from BIAcore International AB, a GE Healthcare company, Uppsala, Sweden). Additionally, a KinExA® (Kinetic Exclusion Assay) assay, available from Sapidyne Instruments (Boise, Id.), can also be used.
The term “variant” refers to a polypeptide that differs from a given polypeptide in amino acid sequence by the addition (e.g., insertion), deletion, or conservative substitution of amino acids, but that retains the biological activity of the given polypeptide (e.g., a variant VEGF antibody can compete with anti-VEGF antibody for binding to VEGF). A conservative substitution of an amino acid, i.e., replacing an amino acid with a different amino acid of similar properties (e.g., hydrophilicity and degree and distribution of charged regions) is recognized in the art as typically involving a minor change. These minor changes can be identified, in part, by considering the hydropathic index of amino acids, as understood in the art (see, e.g., Kyte et al. (1982) J. Mol. Biol. 157: 105-132). The hydropathic index of an amino acid is based on a consideration of its hydrophobicity and charge. It is known in the art that amino acids of similar hydropathic indexes in a protein can be substituted and the protein still retains protein function. In one aspect, amino acids having hydropathic indexes of ±2 are substituted. The hydrophilicity of amino acids also can be used to reveal substitutions that would result in proteins retaining biological function. A consideration of the hydrophilicity of amino acids in the context of a peptide permits calculation of the greatest local average hydrophilicity of that peptide, a useful measure that has been reported to correlate well with antigenicity and immunogenicity (see, e.g., U.S. Pat. No. 4,554,101). Substitution of amino acids having similar hydrophilicity values can result in peptides retaining biological activity, for example immunogenicity, as is understood in the art. In one aspect, substitutions are performed with amino acids having hydrophilicity values within ±2 of each other. Both the hydrophobicity index and the hydrophilicity value of amino acids are influenced by the particular side chain of that amino acid. Consistent with that observation, amino acid substitutions that are compatible with biological function are understood to depend on the relative similarity of the amino acids, and particularly the side chains of those amino acids, as revealed by the hydrophobicity, hydrophilicity, charge, size, and other properties. The term “variant” also includes polypeptide or fragment thereof that has been differentially processed, such as by proteolysis, phosphorylation, or other post-translational modification, yet retains its biological activity or antigen reactivity, e.g., the ability to bind to VEGF. The term “variant” encompasses fragments of a variant unless otherwise defined. A variant may be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%, 78%, 77%, 76%, or 75% identical to the wild type sequence.
Use of Disclosed Binding Proteins in Treating Various Diseases
The binding protein molecules provided herein are useful as therapeutic molecules to treat various diseases, e.g., wherein the targets that are recognized by the binding proteins are detrimental. Such binding proteins may bind one or more targets involved in a specific disease.
Without limiting the disclosure, further information on certain disease conditions is provided.
1. Age-Related Macular Degeneration (AMD)
In various embodiments, one or more of the binding proteins disclosed herein that are capable of binding to VEGF and PDGF and/or their cognate receptors (e.g., a combination of an anti-VEGF and an anti-PDGF binding protein, or a multispecific binding protein capable of targeting both VEGF and PDGF) can be used to treat AMD. In some embodiments, any of the binding proteins disclosed herein can be used to treat AMD, or a binding protein comprising the CDR and/or variable domain sequences from any of the binding disclosed herein. In certain embodiments, the binding protein used to treat AMD is one or more of the binding proteins listed in Tables 27-30, 38-42, 46-50, or 55-58. In certain embodiments, the binding protein used to treat AMD is one or more of the binding proteins listed in Tables 56-58. In certain embodiments, the binding protein is PR-1572102, PR-1572105, or PR-1610561.
Age-Related Macular Degeneration (AMD) is the leading cause of irreversible vision loss in individuals over the age of 50 in the United States and a major cause of blindness worldwide. Globally more than 160 million people suffer from AMD. AMD is an age-related ocular disease that results in blindness due to damage to the macula; the region of the retina responsible for sharp central vision. It is associated with the degeneration of the macula and in particular the retinal pigmented epithelium (RPE).
The disease occurs in two forms, the dry or non-exudative AMD form and the wet or exudative form. The most common form of macular degeneration, dry AMD (non-neovascular), is an early stage of the disease and may result from aging and thinning of macular tissues, deposition of pigment in the macula, or a combination of both processes. Dry AMD is diagnosed when yellowish spots known as drusen accumulate in and around the macula. Drusen are thought to be deposits or debris from nearby deteriorating tissue. The onset of dry AMD is usually associated with age-related changes in Bruch's membrane, a highly specialized matrix for adhesion of retinal pigment epithelial (RPE) cells. These alterations in Bruch's membrane can result in death of RPE cells in the macula, accumulation of drusen, and damage to photoreceptor cells. Gradual central loss of vision may occur with dry AMD, but the symptoms are typically not nearly as severe as with the wet form of the disease. Dry AMD can slowly progress to late-stage geographic atrophy (GA) resulting in a gradual deterioration of retinal cells that can cause severe vision loss. Dry AMD (both early and late stage) is the most common form of AMD representing more than 85% of all diagnosed cases.
The wet or exudative form of the disease usually results in more severe vision loss. Wet macular degeneration mainly affects central vision, causing “blind spots” in the central line of vision. Approximately 10-15% of dry AMD cases progress to wet AMD. Wet AMD is characterized by new blood vessel growth beneath the retina. Clinically, this is referred to as choroidal neovascularization (CNV). Wet AMD accounts for about 10-15% of all cases of AMD. Progression of dry AMD to wet AMD is marked by the development of neovascularization within Bruch's membrane, as well as in the subretinal space. Wet AMD occurs when abnormal blood vessels behind the retina grow under the macula. These new blood vessels tend to be fragile and often leak blood and fluid. The blood and fluid result in macula inflammation and thickening and disrupts the connection between the photoreceptors and the RPE, leading to vision loss. In wet AMD, neovascularization is stimulated by many angiogenic factors; including vascular endothelial growth factor (VEGF), which appears to be the primary angiogenic factor in patients with wet AMD (Miller et al. (1994) Am. J. Pathol. 145(3):574-584). Additionally, VEGF can act as a powerful endothelial cell mitogen, increasing vascular permeability. The primary goals of current AMD treatment are to block or inhibit choroidal neovascularization (CNV) and macular edema following retinal vein occlusion (RVO), stabilize or improve vision, and to reduce the occurrence of adverse effects.
Anti-VEGF agents may reduce choroidal neovascularization (CNV) and leakage, but do not lead to regression of CNV itself. Emerging evidence indicates the important role of pericytes on the maturation of new blood vessels. Anti-PDGF agents can directly block pericyte recruitment and prevent the maturation and stabilization of choroidal neovascularization. If pericytes can be stripped away from new blood vessels, vascular endothelial cells may become more susceptible to VEGF blockade, ultimately leading to a regression of angiogenesis.
Among other functions, VEGF stimulates endothelial cell proliferation/growth, increases vascular permeability, and promotes leukocyte activity capable of damaging retinal endothelial cells (Leung et al. (1989) Science 246(4935):1306-9). In wet AMD, retinal tissues produce and release angiogenic growth factors such as VEGF that bind to specific receptors located on the endothelial cells of nearby preexisting blood vessels. Activation of endothelial cells can result in the release of enzymes targeting tight junctions. These enzymes act on the basement membrane surrounding all existing blood vessels and lead to the formation of holes in the membrane. The endothelial cells proliferate and migrate out through these holes toward the diseased tissue. Specialized adhesion molecules such as integrins promote formation of new blood vessel sprouts, and matrix metalloproteinases (MMPs) dissolve the tissue in front of the sprouting vessel tip in order to accommodate it. Finally, smooth muscle cells (pericytes) provide structural support to these newly formed blood vessel loops and blood flow begins in these new immature vessels. Thus, VEGF may serve as a rate-limiting step in angiogenesis. VEGF also increases vascular permeability by leukocyte-mediated endothelial cell injury, formation of fenestrations, and the dissolution of tight junctions. This leads to intra-retinal fluid accumulation and a detrimental effect on visual acuity. Moreover, VEGF can also cause the release of inflammatory cytokines that further reinforce the cycle of inflammation and angiogenesis.
In some embodiments, treatments inhibiting VEGF, PDGF, and/or the receptors (in a combination therapy or in one molecule) using the binding proteins disclosed herein may offer improved options for patients with wet AMD, while reducing the number of injections, reducing the safety concerns associated with multiple injections, and reducing cost.
2. Diabetic Retinopathy
Diabetic retinopathy is the most common diabetic eye disease and a leading cause of blindness in American adults. It is caused by changes in the blood vessels of the retina. In some people with diabetic retinopathy, blood vessels may swell and leak fluid. In other people, abnormal new blood vessels grow on the surface of the retina. The retina is the light-sensitive tissue at the back of the eye. A healthy retina is necessary for good vision.
Diabetic retinopathy has four stages: (1) Mild Nonproliferative Retinopathy. At this earliest stage, microaneurysms occur. They are small areas of balloon-like swelling in the retina's tiny blood vessels. (2) Moderate Nonproliferative Retinopathy. As the disease progresses, some blood vessels that nourish the retina are blocked. (3) Severe Nonproliferative Retinopathy. Many more blood vessels are blocked, depriving several areas of the retina with their blood supply. These areas of the retina send signals to the body to grow new blood vessels for nourishment. (4) Proliferative Retinopathy. At this advanced stage, the signals sent by the retina for nourishment trigger the growth of new blood vessels. This condition is called proliferative retinopathy. These new blood vessels are abnormal and fragile. They grow along the retina and along the surface of the clear, vitreous gel that fills the inside of the eye. By themselves, these blood vessels do not cause symptoms or vision loss. However, they have thin, fragile walls. If they leak blood, severe vision loss and even blindness can result.
Blood vessels damaged from diabetic retinopathy can cause vision loss in two ways: (1) Fragile, abnormal blood vessels can develop and leak blood into the center of the eye, blurring vision. This is proliferative retinopathy and is the fourth and most advanced stage of the disease. (2) Fluid can leak into the center of the macula, the part of the eye where sharp, straight-ahead vision occurs. The fluid makes the macula swell, blurring vision. This condition is called macular edema. It can occur at any stage of diabetic retinopathy, although it is more likely to occur as the disease progresses. About half of the people with proliferative retinopathy also have macular edema.
In some embodiments, the binding proteins disclosed herein may be used to inhibit VEGF, PDGF, and/or the receptors (in a combination therapy or in one molecule) to treat diabetic retinopathy.
In various embodiments, other diseases may be treated using the binding proteins disclosed herein, including but not limited to other eye disorders, cancers, fibrosis, renal disease, pathologic angiogenesis, wound healing, bone formation, or other diseases associated with aberrant (e.g., elevated) PDGF and/or VEGF expression.
Pharmaceutical Compositions
In various embodiments, pharmaceutical compositions comprising one or more of the binding proteins disclosed herein, either alone or in combination with other prophylactic agents, therapeutic agents, and/or pharmaceutically acceptable carriers, are provided. The pharmaceutical compositions comprising binding proteins provided herein are for use in, but not limited to, diagnosing, detecting, or monitoring a disorder, in preventing, treating, managing, or ameliorating a disorder or one or more symptoms thereof, and/or in research. The formulation of pharmaceutical compositions, either alone or in combination with prophylactic agents, therapeutic agents, and/or pharmaceutically acceptable carriers, are known to one skilled in the art (see, e.g., U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
Methods of administering a pharmaceutical composition or a prophylactic or therapeutic agent provided herein include, but are not limited to, parenteral administration (e.g., intradermal, intramuscular, intraperitoneal, intravitreous, intravenous and subcutaneous), epidural administration, intratumoral administration, mucosal administration (e.g., intranasal and oral routes) and pulmonary administration (e.g., aerosolized compounds administered with an inhaler or nebulizer). In an embodiment, the methods of administering a pharmaceutical composition or a prophylactic or therapeutic agent provided herein include topical eye drops, gels, or creams. The formulation of pharmaceutical compositions for specific routes of administration, and the materials and techniques necessary for the various methods of administration are available and known to one skilled in the art (U.S. Patent Appl. No. 20090311253 and U.S. Pat. No. 7,612,181).
Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. The term “dosage unit form” refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms provided herein are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals. An exemplary, non-limiting range for a therapeutically or prophylactically effective amount of a binding protein provided herein is 0.1-20 mg/kg, for example, 1-10 mg/kg. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
Combination Therapy
In various embodiments, a binding protein provided herein may also be administered with one or more additional therapeutic agents useful in the treatment of various diseases, the additional agent being selected by the skilled artisan for its intended purpose. For example, the additional agent can be a therapeutic agent art-recognized as being useful to treat the disease or condition being treated by the antibody provided herein, such as AMD. The combination can also include more than one additional agent, e.g., two or three additional agents.
Combination therapy agents include, but are not limited to imaging agents, cytotoxic agents, angiogenesis inhibitors, kinase inhibitors, tyrosine kinase inhibitors, tyrosine kinase receptor inhibitors, co-stimulation molecule blockers, adhesion molecule blockers, anti-cytokine antibodies or functional fragments thereof, methotrexate, cyclosporin, rapamycin, FK506, detectable labels or reporters, TNF antagonists, antirheumatics, muscle relaxants, narcotics, non-steroid anti-inflammatory drugs (NSAIDs), analgesics, anesthetics, local anesthetics, sedatives, a hyaluronidase enzyme, neuromuscular blockers, antimicrobials, antipsoriatics, corticosteriods, anabolic steroids, erythropoietin, immunizations, immunoglobulins, immunosuppressives, growth hormones, hormone replacement drugs, radiopharmaceuticals, antidepressants, antipsychotics, stimulants, asthma medications, beta agonists, inhaled steroids, epinephrine or analogs, cytokines, or cytokine antagonists.
Diagnostics
The disclosure herein also provides, in various embodiments, diagnostic applications including, but not limited to, diagnostic assay methods, diagnostic kits containing one or more binding proteins, and adaptation of the methods and kits for use in automated and/or semi-automated systems. The methods, kits, and adaptations provided may be employed in the detection, monitoring, and/or treatment of a disease or disorder in an individual. This is further elucidated below.
The present disclosure also provides a method for determining the presence, amount or concentration of an analyte, or fragment thereof, in a test sample using at least one binding protein as described herein. Any suitable assay as is known in the art can be used in the method. Examples include, but are not limited to, immunoassays and/or methods employing mass spectrometry.
Immunoassays provided by the present disclosure may include sandwich immunoassays, radioimmunoassay (RIA), enzyme immunoassay (EIA), enzyme-linked immunosorbent assay (ELISA), competitive-inhibition immunoassays, fluorescence polarization immunoassay (FPIA), enzyme multiplied immunoassay technique (EMIT), bioluminescence resonance energy transfer (BRET), and homogenous chemiluminescent assays, among others.
A chemiluminescent microparticle immunoassay, in particular one employing the ARCHITECT® automated analyzer (Abbott Laboratories, Abbott Park, Ill.), is an example of an immunoassay.
Methods employing mass spectrometry are provided by the present disclosure and include, but are not limited to MALDI (matrix-assisted laser desorption/ionization) or by SELDI (surface-enhanced laser desorption/ionization).
Methods for collecting, handling, processing, and analyzing biological test samples using immunoassays and mass spectrometry would be well-known to one skilled in the art, are provided for in the practice of the present disclosure (see, e.g., U.S. Pat. No. 7,612,181).
Kits
In various embodiments, a kit for assaying a test sample for the presence, amount or concentration of an analyte, or fragment thereof, in a test sample is also provided. The kit comprises at least one component for assaying the test sample for the analyte, or fragment thereof, and instructions for assaying the test sample for the analyte, or fragment thereof. The at least one component for assaying the test sample for the analyte, or fragment thereof, can include a composition comprising a binding protein, as disclosed herein, and/or an anti-analyte binding protein (or a fragment, a variant, or a fragment of a variant thereof), which is optionally immobilized on a solid phase.
Optionally, the kit may comprise a calibrator or control, which may comprise isolated or purified analyte. The kit can comprise at least one component for assaying the test sample for an analyte by immunoassay and/or mass spectrometry. The kit components, including the analyte, binding protein, and/or anti-analyte binding protein, or fragments thereof, may be optionally labeled using any art-known detectable label. The materials and methods for the creation provided for in the practice of the present disclosure would be known to one skilled in the art (see, e.g., U.S. Pat. No. 7,612,181).
The kit (or components thereof), as well as the method of determining the presence, amount or concentration of an analyte in a test sample by an assay, such as an immunoassay as described herein, can be adapted for use in a variety of automated and semi-automated systems (including those wherein the solid phase comprises a microparticle), as described, for example, in U.S. Pat. Nos. 5,089,424 and 5,006,309, and as commercially marketed, for example, by Abbott Laboratories (Abbott Park, Ill.) as ARCHITECT®.
Other platforms available from Abbott Laboratories include, but are not limited to, AxSYM®, IMx® (see, for example, U.S. Pat. No. 5,294,404, PRISM®, EIA (bead), and Quantum™ II, as well as other platforms. Additionally, the assays, kits and kit components can be employed in other formats, for example, on electrochemical or other hand-held or point-of-care assay systems. The present disclosure is, for example, applicable to the commercial Abbott Point of Care (i-STATED, Abbott Laboratories) electrochemical immunoassay system that performs sandwich immunoassays Immunosensors and their methods of manufacture and operation in single-use test devices are described, for example in, U.S. Pat. Nos. 5,063,081, 7,419,821, 7,682,833, 7,723,099, and 9,035,027; and U.S. Publication No. 20040018577.
Sequences
Table 1 discloses amino acid and nucleotide sequences encoding VEGF-A from different human isoforms and different species. Table 2 discloses amino acid and nucleotide sequences encoding PDGF-BB from different human isoforms and different species. Table 3 discloses human IgG heavy chain and light chain constant domains, including sequences with the indicated amino acid modifications relative to the wild-type sequence. In various embodiments, the constant domains listed in Table 3 can be used with any of the binding proteins disclosed herein. The variable domains of the binding proteins disclosed herein may be attached to constant regions of any immunoglobulin species, isotypes, or mutants. Exemplary modifications in constant domain mutants include those with amino acid mutations intended to increase or reduce constant domain interactions with Fc-gamma receptors, C1q and FcRn, and/or mutations intended to modulate protein stability or valency (full-length and half molecule, heterodimer molecule, etc.). Tables 4 and 5 disclose exemplary heavy and light chain acceptor framework sequences that can be used with any of the CDR sets disclosed herein (i.e., heavy chain acceptor sequences paired with any of the heavy chain CDRs 1-3 disclosed herein, and/or light chain acceptor sequences paired with any of the light chain CDRs 1-3 disclosed herein) to form functional binding sites for PDGF, VEGF, and/or their cognate receptors.





TABLE 1



Amino Acid and Nucleotide Sequences for VEGF-A






Sequence
Sequence

Kind of Sequence
Identifier
123456789012345678901234567890



Human VEGF-A 165
SEQ ID NO:
APMAEGGGQNHHEVVKFMDVYQRSYCHPIE

Amino Acid Sequence
253
TLVDIFQEYPDEIEYIFKPSCVPLMRCGGC



CNDEGLECVPTEESNITMQIMRIKPHQGQH



IGEMSFLQHNKCECRPKKDRARQENPCGPC



SERRKHLFVQDPQTCKCSCKNTDSRCKARQ



LELNERTCRCDKPRR



Human VEGF-A 121
SEQ ID NO:
APMAEGGGQNHHEVVKFMDVYQRSYCHPIE

Amino Acid Sequence
254
TLVDIFQEYPDEIEYIFKPSCVPLMRCGGC



CNDEGLECVPTEESNITMQIMRIKPHQGQH



IGEMSFLQHNKCECRPKKDRARQEKCDKPR



R



Human VEGF-A 110
SEQ ID NO:
APMAEGGGQNHHEVVKFMDVYQRSYCHPIE

Amino Acid Sequence
255
TLVDIFQEYPDEIEYIFKPSCVPLMRCGGC



CNDEGLECVPTEESNITMQIMRIKPHQGQH



IGEMSFLQHNKCECRCDKPRR



Cynomolgus monkey
SEQ ID NO:
APMAEGGGQNHHEVVKFMDVYQRSYCHPIE

VEGF-A 165 Amino Acid
256
TLVDIFQEYPDEIEYIFKPSCVPLMRCGGC

Sequence

CNDEGLECVPTEESNITMQIMRIKPHQGQH



IGEMSFLQHNKCECRPKKDRARQENPCGPC



SERRKHLFVQDPQTCKCSCKNTDSRCKARQ



LELNERTCRCDKPRR



Mouse VEGF-A 164
SEQ ID NO:
APTTEGEQKSHEVIKFMDVYQRSYCRPIET

Amino Acid Sequence
257
LVDIFQEYPDEIEYIFKPSCVPLMRCAGCC



NDEALECVPTSESNITMQIMRIKPHQSQHI



ERMSFLQHSRCECRPKKDRTKPENHCEPCS



ERRKHLFVQDPQTCKCSCKNTDSRCKARQL



ELNERTCRCDKPRR



Rat VEGF-A 164 Amino
SEQ ID NO:
APTTEGEQKAHEVVKFMDVYQRSYCRPIET

Acid Sequence
258
LVDIFQEYPDEIEYIFKPSCVPLMRCAGCC



NDEALECVPTSESNVTMQIMRIKPHQSQHI



GEMSFLQHSRCECRPKKDRTKPENHCEPCS



ERRKHLFVQDPQTCKCSCKNTDSRCKARQL



ELNERTCRCDKPRR



Rabbit VEGF-A Amino
SEQ ID NO:
MNFLLSWVHWSLALLLYLHHAKWSQAAPMA

Acid Sequence
259
EEGDNKPHEVVKFMEVYRRSYCQPIETLVD



IFQEYPDEIEYIFKPSCVPLVRCGGCCNDE



SLECVPTEEFNVTMQIMRIKPHQGQHIGEM



SFLQHNKCECRPKKDRARQENPCGPCSERR



KHLFVQDPQTCKCSCKNTDSRCKARQLELN



ERTCRCDKPRR








































































TABLE 2



Amino Acid and Nucleotide Sequences for PDGF-BB






Sequence
Sequence

Kind of Sequence
Identifier
123456789012345678901234567890



Human PDGF-BB Amino
SEQ ID NO:
SLGSLTIAEPAMIAECKTRTEVFEISRRLI

Acid Sequence
260
DRTNANFLVWPPCVEVQRCSGCCNNRNVQC



RPTQVQLRPVQVRKIEIVRKKPIFKKATVT



LEDHLACKCETVAAARPVT



Human PDGF-BB-RM
SEQ ID NO:
MNRCWALFLSLCCYLRLVSAEGDPIPEELY

(Retention Motif) Amino
261
EMLSDHSIRSFDDLQRLLHGDPGEEDGAEL

Acid Sequence

DLNMTRSHSGGELESLARGRR SLGSLTIAE




PAMIAECKTRTEVFEISRRLIDRTNANFLV





WPPCVEVQRCSGCCNNRNVQCRPTQVQLRP





VQVRKIEIVRKKPIFKKATVTLEDHLACKC




ETVAAARPVT RSPGGSQEQRAKTPQTRVTI



RTVRVRRPPKGKHRKFKHTHDKTALKETLG



A



Cynomolgus monkey
SEQ ID NO:
SLGSLTVAEPAMIAECKTRTEVFEISRRLI

PDGF-BB Amino Acid
262
DRTNANFLVWPPCVEVQRCSGCCNNRNVQC

Sequence

RPTQVQLRPVQVRKIEIVRKKPIFKKATVT



LEDHLACKCETVAAARPVT



Mouse PDGF-BB Amino
SEQ ID NO:
SLGSLAAAEPAVIAECKTRTEVFQISRNLI

Acid Sequence
263
DRTNANFLVWPPCVEVQRCSGCCNNRNVQC



RASQVQMRPVQVRKIEIVRKKPIFKKATVT



LEDHLACKCETIVTPRPVT



Rat PDGF-BB Amino
SEQ ID NO:
SLGSLAAAEPAVIAECKTRTEVFQISRNLI

Acid Sequence
264
DRTNANFLVWPPCVEVQRCSGCCNNRNVQC



RASQVQMRPVQVRKIEIVRKKPVFKKATVT



LEDHLACKCETVVTPRPVT



Rabbit PDGF-BBA Amino
SEQ ID NO:
SLGSLAAAEPAVIAECKTRTEVFQISRNLI

Acid Sequence
265
DRTNANFLVWPPCVEVQRCSGCCNNRNVQC



RASQVQMRPVQVRKIEIVRKKPVFKKATVT



LEDHLACKCETVVTPRPVT




























































TABLE 3



Amino Acid Sequences of Human IgG Heavy Chain and

Light Chain Constant Domains






Sequence
Sequence

Protein
Identifier
123456789012345678901234567890



Ig gamma-1 constant
SEQ ID NO:
ASTKGPSVFFLAPSSKSTSGGTAALGCLVK

region
266
DYFPEPVTVSWNSGALTSGVHTFPAVLQSS



GLYSLSSVVTVPSSSLGTQTYICNVNHKPS



NTKVDKKVEPKSCDKTHTCPPCPAPELLGG



PSVFLFPPKPKDTLMISRTPEVTCVVVDVS



HEDPEVKFNWYVDGVEVHNAKTKPREEQYN



STYRVVSVLTVLHQDWLNGKEYKCKVSNKA



LPAPIEKTISKAKGQPREPQVYTLPPSREE



MTKNQVSLTCLVKGFYPSDIAVEWESNGQP



ENNYKTTPPVLDSDGSFFLYSKLTVDKSRW



QQGNVFSCSVMHEALHNHYTQKSLSLSPGK



Ig gamma-1 constant
SEQ ID NO:
ASTKGPSVFFLAPSSKSTSGGTAALGCLVK

region L234A, L235A
267
DYFPEPVTVSWNSGALTSGVHTFPAVLQSS



GLYSLSSVVTVPSSSLGTQTYICNVNHKPS



NTKVDKKVEPKSCDKTHTCPPCPAPEAAGG



PSVFLFPPKPKDTLMISRTPEVTCVVVDVS



HEDPEVKFNWYVDGVEVHNAKTKPREEQYN



STYRVVSVLTVLHQDWLNGKEYKCKVSNKA



LPAPIEKTISKAKGQPREPQVYTLPPSREE



MTKNQVSLTCLVKGFYPSDIAVEWESNGQP



ENNYKTTPPVLDSDGSFFLYSKLTVDKSRW



QQGNVFSCSVMHEALHNHYTQKSLSLSPGK



Ig gamma-1 constant
SEQ ID NO:
ASTKGPSVFFLAPSSKSTSGGTAALGCLVK

region L234A, L235A,
268
DYFPEPVTVSWNSGALTSGVHTFPAVLQSS

H435A

GLYSLSSVVTVPSSSLGTQTYICNVNHKPS



NTKVDKKVEPKSCDKTHTCPPCPAPEAAGG



PSVFLFPPKPKDTLMISRTPEVTCVVVDVS



HEDPEVKFNWYVDGVEVHNAKTKPREEQYN



STYRVVSVLTVLHQDWLNGKEYKCKVSNKA



LPAPIEKTISKAKGQPREPQVYTLPPSREE



MTKNQVSLTCLVKGFYPSDIAVEWESNGQP



ENNYKTTPPVLDSDGSFFLYSKLTVDKSRW



QQGNVFSCSVMHEALHNAYTQKSLSLSPGK



Ig gamma-1 constant
SEQ ID NO:
ASTKGPSVFFLAPSSKSTSGGTAALGCLVK

region L234A, L235A,
269
DYFPEPVTVSWNSGALTSGVHTFPAVLQSS

H435R

GLYSLSSVVTVPSSSLGTQTYICNVNHKPS



NTKVDKKVEPKSCDKTHTCPPCPAPEAAGG



PSVFLFPPKPKDTLMISRTPEVTCVVVDVS



HEDPEVKFNWYVDGVEVHNAKTKPREEQYN



STYRVVSVLTVLHQDWLNGKEYKCKVSNKA



LPAPIEKTISKAKGQPREPQVYTLPPSREE



MTKNQVSLTCLVKGFYPSDIAVEWESNGQP



ENNYKTTPPVLDSDGSFFLYSKLTVDKSRW



QQGNVFSCSVMHEALHNRYTQKSLSLSPGK



Ig gamma-1 constant
SEQ ID NO:
ASTKGPSVFFLAPSSKSTSGGTAALGCLVK

region C226A, C229A,
270
DYFPEPVTVSWNSGALTSGVHTFPAVLQSS

N297A, F405R (Half

GLYSLSSVVTVPSSSLGTQTYICNVNHKPS

body)

NTKVDKKVEPKSCDKTHTAPPAPAPELLGG



PSVFLFPPKPKDTLMISRTPEVTCVVVDVS



HEDPEVKFNWYVDGVEVHNAKTKPREEQYA



STYRVVSVLTVLHQDWLNGKEYKCKVSNKA



LPAPIEKTISKAKGQPREPQVYTLPPSREE



MTKNQVSLTCLVKGFYPSDIAVEWESNGQP



ENNYKTTPPVLDSDGSFRLYSKLTVDKSRW



QQGNVFSCSVMHEALHNHYTQKSLSLSPGK



Ig Kappa constant region
SEQ ID NO:
RTVAAPSVFIFPPSDEQLKSGTASVVCLLN


271
NFYPREAKVQWKVDNALQSGNSQESVTEQD



SKDSTYSLSSTLTLSKADYEKHKVYACEVT



HQGLSSPVTKSFNRGEC



Ig Lambda constant region
SEQ ID NO:
GQPKAAPSVTLFPPSSEELQANKATLVCLI


272
SDFYPGAVTVAWKADSSPVKAGVETTTPSK



QSNNKYAASSYLSLTPEQWKSHRSYSCQVT



HEGSTVEKTVAPTECS
































































































TABLE 4



Amino Acid Sequences of Heavy Chain Acceptor Frameworks






Protein region/


SEQ ID
Closest
Amino Acid Sequence

NO:
Germline Family
12345678901234567890123456789012



273
VH3-7 FR1
EVQLVESGGGLVQPGGSLRLSCAASGFTFS



274
VH3-7 FR2
WVRQAPGKGLEWVA



275
VH3-7 FR3
RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR



276
JH4 FR4
WGQGTLVTVSS



277
VH3 CONSENUSUS FR1
EVQLVESGGGLVQPGGSLRLSCAASGFTFS



278
VH3 CONSENUSUS FR2
WVRQAPGKGLEWVS



279
VH3 CONSENUSUS FR3
RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR



280
JH4 FR4
WGQGTLVTVSS



281
VH1-46 FR1
QVQLVQSGAEVKKPGASVKVSCKASGYTFT



282
VH1-46 FR2
WVRQAPGQGLEWMG



283
VH1-46 FR3
RVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR



284
JH4 FR4
WGQGTLVTVSS



285
VH3-30 FR1
QVQLVESGGGVVQPGRSLRLSCAASGFTFS



286
VH3-30 FR2
WVRQAPGKGLEWVA



287
VH3-30 FR3
RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR



288
JH3 FR4
WGQGTMVTVSS



289
VH3 CONSENUSUS FR1
EVQLVESGGGLVQPGGSLRLSCAASGFTFS



290
VH3 CONSENUSUS FR2
WVRQAPGKGLEWVS



291
VH3 CONSENUSUS FR3
RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR



292
JH3 FR4
WGQGTMVTVSS



293
VH2-70/JH6 FR1
EVTLRESGPALVKPTQTLTLTCTFSGFSLS



294
VH2-70/JH6 FR2
WIRQPPGKALEWLA



295
VH2-70/JH6 FR3
RLTISKDTSKNQVVLTMTNMDPVDTATYYCAR



296
VH2-70/JH6 FR4
WGQGTTVTVSS



297
VH2-26/JH6 FR1
EVTLKESGPVLVKPTETLTLTCTVSGFSLS



298
VH2-26/JH6 FR2
WIRQPPGKALEWLA



299
VH2-26/JH6 FR3
RLTISKDTSKSQVVLTMTNMDPVDTATYYCAR



300
VH2-26/JH6 FR4
WGQGTTVTVSS



301
VH3-72/JH6 FR1
EVQLVESGGGLVQPGGSLRLSCAASGFTFS



302
VH3-72/JH6 FR2
WVRQAPGKGLEWVG



303
VH3-72/JH6 FR3
RFTISRDDSKNSLYLQMNSLKTEDTAVYYCAR



304
VH3-72/JH6 FR4
WGQGTTVTVSS



305
VH3-21/JH6 FR1
EVQLVESGGGLVKPGGSLRLSCAASGFTFS



306
VH3-21/JH6 FR2
WVRQAPGKGLEWVS



307
VH3-21/JH6 FR3
RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR



308
VH3-21/JH6 FR4
WGQGTTVTVSS



309
VH1-69/JH6 FR1
EVQLVQSGAEVKKPGSSVKVSCKASGGTFS



310
VH1-69/JH6 FR2
WVRQAPGQGLEWMG



311
VH1-69/JH6 FR3
RVTITADKSTSTAYMELSSLRSEDTAVYYCAR



312
VH1-69/JH6 FR4
WGQGTTVTVSS



313
VH1-18/JH6 FR1
EVQLVQSGAEVKKPGASVKVSCKASGYTFT



314
VH1-18/JH6 FR2
WVRQAPGQGLEWMG



315
VH1-18/JH6 FR3
RVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR



316
VH1-18/JH6 FR4
WGQGTTVTVSS



317
IGHV4-59 FR1
EVQLQESGPGLVKPSETLSLTCTVSGGSIS



318
IGHV4-59 FR2
WIRQPPGKGLEWIG



319
IGHV4-59 FR3
RVTISVDTSKNQFSLKLSSVTAADTAVYYCAR



320
IGHV4-59/JH FR4
WGQGTLVTVSS



321
IGHV3-66 FW1
EVQLVESGGGLVQPGGSLRLSCAVSGGSIS



322
IGHV3-66 FW2
WIRQAPGKGLEWIG



323
IGHV3-66 FW3
RVTISVDTSKNSFYLQMNSLRAEDTAVYYCAR



324
IGHV3-66/JH FW4
WGQGTLVTVSS



325
IGHV4-59 FR1
EVQLQESGPGLVKPGETLSLTCTVSGGSIS



326
IGHV4-59 FR2
WIRQAPGKGLEWIG



327
IGHV4-59 FR3
RVTISVDTSKNQFYLKLSSVRAEDTAVYYCAR



328
IGHV4-59/JH FR4
WGQGTLVTVSS



329
IGHV5-51 FR1
EVQLVQSGTEVKKPGESLKISCKVSGGSIS



330
IGHV5-51 FR2
WIRQMPGKGLEWIG



331
IGHV5-51 FR3
QVTISVDTSFNTFFLQWSSLKASDTAMYYCAR



332
IGHV5-51/JH FR4
WGQGTMVTVSS



333
IGHV2-70 FR1
EVTLRESGPALVKPTQTLTLTCTVSGGSIS



334
IGHV2-70 FR2
WIRQPPGKGLEWIG



335
IGHV2-70 FR3
RVTISVDTSKNQFVLTMTNMDPVDTATYYCAR



336
IGHV2-70/JH FR4
WGQGTTVTVSS



337
IGHV3-15 FR1
EVQLLESGGGLVKSGGSLRLSCAASGFTFR



338
IGHV3-15 FR2
WVRQAPGKGLEWVA



339
IGHV3-15 FR3
RFTISRDNSKNTLYLQLNSLRAEDTAVYYCAK



340
IGHV3-15/JH FR4
WGQGTMVTVSS



341
IGHV3-43 FR1
EVQLVESGGGVVQPGGSLRLSCAASGFTFG



342
IGHV3-43 FR2
WVRQAPGKGLEWVA



343
IGHV3-43 FR3
RFTISRDNSKNTLYLQLNSLRAEDTAVYYCAK



344
IGHV3-43/JH FR4
WGQGTMVTVSS










































































































































































TABLE 5



Amino Acid Sequences

of Light Chain Acceptor Frameworks






Protein



region/

SEQ
Closest

ID
Germline
Sequence

NO:
Family
12345678901234567890123456789012



345
O2 FR1
DIQMTQSPSSLSASVGDRVTITC



346
O2 FR2
WYQQKPGKAPKLLIY



347
O2 FR3
GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC



348
JK2 FR4
FGQGTKLEIK



349
L2 FR1
EIVMTQSPATLSVSPGERATLSC



350
L2 FR2
WYQQKPGQAPRLLIY



351
L2 FR3
GIPARFSGSGSGTEFTLTISSLQSEDFAVYYC



352
JK2 FR4
FGQGTKLEIK



353
B3/JK4 FR1
DIVMTQSPDSLAVSLGERATINC



354
B3/JK4 FR2
WYQQKPGQPPKLLIY



355
B3/JK4 FR3
GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC



356
B3/JK4 FR4
FGGGTKVEIKR



357
L2/JK4 FR1
EIVMTQSPATLSVSPGERATLSC



358
L2/JK4 FR2
WYQQKPGQAPRLLIY



359
L2/JK4 FR3
GIPARFSGSGSGTEFTLTISSLQSEDFAVYYC



360
L2/JK4 FR4
FGGGTKVEIKR



361
L15/JK4 FR1
DIQMTQSPSSLSASVGDRVTITC



362
L15/JK4 FR2
WYQQKPEKAPKSLIY



363
L15/JK4 FR3
GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC



364
L15/JK4 FR4
FGGGTKVEIKR



365
L5/JK4 FR1
DIQMTQSPSSVSASVGDRVTITC



366
L5/JK4 FR2
WYQQKPGKAPKLLIY



367
L5/JK4 FR3
GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC



368
L5/JK4 FR4
FGGGTKVEIKR



369
IGLV3-1 FR1
SYELTQPPSVSVSPGQTASITC



370
IGLV3-1 FR2
WYQQKPGQSPVLVIY



371
IGLV3-1 FR3
GIPERFSGSNSGDTATLTISGTQPMDEADYYC



372
IGLV3-1/JL FR4
FGYGTKVTVL



373
IGLV3-1 FR1
SYELTQPPSVSVSPGQTASITC



374
IGLV3-1 FR2
WYQQKPGQSPVLVIY



375
IGLV3-1 FR3
GIPERFSGSNSGDTATLTISGTQPMDEADYYC



376
IGLV3-1/JL FR4
GGGTKLTVLG



377
IGLV3-1 FR1
YELTQPPSVSVSPGQTASITC



378
IGLV3-1 FR2
WYQQKPGQSPVLVIY



379
IGLV3-1 FR3
GIPERFSGSNSGDTATLTISGTQPMDEADYYC



380
IGLV3-1/JL FR4
GGGTKLTVLG



381
IGLV3-1 FR1
LYVLTQPPSVSVSPGQTASITC



382
IGLV3-1 FR2
WYQQKPGQSPVLVIY



383
IGLV3-1 FR3
GIPERFSGSNSGDTATLTISGTQTMDEADYLC



384
IGLV3-1/JL FR4
FGGGTKVTVLG



385
IGKV6D-21 FR1
EYVLTQSPDFQSVTPKEKVTITC



386
IGKV6D-21 FR2
WYQQKPDQSPKLVIY



387
IGKV6D-21 FR3
GVPSRFSGSNSGDDATLTINSLEAEDAATYYC



388
IGKV6D-21/JK
FGQGTKVEIKR


FR4



389
IGKV3D-15 FR1
EYVLTQSPATLSVSPGERATLSC



390
IGKV3D-15 FR2
WYQQKPGQSPRLVIY



391
IGKV3D-15 FR3
DIPARFSGSNSGDEATLTISSLQSEDFAVYYC



392
IGKV3D-15/JK
FGQGTRLEIKR


FR4



393
IGKV4-1 FR1
DYVLTQSPDSLAVSLGERATINC



394
IGKV4-1 FR2
WYQQKPGQSPKLVIY



395
IGKV4-1 FR3
GIPDRFSGSNSGDDATLTISSLQAEDVAVYYC



396
IGKV4-1/JK FR4
FGGGTKVEIKR



397
IGLV3-1 FR1
LPVLTQPPSVSVSPGQTASITC



398
IGLV3-1 FR2
WYQQKPGQSPVLVIY



399
IGLV3-1 FR3
GIPERFSGSNSGNTATLTISGTQTMDEADYLC



400
IGLV3-1/JL FR4
FGGGTKVTVL



401
IGLV3-1 FR1
SYELTQPPSVSVSPGQTASITC



402
IGLV3-1 FR2
WYQQKPGQSPVLVIY



403
IGLV3-1 FR3
GIPERFSGSNSGNTATLTISGTQTMDEADYLC



404
IGLV3-1/JL FR4
FGGGTKLTVL























































































































































TABLE A



Select Heavy Chain and Light Chain Variable Domain Sequences

(CDRs in bold)





SEQ

Sequence

ID NO
VD name
12345678901234567890123456789012







1
hBDI-9E8.4 VH
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGKALEW


(PDGF)
LA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPVDTATYYCA



R IESIGTTYSFDY WGQGTMVTVSS



2
hBDI-9E8.4 VL
EFVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQAPRLV


(PDGF)
IY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QSYDINID



IV FGGGTKVEIK



3
hBDI-5H1.9
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTFGMGVG WIRQPPGKALEW


VH (PDGF)
LA NIWWDDDKYYNPSLKN RLTISKDTSKNQAVLTITNMDPVDTATYYCA



R ISTGISSYYVMDA WGQGTTVTVSS



4
hBDI-5H1.9 VL
DFVLTQSPDSLAVSLGERATINC ERSSGDIGDTYVS WYQQKPGQPPKNV


(PDGF)
IY GNDQRPS GVPDRFSGSGSGNSATLTISSLQAEDVAVYFC QSYDSDID



IV FGGGTKVEIK



5
hBDI-9E8.12
EVQLVESGGGLVQPGGSLRLSCAFS GFSLSTYGMGVG WIRQAPGKGLEW


VH (PDGF)
LA NIWWDDDKYYNPSLKN RLTISKDTSKNQAYLQINSLRAEDTAVYYCA



R IESIGTTYSFDY WGQGTLVTVSS



6
hBDI-9E8.12
DFQLTQSPSSLSASVGDRVTITC ERSSGDIGDSYVS WYQQKPGKAPKNV


VL (PDGF)
IY ADDQRPS GVPSRFSGSGSGNSASLTISSLQPEDFATYYC QSYDINID



IV FGQGTKVEIK



7
hBDI-9E8.9 VH
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGKALEW


(PDGF)
LA NIWWDDDKYYNPSLKN RLTISKDTSKNQAVLTITNMDPVDTATYYCA



R IESIGTTYSFDY WGQGTTVTVSS



8
hBDI-9E8.9 VL
DFVLTQSPDSLAVSLGERATINC ERSSGDIGDSYVS WYQQKPGQPPKNV


(PDGF)
IY ADDQRPS GVPDRFSGSGSGNSASLTISSLQAEDVAVYFC QSYDINID



IV FGGGTKVEIK



9
hBDI-9E8.12
EVQLVESGGGLVQPGGSLRLSCAFS GFSLSTYGMGVG WIRQAPGKGLEW


VH (PDGF)
LA NIWWDDDKYYNPSLKN RLTISKDTSKNQAYLQINSLRAEDTAVYYCA



R IESIGTTYSFDY WGQGTLVTVSS



10
hBDI-9E8.12
DFQLTQSPSSLSASVGDRVTITC ERSSGDIGDSYVS WYQQKPGKAPKNV


VL (PDGF)
IY ADDQRPS GVPSRFSGSGSGNSASLTISSLQPEDFATYYC QSYDINID



IV FGQGTKVEIK



11
hBDI-9E8.4E
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGKALEW


VH (PDGF)
LA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPVDTATYYCA



R IESIGTTYSFDY WGQGTMVTVSS



12
hBDI-9E8.4E
EFVLTQSPGTLSLSPGERATLSC ERSSGDIGESYVS WYQQKPGQAPRLV


VL (PDGF)
IY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QSYDINID



IV FGGGTKVEIK



13
hBFU-3E2.1
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFTESYMY WVKQAPGQGLELIG


VH (PDGF)
RIDPEDGSTDYVEKFKN KATLTADKSTSTAYMELSSLRSEDTAVYFCAR



FGARSYFYPMDA WGQGTTVTVSS



14
hBFU-3E2.1 VL
ETVLTQSPATLSLSPGERATLSC RASESVSTLMH WYQQKPGQQPRLLIY


(PDGF)
GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVYFC QQSWNDPWTF



GGGTKVEIK



15
CL-33675 VH
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGKALEW


(PDGF)
LA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPVDTATYYCA



R IESSGPKYSFDY WGQGTMVTVSS



16
CL-33675 VL
EIVLTQSPGTLSLSPGERATLSC RASSGSIWYSFVS WYQQKPGQAPRLL


(PDGF)
IY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QSYGINID



VV FGGGTKVEIK



17
hBDB-4G8.3
EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGLEWMG


VH (VEGF)
WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAEDTAVYYCAR



TNYYYRSYIFYFDY WGQGTMVTVSS



18
hBDB-4G8.3
DTVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQAPRLLIY


VL (VEGF)
GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVYFC QQSWNDPFT F



GQGTKLEIK



19
hBDB-4G8.13
EIQLVQSGTEVKKPGESLKISCKAS GYTFTNYGMY WVKQMPGKGLEYMG


VH (VEGF)
WINTETGKPTYADDFKG RFTFSLDKSFNTAFLQWSSLKASDTAMYFCAR



TNYYYRSYIFYFDY WGQGTMVTVSS



20
hBDB-4G8.13
ETVLTQSPATLSVSPGERATLSC RASESVSTHMH WYQQKPGQAPRLLIY


VL (VEGF)
GASNLES GVPARFSGSGSGTDFTLTISSLQSEDFAVYFC QQSWNDPFT F



GQGTRLEIK



21
hBDB-4G8.14
EIQLVQSGGGVVQPGGSLRLSCAAS GYTFTNYGMY WVKQAPGKGLEYMG


VH (VEGF)
WINTETGKPTYADDFKG RFTFSLDTSKSTAYLQLNSLRAEDTAVYFCAR



TNYYYRSYIFYFDY WGQGTLVTVSS



22
hBDB-4G8.14
DTVLTQSPSTLSASPGERATISC RASESVSTHMH WYQQKPGQAPKLLIY


VL (VEGF)
GASNLES GVPSRFSGSRSGTDFTLTISSLQPEDFAVYFC QQSWNDPFT F



GQGTKVEIK



23
hBDB-4G8.15
EVQLVESGGGLVQPGGSLRLSCAAS GYTFTNYGMY WVKQAPGKGLEYMG


VH (VEGF)
WINTETGKPTYADDFKG RFTFSLDTSKSTAYLQMNSLRAEDTAVYFCAR



TNYYYRSYIFYFDY WGQGTLVTVSS



24
hBDB-4G8.15
DTQLTQSPSSLSASVGDRVTISC RASESVSTHMH WYQQKPGKAPKLLIY


VL (VEGF)
GASNLES GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC QQSWNDPFT F



GQGTKVEIK



25
hBEW-9A8.12
EVQLVQSGAEVKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGLEWMG


VH (VEGF)
WINTETGKPIYADDFKG RVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR



VDYDGSFWFAY WGQGTLVTVSS



26
hBEW-9A8.12
DTQLTQSPSSLSASVGDRVTITC RASESVSTVIH WYQQKPGKQPKLLIH


VL (VEGF)
GASNLES GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC QQHWNDPPT F



GQGTKLEIK



27
hBDB-4G8.2
EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGLEWMG


VH (VEGF)
WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAEDTAVYYCAR



TNYYYRSYIFYFDY WGQGTMVTVSS



28
hBDB-4G8.2
ATQLTQSPSLSASVGDRVTITC RASESVSTHMH WYQQKPGKQPKLLIYG


VL (VEGF)
ASNLES GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC QQSWNDPFT FG



QGTKLEIK



29
hBDB-4G8.4
EIQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGLEYMG


VH (VEGF)
WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAEDTAVYFCAR



TNYYYRSYIFYFDY WGQGTMVTVSS



30
hBDB-4G8.4
AIQLTQSPSSLSASVGDRVTITC RASESVSTHMH WYQQKPGKAPKLLIY


VL (VEGF)
GASNLES GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSWNDPFT F



GQGTKLEIK



31
hBDB-4G8.5
EIQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGLEYMG


VH (VEGF)
WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAEDTAVYFCAR



TNYYYRSYIFYFDY WGQGTMVTVSS



32
hBDB-4G8.5
ATQLTQSPSLSASVGDRVTITC RASESVSTHMH WYQQKPGKQPKLLIYG


VL (VEGF)
ASNLES GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC QQSWNDPFT FG



QGTKLEIK



33
hBDB-4G8.12
EIQLVQSGAEVKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGLEYMG


VH (VEGF)
WINTETGKPTYADDFKG RFTFTLDTSTSTAYMELRSLRSDDTAVYFCAR



TNYYYRSYIFYFDY WGQGTMVTVSS



34
hBDB-4G8.12
DTVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQAPRLLIY


VL (VEGF)
GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVYFC QQSWNDPFT F



GQGTKLEIK



35
hBEW-9E10.1
EIQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVKQAPGQGLEYMG


VH (VEGF)
WIDTETGRPTYADDFKG RFVFSLDTSVSTAYLQISSLKAEDTAVYFCAR



WSGDTTGIRGPWFAY WGQGTLVTVSS



36
hBEW-9E10.1
DIRMTQSPSSLSASVGDRVTIEC LASEDIYSDLA WYQQKPGKSPKLLIY


VL (VEGF)
NANGLQN GVPSRFSGSGSGTDYSLTISSLQPEDVATYFC QQYNYFPGT F



GQGTKLEIK



37
hBEW-9E10.6
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFTNYGMY WVRQAPGQGLEWMG


VH (VEGF)
WIDTETGRPTYADDFKG RFTFTADKSTSTAYMELSSLRSEDTAVYYCAR



WSGDTTGIRGPWFAY WGQGTLVTVSS



38
hBEW-9E10.6
DIRMTQSPSSLSASVGDRVTITC LASEDIYSDLA WYQQKPGKSPKLLIY


VL (VEGF)
NANGLQN GVPSRFSGSGSGTDYTLTISSLQPEDVATYFC QQYNYFPGT F



GQGTKLEIK



39
hBEW-1B10.1
EVQLVESGGGLVQPGGSLRLSCAAS GFSFSKYDMA WFRQAPGKGLEWVA


VH (VEGF)
SITTSGVGTYYRDSVKG RFTVSRDNAKSTLYLQMNSLRAEDTAVYYCAR



GYGAMDA WGQGTTVTVSS



40
hBEW-1B10.1
DIQMTQSPSSLSASVGDRVTITC KASQDIDDYLS WYQQKPGKSPKLVIY


VL (VEGF)
AATRLAD GVPSRFSGSGSGTDYTLTISSLQPEDFATYYC LQSSSTPWT F



GGGTKVEIK



41
hBEW-1E3.4
EIQLVQSGSELKKPGASVKVSCKAS GYPFTNSGMY WVKQAPGQGLEYMG


VH (VEGF)
WINTEAGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAEDTAVYFCAR



WGYISDNSYGWFDY WGQGTLVTVSS



42
hBEW-1E3.4
ATQLTQSPSSLSASVGDRVTISC RASEGVYSYMH WYQQKPGKQPKLLIY


VL (VEGF)
KASNLAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC HQNWNDPLT F



GQGTKLEIK



43
CL-34565 VH
EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGLEWMG


(VEGF)
WIDTETGDPTYADDFKGR FVFSLDTSVSTAYLQISSLKAEDTAVYYCAR



TNYYYRNYMFYFDY WGQGTMVTVSS



44
CL-34565 VL
EIVLTQSPATLSLSPGERATLFC RASQSVSNHMH WYQQKPGQAPRLLIY


(VEGF)
GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVYYC QQSWYDPIT F



GQGTKLEIK



211
hBDI-5H1.12
EVQLVESGGGLVQPGGSLRLSCAFS GFSLSTFGMGVG WIRQAPGKGLEW


VH (PDGF)
LA NIWWDDDKYYNPSLKN RLTISKDTSKNQAYLQINSLRAEDTAVYYCA



R ISTGISSYYVMDA WGQGTLVTVSS



212
hBDI-5H1.12
DFQLTQSPSSLSASVGDRVTITC ERSSGDIGDTYVS WYQQKPGKAPKNV


VL (PDGF)
IY GNDQRPS GVPSRFSGSGSGNSATLTISSLQPEDFATYFC QSYDSDID



IV FGQGTKVEIK
















































































































































































































It will be readily apparent to those skilled in the art that other suitable modifications and adaptations of the methods described herein are obvious and may be made using suitable equivalents without departing from the scope of the embodiments disclosed herein. Having now described certain embodiments in detail, the same will be more clearly understood by reference to the following examples, which are included for purposes of illustration only and are not intended to be limiting.
EXAMPLES
Example 1
In Vitro Assays Used to Determine the Functional Activity of Anti-VEGF-A Antibodies, Anti-PDGF-BB Antibodies, Anti-VEGFR Antibodies, Anti-PDGFR-B Antibodies, and DVD-Ig Proteins
Example 1.1
Affinity Determination Using BIACORE® Surface Plasmon Resonance Technology for Antigen Binding
The BIACORE® surface plasmon resonance assay (Biacore, Inc., Piscataway, N.J.) determines the affinity of antibodies with kinetic measurements of on-rate and off-rate constants. Binding of anti-VEGF-A antibodies, anti-PDGF-BB antibodies, anti-VEGFR antibodies, anti-PDGFR-B antibodies, or anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules, to a purified recombinant VEGF-A, PDGF-BB, VEGFR extracellular domain (ECD), PDGFR-B ECD or their Fc fusion proteins was determined by surface plasmon resonance-based measurements with a Biacore® instrument (either a Biacore 2000, Biacore 3000, or Biacore T100; GE Healthcare, Piscataway, N.J.) using running buffer HBS-EPB (10 mM HEPES [pH 7.4], 150 mM NaCl, 3 mM EDTA, 0.1 mg/ml BSA and 0.005% surfactant P20) at 25° C. For example, approximately 9000 RU of goat anti-human Fc specific polyclonal antibody (Thermo Fisher Scientific Inc., Rockford, Ill.) diluted in 10 mM sodium acetate (pH 4.5) is directly immobilized across a CM5 research grade biosensor chip using a standard amine coupling kit according to manufacturer's instructions and procedures at 25 μg/ml. Unreacted moieties on the biosensor surface were blocked with ethanolamine. For kinetic analysis, rate equations derived from the 1:1 Langmuir binding model were fitted simultaneously to multiple antigen injections (using global fit analysis) with the use of Scrubber 2 (BioLogic Software), Biacore Biaevaluation 4.0.1 software or Biacore T100 Evaluation software. Purified antibodies or DVD-Ig molecules were diluted in running buffer for capture across goat anti-human Fc reaction surfaces. Antibodies or DVD-Ig molecules to be captured as a ligand (1 μg/ml) were injected over reaction matrices at a flow rate of 10 μl/minute. During the assay, all measurements were referenced against the capture surface alone (i.e., with no captured antibody or DVD-Ig molecule). The association and dissociation rate constants, K on (M −1 s −1 ) and K off (s −1 ) were determined under a continuous flow rate of 80 μl/minute. Rate constants were derived by making kinetic binding measurements at different antigen concentrations ranging from 1.23-900 nM, as a 3-fold dilution series, and included buffer-only injections (to be used for double referencing). The equilibrium dissociation constant K D (M) of the reaction between antibodies and the target antigen was then calculated from the kinetic rate constants by the following formula: K D =K off /K on . Binding was recorded as a function of time and kinetic rate constants were calculated. In this assay, on-rates as fast as 10 6 M −1 s −1 and off-rates as slow as 10 −6 s −1 could be measured.
In some experiments, the conditions below were used for affinity determination:
Chip surface: CM5 chip with goat anti human Fc IgG (5000 RU).
Reference: Goat IgG (capture 5000 RU).
Running buffer: HBS-EP, 0.1 mg/ml BSA
DVD-Ig or mAbs were captured at 1 μg/ml, at 70-200 RU.
Recombinant ECD proteins were serially diluted 1:5 at 0.016-50 nM.
Association time was 5 min and dissociation time was observed for 10 and 30 min.
Flow rate was 50 ul/min.
Surface regeneration: two 30s pulses of 10 mM Glycine, pH 1.5, at 50 μl/min.
Example 1.2
Surface Resonance FcγRIIa, FcγRIIb, FcγRIIIa, and FcRn Binding Assay
The binding of VEGF/PDGF DVD-Ig molecules to recombinant FcγRs captured via 6×His-tag (SEQ ID NO: 405) was assessed using a Biacore T200 (GE Healthcare) instrument. A CM5 chip (GE Healthcare, Pittsburgh, Pa.) with mouse anti-6×His antibodies (“6×His” disclosed as SEQ ID NO: 405) that were directly immobilized on the chip via amine coupling according to the GE Healthcare protocol to the density of 10000RU (all flow cells) was used for experiments. Human FcγRs were captured on flow cells 2, 3 and 4. Flow cell 1 was used as a reference surface. HBS-EP+ was used as the running buffer. Anti VEGF/PDGF DVD-Igs were injected over all the flow cells at a flow rate of 50 μL/minute for 1-2 minutes at concentrations of 31.25; 62.5, 125, 250, 500, 1000, 2000 and 4000 nM, followed by 1-3 minutes of dissociation. The chip surfaces were regenerated with an injection of 10 mM glycine pH 1.5 at a flow rate of 100 μL/minute over all four flow cells after each cycle.
For FcRn binding analysis, VEGF/PDGF DVD-Igs were directly immobilized on a CM5 chip by amine coupling according to the manufacturer's (GE Healthcare) protocol to a density of approximately 750 RU. Flow cell 1, where blank immobilization was performed, did not contain DVD-Igs and was used as a reference surface. Human, cynomolgus, mouse, rat and rabbit recombinant FcRns were injected over all the flow cells at a flow rate of 50 μL/minute for 1 minute at a concentrations range of from 2.7 to 6000 nM (three fold serial dilution), followed by a 2 minute dissociation time. The surfaces were regenerated with an injection of 10 mM HCl at 100 μL/minute for 2 seconds followed by an injection of HBS-EP+, pH 7.4, at a flow rate of 50 μL/minute for 30 seconds over all four flow cells. Samples were prepared and run in two running buffer systems, pH 6.0 MES-EP+, and pH 7.4 HBS-EP-EP+. Recombinant human FcγRIIIa V158 and rat and mouse FcRn data were fitted to 1:1 kinetic model. Recombinant human FcγRIIa R131 and FcγRIIa H131, FcγRIIIa F158, and recombinant human, cynomolgus and rabbit FcRn binding data were fitted to a steady state affinity model. Biacore T200 Evaluation Software version 2.0 was used to fit all the data.
Example 1.3
VEGF-A Binding Activity Determined by Capture ELISA
To identify molecules that could bind hVEGF 165 , a direct binding ELISA was performed. 96-well high binding neutravidin plates (Thermo Scientific cat#15507) were coated with 0.25 μg/mL/6.51E-9 M biotinylated recombinant human VEGF 165 (AP PR-1361002, 50 μL/well in D-PBS), and shaken for 1.5 hours at 25° C. During the coating step, supernatant, antibodies, benchmark compounds or DVD-Ig were diluted in 10% Superblock (Thermo Scientific, cat#37535) and an eight point titration of each sample molecule was performed. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20). The sample molecule titration was added to the coated plate at 50 μL in duplicate and incubated for one hour at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. The appropriate anti-species-IgG HRP conjugate was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates (50 μL) for forty-five minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, Lexington, Ky. cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, Radnor, Pa. cat#BDH3500-1) and the absorbance was read at 450 nm-570 nm. An increase in optical density indicates the binding of the test molecule to biotinylated recombinant human VEGF 165 . Data was analyzed using Softmax Pro 4.8 software and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.4
VEGF-A Blocking Activity Determined by Inhibition of VEGF-R2 Interaction with Human VEGF 165
To identify molecules that could block the binding of hVEGF 165 to the hVEGF-R2 (KDR/Flk-1) receptor, a competition ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 0.5 μg/mL/2.27E-9 M recombinant human VEGF-R2-Fc (R&D Systems cat#357-KD), 50 μL/well in D-PBS), shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, supernatant, antibodies, benchmark compounds or DVD-Ig were diluted in 1% Blocker BSA (Thermo Scientific cat#37525) and an eight point titration of each sample molecule was performed. The biotinylated human VEGF 165 (AP, PR-1361002) was diluted in 1% Blocker BSA at 35 ng/mL. The sample molecule titration was added to the biotinylated human VEGF 165 (17.5 ng/mL/4.56E-10 M final concentration) and pre-incubated for 45 minutes at 25° C. with shaking. The pre-incubated sample/hVEGF 165 complex was added to the coated plate at 50 μL in duplicate and incubated for 30 minutes at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Streptavidin-polyHRP-40 (Fitzgerald cal#65r-s104phrp) was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates (50 μL) for 45 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. A decrease in observed optical density indicates the test molecule is blocking the hVEGF 165 binding to the hVEGF-R2-Fc. Data was analyzed using Softmax Pro 4.8 software and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.5
Mouse VEGF-A Blocking Activity Determined by Inhibition of Mouse VEGF-R2 Interaction with Mouse VEGF 164
To identify molecules that could block the binding of mVEGF 164 to the mVEGF-R2, a competition ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 2 μg/mL anti-human IgG-Fc (Thermo-Scientific, cat 31125) shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were washed four times with wash buffer (TBS, 0.05% Tween-20) and 1 μg/mL/4.55E-9 M recombinant mouse VEGF-R2-Fc (R&D Systems cat#443-KD)(50 μL/well in D-PBS) was added to wells and incubated for 1.5 hour at 25° C. with shaking. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, hybridoma supernatants were diluted in 1% Blocker BSA (Thermo Scientific cat#37525). The mouse VEGF 164 (R&D Systems cat#493-MV-005) was diluted in 1% Blocker BSA to 20 ng/mL. The diluted sample was added to the mouse VEGF 164 (10 ng/mL/5.15E-10 M final concentration) and pre-incubated for 45 minutes at 25° C. with shaking. The pre-incubated sample/mVEGF 164 complex was added to the coated plate at 50 μL and incubated for 30 minutes at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. The detection reagent biotinylated goat anti-mVEGF 164 (R&D Systems cat#BAF-493) was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates for 1 hour at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Streptavidin-polyHRP-40 (Fitzgerald cat#65r-s104phrp) was diluted in assay diluent and added to plates (50 μK) for 45 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. A decrease in observed optical density indicates the test molecule is blocking the mVEGF 164 binding to the mouse VEGF-R2-Fc. Data was analyzed using Softmax Pro 4.8 software and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.6
VEGF-A Blocking Activity Determined by VEGFR2 (Tyr1054) Phosphorylation
To test candidate molecules for the ability to neutralize hVEGF-A activity, a cell based human VEGF-R2 (KDR/Flk-1) phosphorylation assay was performed. Stably transfected VEGFR2-3T3 cells (AP) were trypsinized, washed in D-PBS and resuspended at 3.5E5 cells/mL in growth media assay (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate, 400 μg/mL geneticin and 10% FBS). Cells were plated at 3.5E4 cells/well in 96-well plates (Costar cat#3599) and incubated for 6 hours at 37° C., 5% CO 2 . Growth media was removed and cells were washed with D-PBS. Starvation media was added to wells (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin and 1 mM sodium pyruvate) and cells were incubated for 18 hours at 37° C., 5% CO 2 . The following day, the MSD anti-VEGFR2-phospho assay plate (Mesoscale VEGFR2-Tyr1054 phospho-MSD kit cat# K151DJD-2) was blocked with MSD Blocker-A for 1 hour at 25° C. with shaking. During blocking, anti-VEGF-A monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in growth media and pre-incubated with recombinant human VEGF 165 (AP, PR-1350437) (50 ng/ml/1.3E-9 M final concentration), hVEGF 111 (R&DSystems, cat#5336-VE-10/CF) (50 ng/mL/1.9E-9 M final concentration) or rabbit VEGF 165 (AbbVie, PR-1563693.0) (50 ng/mL/1.24E-9 M final concentration) for 30 minutes at 25° C. with shaking. Starvation media was removed from wells and pre-incubated sample added to cells in duplicate (100 μL) for 8 minutes at 37° C., 5% CO 2 Immediately following incubation, plates were transferred to ice where media was removed and cells washed with ice-cold D-PBS. Plates were frozen for 10 minutes at −80° C. Ice-cold lysis buffer (CST cat#9803S) containing 1 mM PMSF was added to cells (50 μL) on ice. Plates were centrifuged at 3000 rpm for 15 minutes at 4° C. The MSD plate was washed four times with wash buffer (TBS, 0.05% Tween-20). The cell lysates were transferred to MSD plate (40 μL) and incubated for 1 hour at 25° C. with shaking. Following incubation, the MSD plate was washed four times with wash buffer. The anti-phospho-Tyr1054-IgG-sulfotag reagent was diluted in detection solution (K151DJD-2 components) and 25 μL added to foil covered wells for 1 hour at 25° C. with shaking. Plates were washed four times with wash buffer, 150 μL MSD read buffer (K151DJD-2 component) added to wells and plates read on MSD Sector Imager 6000. A decrease in observed signal indicates the test molecule is neutralizing the hVEGF-A mediated activation. Data was analyzed using Graphpad Prism software and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.7
VEGF-A Blocking Activity Determined by Inhibition of Human VEGF 165 Stimulated VEGFR2-3T3 Cell Proliferation/Survival
To screen candidate molecules for the ability to neutralize hVEGF 165 activity, a cell based proliferation assay was performed. Stably transfected VEGFR2-3T3 cells (AP) were trypsinized, washed in D-PBS and resuspended at 8.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 4,250 cells/well (50 μL) on black 96-well plates and incubated for 24 hours at 37° C., 5% CO 2 . The following day, anti-VEGF-A monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant human VEGF 165 (AP, PR-1350437) (40 ng/ml/1.04E-9 M final concentration in assay well) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% C0 2 for 72 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using an ATPlite kit (Perkin Elmer, Waltham, Mass.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the hVEGF 165 induced proliferation. Data was analyzed and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.8
VEGF-A Blocking Activity Determined by Inhibition of HumanVEGF 111 and HumanVEGF 121 Stimulated VEGFR2-3T3 Cell Proliferation/Survival
To test the ability of candidate molecules to neutralize hVEGF 111 and hVEGF 121 activity, a cell based proliferation assay was performed. Stably transfected VEGFR2-3T3 cells (AP) were trypsinized, washed in D-PBS and resuspended at 8.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 4,250 cells/well (50 μL) on black 96-well plates and incubated for 24 hours at 37° C., 5% CO 2 . The following day, anti-VEGF-A monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with either recombinant human VEGF 111 (R&D Systems, cat#5336-VE) (10 ng/ml/3.85E-10 M final concentration) or human VEGF 121 (R&D Systems, cat#4644-VS) (10 ng/ml/3.57E-10 M final concentration in assay well) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO 2 for 72 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using an ATPlite kit (Perkin Elmer, Waltham, Mass.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the hVEGF 111 or hVEGF 121 induced proliferation. Data was analyzed and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.9
VEGF-A Blocking Activity Determined by Inhibition of Rabbit VEGF 165 Stimulated VEGFR2-3T3 Cell Proliferation/Survival
To screen candidates for the ability to neutralize rabbitVEGF 165 , a cell based proliferation assay was performed. Stably transfected VEGFR2-3T3 cells (AP) were trypsinized, washed in D-PBS and resuspended at 8.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 4,250 cells/well (50 μL) on black 96-well plates and incubated for 24 hours at 37° C., 5% CO 2 . The following day, anti-VEGF-A monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant rabbit VEGF 165 (AbbVie, PR-1563693.0) (40 ng/ml/9.92E-10M final concentration in assay well) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO 2 for 72 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using an ATPlite kit (Perkin Elmer, Waltham, Mass.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the rabbitVEGF 165 induced proliferation. Data was analyzed and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.10
VEGF-A Blocking Activity Determined by Inhibition of Human VEGF 165 Stimulated Endothelial Cell Proliferation/Survival
To test for the ability to neutralize hVEGF 165 , a cell based proliferation assay was performed. Human microvascular endothelial cells (Lonza, cat#CC-2516) were maintained in EBM-2 (Lonza cat#CC3156) supplemented with EGM-2V singlequots (Lonza cat#3202). The day of the assay, the cells (passage 2-7) were trypsinized, washed in D-PBS and resuspended at 1E5 cells/mL in assay media (M199, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 10 mM HEPES and 10% FBS). Cells were plated at 5,000 cells/well (50 μL) on 96-well gelatin coated plates (BD Biocoat cat#354689) and incubated at 37° C., 5% CO 2 . The anti-VEGF-A monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant human VEGF 165 (AP, PR-1350437) (5 ng/ml/1.3E-10 M final concentration in assay well) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO 2 for 72 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, Wis.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the hVEGF 165 induced proliferation. Data was analyzed and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.11
Generation of Naturally Derived Human VEGF-A and Reactivity to the Anti-VEGF Antibodies or Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Proteins
To identify molecules that could bind naturally derived human VEGF-A, a sandwich ELISA was performed. Native human VEGF-A was obtained from the supernatant of Y-79 cells (ATCC, cat#HTB-18) grown in the presence of dimethyloxalylglycine (Sigma-Aldrich, cat#D3695). The naturally derived material was quantified using the R&D Systems VEGF Duoset kit (cat#DY293B). 96-well Costar high binding plates (#3369) were coated with 13.3E-8 M antibodies, benchmark compounds or DVD-Ig in D-PBS, shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were blocked with Superblock blocking buffer (Thermo Scientific, cat#37535) followed by four washes with wash buffer (TBS, 0.05% Tween-20). The naturally derived human VEGF-A supernatant was serially diluted in assay diluent (1% Blocker BSA; Pierce, cat#37525) for final test concentrations of 2900 ng/mL-11.88 ng/mL. The dilutions were added to the plates (50 μL) and incubated for 2 hours at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Detection antibody from the R&D Systems Duoset kit (Part 840163, cat#DY293B) was diluted in assay diluent and added to plates (50 μL) for 2 hours at 25° C. with shaking. Plates were then washed four times with wash buffer. The streptavidin-HRP from the R&D Systems Duoset kit (Part 890803, cat#DY293B) was diluted in assay diluent and added to plates (50 μL) for 35 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. An increase in optical density indicates binding of the test molecule to the naturally derived human VEGF-A. Data was analyzed using Softmax Pro 4.8 software and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.12
PDGF-BB Binding Activity Determined by Capture ELISA
To identify molecules that could bind hPDGF-BB, a direct binding ELISA was performed. 96-well high binding neutravidin plates (Thermo Scientific cat#15507) were coated with 0.5 μg/mL/1.99E-8 M recombinant human PDGF-BB-biotin (CST cat#8912BF; labeled at AbbVie, 50 μL/well in D-PBS), shaken for 2 hours at 25° C. During the coating step, supernatants, benchmark compounds or DVD-Ig were diluted in 10% Superblock (Thermo Scientific, cat#37525) and an eight point titration of each sample molecule was performed. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20). The sample molecule titration was added to the coated plate at 50 μL in duplicate and incubated for one hour at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. The appropriate anti-species-IgG HRP conjugate was in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates (50 μL) for one hour at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. An increase in optical density indicates binding of the test molecule to biotinylated recombinant human PDGF-BB. Data was analyzed using Softmax Pro 4.8 software and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.13
PDGF-BB Blocking Activity Determined by Inhibition of PDGF-Rβ Interaction with Human PDGF-BB
To identify molecules that could block the binding of hPDGF-BB to the hPDGF-Rβ, a competition ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 0.5 μg/mL/2.98E-9 M recombinant human PDGF-Rβ-Fc (R&D Systems #385-PR, 50 μL/well in D-PBS), shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, supernatants, antibodies, benchmark compounds or DVD-Ig were diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and an eight point titration of each sample molecule was performed. The recombinant human PDGF-BB-biotin (CST cat#8912BF; labeled at AbbVie) was diluted in assay diluent at 20 ng/mL. The sample molecule titration was added to the human PDGF-BB-biotin (10 ng/mL/3.97E-10 M final concentration) and pre-incubated for 45 minutes at 25° C. with shaking. The pre-incubated sample/PDGF-BB complex was added to the coated plate at 50 μL in duplicate and incubated for 35 minutes at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Detection reagent Streptavidin-polyHRP-40 (Fitzgerald, cat#65r-s104phrp) was diluted in assay diluent and added to plates (50 μL) for 45 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. A decrease in observed optical density indicates the test molecule is blocking the hPDGF-BB binding to the human PDGF-Rβ-Fc. Data was analyzed using Softmax Pro 4.8 software and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.14
PDGF-BB Blocking Activity Determined by PDGFRβ (Tyr751) Phosphorylation
To test candidate molecules for the ability to neutralize hPDGF-BB activity, a cell based PDGF-Rβ phosphorylation assay was performed. Balb-3T3 cells (ATCC cat# CCL-163) were trypsinized, washed in D-PBS and resuspended at 3.5E5 cells/mL in growth media assay (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate, and 10% FCS). Cells were plated at 3.5E4 cells/well in 96-well plates (Costar cat#3599) and incubated for 20 hours at 37° C., 5% CO 2 . Growth media was removed and cells were washed with D-PBS. Starvation media was added to wells (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin and 1 mM sodium pyruvate) and cells were incubated for 18 hours at 37° C., 5% CO 2 . The following day, the MSD anti-PDGF-Rβ phospho-assay plate (Mesoscale PDGF-Rβ-Tyr751 phospho-MSD kit cat# K150DVD-2) was blocked with MSD Blocker-A for 1 hour at 25° C. with shaking. During blocking, anti-PDGF-BB supernatants, monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in growth media and pre-incubated with recombinant human PDGF-BB (CST, cat#8912BF) (20 ng/ml/7.94E-10 M final concentration) and rat PDGF-BB (R&D Systems,cat#520-BB) (70 ng/ml/1.4E-9 M final concentration) for 30 minutes at 25° C. with shaking. Starvation media was removed from wells and pre-incubated sample added to cells in duplicate (100 μL) for 8 minutes at 37° C., 5% CO 2 . Immediately following incubation, plates were transferred to ice where media was removed and cells washed with ice-cold D-PBS. Plates were frozen for 10 minutes at −80° C. On ice, ice-cold lysis buffer (CST cat#9803S) containing 1 mM PMSF was added to cells (50 μL). Plates were centrifuged at 3000 rpm for 15 minutes at 4° C. The MSD plate was washed four times with wash buffer (TBS, 0.05% Tween-20). The cell lysates were transferred to MSD plate (40 μL) and incubated 1 hour at 25° C. with shaking. Following incubation, the MSD plate was washed four times with wash buffer. The anti-phospho-Tyr751-IgG-sulfotag reagent was diluted in detection solution (K150DVD-2 components) and 25 μl added to foil covered wells for 1 hour at 25° C. with shaking. Plates were washed four times with wash buffer, 150 μL MSD read buffer (K150DVD-2 component) added to wells and plates read on MSD Sector Imager 6000. A decrease in observed reporter signal indicates the test molecule is neutralizing the hPDGF-BB mediated activation. Data was analyzed using Graphpad Prism software and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.15
PDGF-BB Blocking Activity Determined by Inhibition of Human PDGF-BB Stimulated NIH-3T3 Cell Proliferation/Survival
To screen candidate molecules for the ability to neutralize hPDGF-BB activity, a cell based proliferation assay was performed. NIH-3T3 cells (ATCC, cat#CRL-1658) were trypsinized, washed in D-PBS and resuspended at 4.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 2,250 cells/well (50 μL) on black 96-well plates and incubated for 5 hours at 37° C., 5% CO 2 . During cell incubation, anti-PDGF-BB monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant human PDGF-BB (CST, cat#8912BF) (1.67 ng/ml/6.63E-11 M final concentration) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO 2 for 44 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, Wis.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the hPDGF-BB induced proliferation. Data was analyzed and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.16
PDGF-BB Blocking Activity Determined by Inhibition of Cynomolgus PDGF-BB Stimulated NIH-3T3 Cell Proliferation/Survival
To screen candidate molecules for the ability to neutralize cynomolgus PDGF-BB activity, a cell based proliferation assay was performed. NIH-3T3 cells (ATCC, cat#CRL-1658) were trypsinized, washed in D-PBS and resuspended at 4.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 2,250 cells/well (50 μL) on black 96-well plates and incubated for 5 hours at 37° C., 5% CO 2 . During cell incubation, anti-PDGF-BB monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant cynomolgus PDGF-BB (AP, PR-1575400) (4 ng/ml/1.61E-10 M final concentration in assay well) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO 2 for 44 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, Wis.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the cynoPDGF-BB induced proliferation. Data was analyzed and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.17
PDGF-BB Blocking Activity Determined by Inhibition of Murine PDGF-BB Stimulated NIH-3T3 Cell Proliferation/Survival
To test candidate molecules for the ability to neutralize mouse PDGF-BB activity, a cell based assay was performed. NIH-3T3 cells (ATCC, cat#CRL-1658) were trypsinized, washed in D-PBS and resuspended at 4.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 2,250 cells/well (50 μL) on black 96-well plates and incubated for 5 hours at 37° C., 5% CO 2 . During cell incubation, anti-PDGF-BB monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant murine PDGF-BB (Abnova, cat#0309-200-58-S) (2 ng/ml/8.13E-11 M final concentration) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% CO 2 for 44 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, Wis.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the murine PDGF-BB induced proliferation. Data was analyzed and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.18
PDGF-BB Blocking Activity Determined by Inhibition of Rat PDGF-BB Stimulated NIH-3T3 Cell Proliferation/Survival
To test candidate molecules for the ability to neutralize rat PDGF-BB activity, a cell based assay was performed. NIH-3T3 cells (ATCC, cat#CRL-1658) were trypsinized, washed in D-PBS and resuspended at 4.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 2,250 cells/well (50 μL) on black 96-well plates and incubated for 5 hours at 37° C., 5% CO 2 . During cell incubation, anti-PDGF-BB monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media and pre-incubated with recombinant rat PDGF-BB (R&D Systems,cat#520-BB) (2 ng/ml/8.0E-11 M final concentration) for 1 hour at 25° C. with gentle shaking. The pre-incubated samples were then added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% C0 2 for 44 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, Wis.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the rat PDGF-BB induced proliferation. Data was analyzed and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.19
Generation of Naturally Derived Human PDGF-BB and Reactivity to the Anti-PDGF-BB Antibodies or Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Proteins
The native form of human PDGF was purified from platelets by a modified protocol from Antoniades et al. (Antoniades et al. (1979) Proc. Natl. Acad. Sci. USA 76(4): 1809-1813. In the modified protocol, ten units of platelets (Bioreclamation Inc.) were thawed, washed with 12 ml of Platelet Wash Buffer (HBSS—Gibco #14175/0.3% BSA/10 mM EDTA) and centrifuged. The platelets were then suspended in 25 ml of Buffer A (20 mM NaHPO4, pH 7.4, 80 mM NaCl in a 50 ml tube). From here the platelet wash (50 ml tube) and the suspended platelets were worked up in parallel using the same protocol.
Both the suspended platelets and platelets wash tubes were placed into a boiling water bath for 10 minutes, after which the contents of the tubes were cooled on ice. The supernatant was separated from the pellet by centrifugation. The supernatant was placed aside at 4° C. and the pellet was extracted with 30 ml Buffer B (20 mM NaHPO4, pH 7.4, 1M NaCl) by stirring overnight at 4° C. The supernatant was separated from the pellet by centrifugation. The supernatant was placed aside (4° C.) and the pellet was extracted with 30 ml Buffer B by stirring overnight at 4° C. This was repeated two more times. All the supernatants were then dialyzed separately against Buffer A. After removal from dialysis, they were all analyzed for protein content and PDGF-BB (ELISA) (See Table 6).





TABLE 6



Native PDGF Extraction from Human Platelets












Total





Volume
PDGF-BB
PDGF-BB
Protein
Total Protein
ng PDGF-BB

Sample
(ml)
(ng/mL)
(ng)
(mg/mL)
(mg)
per mg Protein











Boiled platelet







Supernatant
50
4.52
226.18
0.63
31.50
7.18

Pellet

Extraction 1
35
8.77
306.95
0.31
10.85
28.29

Extraction 2
35
3.79
132.76
0.25
8.58
15.48

Extraction 3
35
1.26
44.03
0.10
3.43
12.83

Extraction 4
37
1.53
56.65
0.19
7.03
8.05

Platelet Wash

Boiled

Supernatant
27
7.49
202.12
0.64
17.28
11.70

Extracted Pellet
37
10.89
402.75
0.90
33.15
12.15

Total
256
5.36
1371.32
0.44
111.82
12.26










































TABLE 7



Native PDGF Purification from Human Platelets














Specific





Total

Activity


PDGF-

PDGF-
Total
ng
Endotoxin Levels











Platelet
BB
Volume
BB
Protein
PDGF/mg

EU/mg


Purification
(ng/mL)
(mL)
(ng)
(mg)
Protein
EU/ml
protein
EU/μg PDGF













Eluate 1
214.94
6.74
1449
0.443
3266.49
2.36
35.87
10.98

Flow
1.17
500
585
110.5
5.29

Thru 1

































Due to low specific activity (ng PDGF-BB per mg protein), the supernatants were subjected to further purification by CM sepharose. The supernatants were applied (with washing Buffer A) to a 20 ml CM sepharose column (GE Healthcare cat#17-0719-01) and the PDGF was eluted with Buffer B. Subsequently the eluted protein was dialyzed against Buffer A. From here the protein that was eluted and subsequently dialyzed as well as the flow through were all analyzed for protein content and PDGF-BB (ELISA). At this point the specific activity (eluate 1) was high enough to be queried in the assay.
To identify molecules that could bind naturally derived human PDGF-BB, a sandwich ELISA was performed. The native human PDGF-BB was isolated and purified from human platelets (AbbVie, PR-1566692). This material was quantified using the R&D Systems PDGF-BB Duoset kit (cat#DY220). 96-well Costar high binding plates (#3369) were coated with 13.3E-8 M antibodies, benchmark compounds or DVD-Ig in D-PBS, shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were blocked with Superblock blocking buffer (Thermo Scientific, cat#37535) followed by four washes with wash buffer (TBS, 0.05% Tween-20). The native human PDGF-BB was serially diluted in assay diluent (1% Blocker BSA; Pierce, cat#37525) for final test concentrations of 2000 ng/mL-2.74 ng/mL (5.4E-8 M-7.5E-11 M). The dilutions were added to the plates (50 μL) and incubated for 2 hours at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Detection antibody from the R&D Systems Duoset kit (Part 840926, cat#DY220) was diluted in assay diluent and added to plates (50 μL) for 2 hours at 25° C. with shaking. Plates were then washed four times with wash buffer. The streptavidin-HRP from the R&D Systems Duoset kit (Part 890803, cat#DY220) was diluted in assay diluent and added to plates (50 μL) for 35 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. An increase in optical density indicates binding of the test molecule to the naturally derived human PDGF-BB. Data was analyzed using Softmax Pro 4.8 software and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.20
hVEGF-A Neutralization Potency of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Proteins when Pre-Incubated with hPDGF-BB
To test candidate molecules for the ability to neutralize hVEGF-A activity in the presence of hPDGF-BB, a cell based VEGF-R2 (KDR/Flk-1) phosphorylation assay was performed. Stably transfected VEGFR2-3T3 cells (AP) were trypsinized, washed in D-PBS and resuspended at 3.5E5 cells/mL in growth media assay (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate, 400 μg/mL geneticin and 10% FBS). Cells were plated at 3.5E4 cells/well in 96-well plates (Costar cat#3599) and incubated for 6 hours at 37° C., 5% CO 2 Growth media was removed and cells were washed with D-PBS. Starvation media was added to wells (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin and 1 mM sodium pyruvate) and cells were incubated for 18 hours at 37° C., 5% CO 2 . The following day, the MSD anti-VEGFR2-phospho assay plate (Mesoscale VEGFR2-Tyr1054 phospho-MSD kit, cat#K151DJD-2) was blocked with MSD Blocker-A for 1 hour at 25° C. with shaking. During blocking, anti-VEGF-A monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in growth media and pre-incubated with recombinant human PDGF-BB (CST cat#8912BF) (0.992 μg/ml/3.94E-8 M final concentration) for 30 minutes at 25° C. with shaking. Following the first pre-incubation step, recombinant human VEGF 165 (AP, PR-1350437) was added to the samples for a final concentration of human VEGF 165 of 50 ng/ml/1.3E-9 M and of hPDGF-BB of 0.496 μg/ml/1.97E-8 M final concentration for 30 minutes at 25° C. with shaking. Starvation media was removed from wells and pre-incubated sample added to cells in duplicate (100 μL) for 8 minutes at 37° C., 5% CO 2 . Immediately following incubation, plates were transferred to ice where media was removed and cells washed with ice-cold D-PBS. Plates were frozen for 10 minutes at −80° C. Ice-cold lysis buffer (CST cat#9803S) containing 1 mM PMSF was added to cells (50 μL) on ice. Plates were centrifuged at 3000 rpm for 15 minutes at 4° C. The MSD plate was washed four times with wash buffer (TBS, 0.05% Tween-20). The cell lysates were transferred to MSD plate (40 μL) and incubated 1 hour at 25° C. with shaking. Following incubation, the MSD plate was washed four times with wash buffer. The anti-phospho-Tyr1054-IgG-sulfotag reagent was diluted in detection solution (K151DJD-2 components) and 25 L added to foil covered wells for 1 hour at 25° C. with shaking. Plates were washed four times with wash buffer, 150 μL MSD read buffer (K151DJD-2 component) added to wells and plates read on MSD Sector Imager 6000. A decrease in observed signal indicates the test molecule is neutralizing the hVEGF 165 mediated activation in the presence of hPDGF-BB. Data was analyzed using Graphpad Prism software and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.21
PDGF Neutralization Potency of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Proteins when Pre-Incubated with VEGF
To test candidate molecules for the ability to neutralize hPDGF-BB activity in the presence of hVEGF-A, a cell based proliferation assay was performed. NIH-3T3 cells (ATCC, cat#CRL-1658) were trypsinized, washed in D-PBS and resuspended at 4.5E4 cells/mL in assay media (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate and 0.1% BSA). Cells were plated at 2,250 cells/well (50 μL) on black 96-well plates and incubated for 5 hours at 37° C., 5% CO 2 . During cell incubation, anti-PDGF-BB monoclonal antibodies, benchmark compounds or DVD-Ig were serially diluted in assay media containing hVEGF 165 (4 μg/mL/104.2 nM). The samples were pre-incubated with recombinant human PDGF-BB in assay media (CST, cat#8912BF) (3.34 ng/ml/1.33E-10 M final concentration in well) for 1 hour at 25° C. with gentle shaking. The final concentrations of ligand in assay wells were hVEGF 165 2.6E-8 M and hPDGF-BB 6.63E-11 M. The pre-incubated samples were added to the cells (50 μL) in triplicate and plates were incubated at 37° C., 5% C0 2 for 44 hours. Cell survival/proliferation was measured indirectly by assessing ATP levels using a CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, Madison, Wis.) according to the manufacturer's instructions. A decrease in observed signal indicates the test molecule is neutralizing the hPDGF-BB induced proliferation in the presence of hVEGF 165 . Data was analyzed and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.22
Human VEGF-R2 Binding Activity of the Anti-VEGF-R2 Antibodies
To identify molecules which could bind VEGF-R2 (KDR/Flk-1), a direct binding ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 0.5 μg/mL/2.27E-9 M recombinant human VEGF-R2-Fc (R&D Systems cat#357-KD), 50 μL/well in D-PBS), shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, supernatant, antibodies or benchmark compounds were diluted in 1% Blocker BSA (Thermo Scientific cat#37525) and an eight point titration of each sample molecule was performed. The samples were added to wells and incubated for one hour at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. The appropriate anti-species-IgG HRP conjugate was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates (50 μL) for forty-five minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. An increase in observed optical density indicates the test molecule is binding the human VEGF-R2-Fc. Data was analyzed using Softmax Pro 4.8 software and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.23
Human VEGF-R2 Blocking Activity of the Anti-VEGF-R2 Antibodies as Determined by Inhibition of Human VEGF-R2 Interaction with Human VEGF 165
To identify molecules which could block the binding of VEGF-R2 (KDR/Flk-1) to hVEGF 165 , a competition ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 0.5 μg/mL/2.27E-9 M recombinant human VEGF-R2-Fc (R&D Systems cat#357-KD), 50 μL/well in D-PBS), shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, supernatant, antibodies or benchmark compounds were diluted in 1% Blocker BSA (Thermo Scientific cat#37525) and an eight point titration of each sample molecule was performed. The samples were added to wells and incubated for 30 minutes at 25° C. with shaking. The biotinylated human VEGF 165 (AP, PR-1361002) was diluted in 1% BSA at 35 ng/mL. This was added to wells (17.5 ng/mL/4.56E-10 M final concentration) and incubation was continued for 30 minutes at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Streptavidin-polyHRP-40 (Fitzgerald cat#65r-s104phrp) was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates (50 μL) for 45 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. A decrease in observed optical density indicates the test molecule is blocking the human VEGF-R2-Fc binding to hVEGF 165 . Data was analyzed using Softmax Pro 4.8 software and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.24
VEGF-A Blocking Activity of the Anti-VEGF-R2 Antibodies as Determined by VEGFR2 (Tyr1054) Phosphorylation
To test candidate molecules for the ability to neutralize hVEGF-R2 activity, a cell based VEGF-R2 (KDR/Flk-1) phosphorylation assay was performed. Stably transfected VEGFR2-3T3 cells (AP) were trypsinized, washed in D-PBS and resuspended at 3.5E5 cells/mL in growth media assay (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate, 400 μg/mL geneticin and 10% FBS). Cells were plated at 3.5E4 cells/well in 96-well plates (Costar cat#3599) and incubated for 6 hours at 37° C., 5% CO 2 . Growth media was removed and cells were washed with D-PBS. Starvation media was added to wells (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin and 1 mM sodium pyruvate) and cells were incubated for 18 hours at 37° C., 5% CO 2 . The following day, the MSD anti-VEGR2-phospho assay plate (Mesoscale VEGFR2-Tyr1054 phospho-MSD #kit cat K151DJD-2) was blocked with MSD Blocked with MSD Blocker-A for 1 hour at 25° C. with shaking. During blocking, anti-VEGF-R2 supernatant, monoclonal antibodies and benchmark compounds were serially diluted in growth media and pre-incubated with recombinant human VEGFR2-Fc (R&D Systems, cat#357-KD) (500 ng/ml/2.27E-9 M final concentration) for 30 minutes at 25° C. with shaking. Recombinant human VEGF 165 (AP, PR-1350437) (50 ng/ml/1.3E-9 M final concentration) was added to the wells and incubation was continued for 30 minutes at 25° C. with shaking. Starvation media was removed from wells and pre-incubated sample added to cells in duplicate (100 μL) for 8 minutes at 37° C., 5% CO 2 . Immediately following incubation, plates were transferred to ice where media was removed and cells washed with ice-cold D-PBS. Plates were frozen for 10 minutes at −80° C. Ice-cold lysis buffer (CST cat#9803S) containing 1 mM PMSF was added to cells (50 μL) on ice. Plates were centrifuged at 3000 rpm for 15 minutes at 4° C. The MSD plate was washed four times with wash buffer (TBS, 0.05% Tween-20). The cell lysates were transferred to MSD plate (40 μL) and incubated 1 hour at 25° C. with shaking. Following incubation, the MSD plate was washed four times with wash buffer. The anti-phospho-Tyr1054-IgG-sulfotag reagent was diluted in detection solution (K151DJD-2 components) and 25 μL added to foil covered wells for 1 hour at 25° C. with shaking. Plates were washed four times with wash buffer, 150 μL MSD read buffer (K151DJD-2 component) added to wells and plates read on MSD Sector Imager 6000. An increase in observed signal indicates the test molecule is neutralizing the exogeneous hVEGFR2 and allowing for hVEGF 165 mediated activation. Data was analyzed using Graphpad Prism software and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.25
Mouse VEGF-R2 Blocking Activity of the Anti-VEGF-R2
Antibodies as Determined by Inhibition of Mouse VEGF-R2 Interaction with Mouse VEGF 164
To identify molecules which could block the binding of mVEGF 164 to the mVEGF-R2, a competition ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 1 μg/mL/4.55E-9 M recombinant mouse VEGF-R2-Fc (R&D Systems cat#443-KD)(50 μL/well in D-PBS) shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were washed four times with wash buffer (TBS, 0.05% Tween-20). Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, hybridoma supernatants and rat IgG were diluted in 1% Blocker BSA (Thermo Scientific cat#37525). The sample was added to the plates (50 μL) and incubated for 45 minutes at 25° C. with shaking. The mouse VEGF 164 (R&D Systems cat#493-MV-005) was diluted in 1% Blocker BSA to 20 ng/mL and added to wells for a final concentration of 10 ng/mL/5.15E-10 M final concentration. Incubation was continued for 30 minutes at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. The detection reagent biotinylated goat anti-mVEGF 164 (R&D Systems cat#BAF-493) was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates for 1 hour at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Streptavidin-polyHRP-40 (Fitzgerald cat#65r-s104phrp) was diluted in assay diluent and added to plates (50 μL) for 45 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. A decrease in observed optical density indicates the test molecule is blocking the mouse VEGF-R2-Fc binding to the mVEGF 164 . Data was analyzed using Softmax Pro 4.8 software and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.26
PDGF-Rβ Binding Activity of the Anti-PDGF-Rβ Antibodies
To identify molecules which bind hPDGF-Rβ, a direct ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 0.5 μg/mL/2.98E-9 M recombinant human PDGF-Rβ-Fc (R&D Systems #385-PR, 50 μL/well in D-PBS), shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, supernatants, antibodies and benchmark compounds were diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and an eight point titration of each sample molecule was performed. The samples were added to wells and incubated for one hour at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. The appropriate anti-species-IgG HRP conjugate was diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and added to plates (50 μL) for forty-five minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. An increase in observed optical density indicates the test molecule is binding the human PDGF-Rβ-Fc. Data was analyzed using Softmax Pro 4.8 software and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.27
PDGF-Rβ Blocking Activity of the Anti-PDGF-Rβ Antibodies as Determined by Inhibition of PDGF-Rβ Interaction with Human PDGF-BB
To identify molecules which could block the binding of hPDGF-Rβ to hPDGF-BB, a competition ELISA was performed. 96-well Costar high binding plates (#3369) were coated with 0.5 μg/mL/2.98E-9 M recombinant human PDGF-Rβ-Fc (R&D Systems #385-PR, 50 μL/well in D-PBS), shaken for 2 hours at 25° C. and stored overnight at 4° C. Plates were then washed four times with wash buffer (TBS, 0.05% Tween-20) and blocked with Superblock blocking buffer (Thermo Scientific, cat#37535). During the blocking step, supernatants, antibodies and benchmark compounds were diluted in assay diluent (10% Superblock containing 0.05% surfactamps) and an eight point titration of each sample molecule was performed. The samples were added to wells and incubated for 30 minutes at 25° C. with shaking. The recombinant human PDGF-BB-biotin (CST cat#8912BF; labeled at ABC) was diluted in assay diluent at 20 ng/mL. This was added to wells (10 ng/mL/3.97E-10 M final concentration) and incubation was continued for 35 minutes at 25° C. with shaking. Following incubation, plates were washed four times with wash buffer. Detection reagent Streptavidin-polyHRP-40 (Fitzgerald, cat#65r-s104phrp) was diluted in assay diluent and added to plates (50 μL) for 45 minutes at 25° C. with shaking. Plates were washed four times with wash buffer and developed with the addition of Enhanced K-blue TMB substrate (Neogen, cat#308177). The reaction was stopped with 2N sulfuric acid (VWR, cat# BDH3500-1) and the absorbance was read at 450 nm-570 nm. A decrease in observed optical density indicates the test molecule is blocking the human PDGF-Rβ-Fc binding to hPDGF-BB. Data was analyzed using Softmax Pro 4.8 software and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.28
PDGF-Rβ Blocking Activity of the Anti-PDGF-Rβ Antibodies as Determined by PDGFRβ (Tyr751) Phosphorylation
To test candidate molecules for the ability to neutralize hPDGF-Rβ activity, a cell based PDGF-Rβ phosphorylation assay was performed. Balb-3T3 cells (ATCC cat# CCL-163) were trypsinized, washed in D-PBS and resuspended at 3.5E5 cells/mL in growth media assay (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin, 0.1% MEM non-essential amino acids, 1 mM sodium pyruvate, and 10% FCS). Cells were plated at 3.5E4 cells/well in 96-well plates (Costar cat#3599) and incubated for 20 hours at 37° C., 5% CO 2 . Growth media was removed and cells were washed with D-PBS. Starvation media was added to wells (DMEM, 2 mM L-glutamine, 100 units/mL penicillin/100 μg/mL streptomycin and 1 mM sodium pyruvate) and cells were incubated for 18 hours at 37° C., 5% CO 2 . The following day, the MSD anti-PDGFRβ-phospho-assay plate (Mesoscale PDGF-Rβ-Tyr751 phospho-MSD kit cat# K150DVD-2) was blocked with MSD Blocker-A for 1 hour at 25° C. with shaking. During blocking, supernatants, antibodies or benchmark compounds were serially diluted in growth media and pre-incubated with 500 ng/mL/2.98E-9 M hPDGF-Rβ (R&D System, cat 385-PR) for 30 minutes at 25° C. Recombinant human PDGF-BB (CST, cat#8912BF) (20 ng/ml/7.94E-10 nM final concentration) was added to the wells and incubation was continued for 30 minutes at 25° C. with shaking. Starvation media was removed from wells and pre-incubated sample added to cells in duplicate (100 μL) for 8 minutes at 37° C., 5% CO 2 . Immediately following incubation, plates were transferred to ice where media was removed and cells washed with ice-cold D-PBS. Plates were frozen for 10 minutes at −80° C. Ice-cold lysis buffer (CST cat#9803S) containing 1 mM PMSF was added to cells (50 μL) on ice. Plates were centrifuged at 3000 rpm for 15 minutes at 4° C. The MSD plate was washed four times with wash buffer (TBS, 0.05% Tween-20). The cell lysates were transferred to MSD plate (40 μL) and incubated 1 hour at 25° C. with shaking. Following incubation, the MSD plate was washed four times with wash buffer. The anti-phospho-Tyr751-IgG-sulfotag reagent was diluted in detection solution (K150DVD—2 components) and 25 μL added to foil covered wells for 1 hour at 25° C. with shaking. Plates were washed four times with wash buffer, 150 μL MSD read buffer (K150DVD-2 components) added to wells and plates read on MSD Sector Imager 6000. An increase in observed signal indicates the test molecule is neutralizing the exogeneous hPDGF-Rβ and allowing for hPDGF-BB mediated activation. Data was analyzed using Graphpad Prism software and IC 50 values calculated using a sigmoidal dose response (variable slope) fit in GraphPad Prism 5.
Example 1.29
Reactivity of Anti-PDGF-BB Antibodies and Anti-VEGF-A/anti-PDGF-BB DVD-Ig Molecules to ECM-associated PDGF-BB
Both recombinant cell line HEK293 cells over-expressing PDGFBB-RM and HUVEC naturally expressing ECM-associated PDGF-BB cells were used for staining.
HEK293 Cell Staining:
PDGFB-RM transient transfected HEK 293 cells and parental HEK293 cells were re-suspended at 1E6 cells/mL in PBS and fixed in 4% paraformaldehyde at RT for 10 minutes, washed with PBS and 2E5 cells/tube were incubated in blocking buffer (10% goat serum in PBS) for one hour on ice. Cells were washed with PBS and incubated with primary antibodies or DVD-Ig molecules at 33 nM in antibody dilution buffer (5% goat serum in PBS) for one hour on ice. Cells were washed three times with PBS and incubated with Alexa Fluo 488 conjugated Goat anti-Human IgG (Jackson Immune, code: 109-546-098; lot: 108427) 1:400 dilution in antibody dilution buffer, incubated on ice for 45 minutes, cells were washed three times with PBS and cytospin onto glass slides and mounted with mounting media with DAPI. Pictures were taken by fluorescent microscopy.
HUVEC Staining:
The anti-VEGF/anti-PDGF DVD-Ig was further assessed for its staining on naturally derived ECM-associated PDGF-BB on HUVEC cells. HUVECs (Lonza, cat#: C2519A lot: 181607) were trypsinized, resuspended at 2E4 cells/mL in culture media (Lonza, EGM2 MV Bulletkit: CC-3202). Cells were plated at 10,000 cells/500 μl/well in 8-chamber glass slide and incubated for 16 hours at 37° C., 5% CO 2 . After incubation, cells were fixed with 200 μl 4% paraformaldehyde at RT for 10 minutes, washed with PBS and incubated in blocking buffer (10% goat serum in PBS) for one hour on ice. Cells were washed with PBS 3× and incubated with primary antibodies or DVD-Ig molecules at 33 nM in antibody dilution buffer (5% goat serum in PBS) for one hour on ice. Cells were washed three times with PBS and incubated with Alexa Fluo 488 conjugated Goat anti-Human IgG (JacksonImmune, code: 109-546-098; lot: 108427) 1:400 dilution in antibody dilution buffer, incubate on ice for 45 minutes, cells were washed three times with PBS and mounted with mounting media with DAPI. Pictures were taken by fluorescent microscopy.
A. Example 1.30
Inhibition of Sprouting in HUVEC/MSC Co-culture Sprouting Assay by Anti-VEGF-A/anti-PDGF-BB DVD-Ig Molecules
In early therapeutic treatment mode, Cytodex-3 beads (Sigma-Aldrich, cat# C3275) were coated with HUVEC cells (Lonza) overnight, and then embedded (100 beads/well) with human mesenchymal stem cells (Lonza, 20,000 cells/well) in fibrin gel in 24-well tissue culture plates. A 1:1 mixture of fresh EGM-2 complete media (Lonza) and fibroblast (Lonza) conditioned EGM-2 media were added on top of the fibrin gel along with 2 ng/mL of recombinant human HGF. Medium was replaced every 2-3 days till the end of the experiment. After EC sprouts and pericyte covering were formed usually on day 4, anti-VEGF-A (4G8.4), anti-PDGFBB (9E8.) or anti-PDGFBB/VEGF-A DVD-Ig, were added to the culture medium at 10 nM starting. 10 days later cells were fixed in 4% PFA overnight at 4° C. Endothelial cells were stained with anti-PECAM (Abcam, ab32457), followed by fluorescence-conjugated secondary antibody, and pericytes were labeled with anti-aSMA-Cy3 (Sigma, C6198). Cells were then viewed by an inverted fluorescence microscope and 5× images were captured ( FIGS. 2 and 3 ).
Example 2
Analytical Methods and Techniques for Physicochemical Property Characterizations of DVD-Ig Proteins
Example 2.1
Size Exclusion Chromatography Technique
Size exclusion chromatography (SEC) is used to separate proteins based on size. Proteins are carried in an aqueous mobile phase and through a porous stationary phase resin packed in a column. The retention time in the column is a function of the hydrodynamic size of the protein and the size of the pores in the packed resin bed. Smaller molecules can penetrate into smaller pores in the resin and are retained longer than larger molecules. Samples at 1 mg/ml, or diluted with formulation buffer to this concentration, are injected onto the SEC column at a volume of 10 μl. Upon elution from the column, the proteins are detected by UV absorbance. The SEC method uses a TSK gel guard (TOSOH Biosciences, Montgomeryville, Pa., cat. no. 08543) and a TSK gel G3000SWxL (TOSOH Biosciences, Montgomeryville, Pa., cat. no. 08541). The mobile phase was 100 mM Na 2 HPO 4 , 100 mM Na 2 SO 4 , pH 6.8. The flow rate is 0.25 ml/minute. The column temperature is room temperature. The autosampler temperature is 2-8° C. The total run time is 55 minutes. The detection is based on UV absorbance at 214 nm wavelength, with band width set at 8 nm, using reference wavelength at 360 nm with band width 100 nm. The resulting chromatogram is analysed for the distribution of different size species (aggregate, monomer, and fragment) by the percentage of the total area of the signal.
Example 2.2
Differential Scanning Calorimetry Technique
The thermal stability of the protein samples was assessed using a differential scanning calorimetry (DSC) instrument. The DSC instrument used was an automated VP-DSC equipment with Capillary Cell (Microcal, GE Healthcare Ltd./Microcal, Buckinghamshire, UK). Unfolding of molecules was studied applying a 1° C./minute scan rate over a 25° C.-95° C. temperature range for samples at 1 mg/mL. Additional measurement parameters applied were a fitting period of 16 seconds, a pre-scan wait time of 10 minutes, and measurements were performed in none-feedback mode. For each measurement, 420 μL of sample or blank buffer was filled into the designated receptacle within the DSC instrument. The thermograms obtained (heat capacity versus temperature) were fitted to a non-two state model to obtain the midpoint temperatures and enthalpies of the different transitions.
Example 2.3
Sample Preparation
The antibodies and DVD-Ig molecules were initially obtained as a solution and diluted below 10 mg/ml with the formulation buffer. Each sample was then inserted into a separate dialysis cartridge (Slide-a-lyzer cassette, 10,000 MWCO, 3-12 mL capacity, Thermo Scientific, USA, Cat. No. 66810) and dialyzed against 2 L of the formulation buffer with continuous stirring via a magnetic stir bar for 18-24 hours. The samples were then retrieved from the cartridge and briefly spun down in a centrifuge and/or passed through 0.45 μm PVDF filters to remove any precipitation or particles. This was followed by up-concentration of the DVD-Ig solutions with centrifuge spin filters (Amicon Ultra 30,000 MWCO Regenerated Cellulose) to reach the desired protein concentration which was confirmed by UV measurements at 280 nm. If the solutions were above the desired concentration, they were diluted to that concentration with the formulation buffer.
Example 2.4
Storage Stability Analysis Method
The antibodies and DVD-Ig molecule solutions prepared according to Example 2.3 were analyzed for their physical stability during storage at 40° C., 25° C., and/or 5° C. Both 25° C. (room temperature) and 5° C. (storage temperature) are typical temperatures at which the samples would be subjected either during preparation and storage for manufacture or as part of the final drug product presentation. Storage at 40° C. is considered an accelerated stability condition which provides an indication of long-term stability prospects. The samples were aliquoted into low volume containers (<0.1 ml), tightly sealed, and placed at the designated temperatures (sometimes in a water bath). The samples were then pulled at periodic intervals and a small portion was removed for analysis by SEC (Example 2.1).
Example 2.5
Freeze-Thaw Analysis Method
The antibody and DVD-Ig molecule solutions prepared according to Example 2.3 were analyzed for their physical stability during freeze/thaw stress. Samples were aliquoted into low volume containers (<1 ml) and tightly sealed. The samples were then placed at −80° C. for at least 6 hours and then thawed at 30° C. in a water bath. This was repeated three more times. After the second and fourth thaws, a small portion of each sample was removed for analysis by SEC (Example 2.1).
DVD-Ig solutions are typically frozen at −80° C. for long term storage as well as shipping to remote manufacturing sites. The samples are then thawed in order to complete the drug product manufacturing process. Stability due to freeze-thawing was assessed at low concentration in order to evaluate greater exposure of protein molecules to the denaturing ice-water interfaces. At higher concentrations, proportionally less protein encounters the ice-water interface, instead interacting with other protein molecules.
Example 2.6
Viscosity Determination Method
The antibody and DVD-Ig molecule solutions prepared according to Example 2.3 were analyzed for their viscosity at room temperature (˜23° C.) with a Malvern Viscosizer 200 instrument. The viscosity serves as an indication of the ease of delivery of the sample through a small diameter needle attached to a syringe, a likely drug product presentation. A higher viscosity requires a greater force for delivery, and vice-versa.
Example 2.7
Intact and Reduced Molecular Weight Determination
The intact molecular weights of the three samples shown in Table 8 were acquired. Each sample was diluted to 1 mg/mL with Milli-Q water. 1.0 μL of the 1 mg/mL sample was injected onto an Agilent 6510 Q-Tof LC/MS system with a C4 MicroTrap column. Table 9 shows the HPLC gradient for intact molecular weight analysis. Buffer A was 0.02% TFA, 0.08% FA in water. Buffer B was 0.02% TFA, 0.08% FA in acetonitrile. The flow rate was 50 μL/minute. The column temperature was set at 60° C. The mass spectrometer was operated at 5 kvolts spray voltage and the scan range was from 600 to 3200 mass to charge ratio. The deglycosylated intact molecular weights of all three samples were measured by Agilent 6510 Q-Tof LC/MS system after the samples were deglycosylated. 100 μL of 1 mg/mL sample was mixed with 5 μL of 10% N-octylglucoside and 2 μL of PNGase F enzyme. The sample was incubated at 37° C. for 18 hours. 1.0 μg of the deglycosylated sample was injected onto an Agilent 6510 Q-Tof LC/MS system with a C4 MicroTrap for deglycosylated intact molecular weight analysis.
The reduced molecular weights of all three samples were obtained. Each sample was diluted to 1 mg/mL with Milli-Q water. 1.0 μL of 1M DTT was added to 100 μL of a 1 mg/mL sample and incubated at 37° C. for 30 minutes. 2.0 μL of the reduced sample was injected onto an Agilent 6510 Q-Tof LC/MS system with a diphenyl column. The HPLC gradient for reduced molecular weight analysis is shown in Table 9. The mass spectrometer was operated at 5 kvolts spray voltage and the scan range was from 600 to 3200 mass to charge ratio.





TABLE 8



VEGF/PDGF DVD-Ig Formulations










Concentration


Sample ID
Lot
Detailed name
(mg/mL)
Formulation









PR-1572102
Lot 2211502
hu VEGF 4G8.3-GS-hu PDGF
6.5
30 mM histidine,



9E8.4 (germline) [hu IgG1/k]

8% sucrose pH



LALA H435A

5.2

PR-1572105
Lot 2211597
hu VEGF 4G8.3-SL-hu PDGF
1.5
30 mM Histidine,



9E8.4 (germline) [hu IgG1/k]

8% Sucrose pH



LALA H435A

5.2

PR-1610561
Lot 2213329
hu VEGF 9E10.1-GS-hu PDGF
5
30 mM Histidine,



33675 [hu IgG1/k] LALA H435A

8% sucrose, pH





5.2






































TABLE 9



PLC Operating Conditions For Intact And Reduced Molecular Weight






Intact/C4

Reduced/Diphenyl







Time (min)
% Buffer B
Time (min)
% Buffer B








0
5
0
5

5
5
5
30

5.5
95
30
40

10
95
32
90

10.5
5
37
90

15
5
39
5



44
5


































Example 2.8
Oligosaccharide Profiles Determined by Fc Molecular Weight Measurement
Samples were partially digested with Lys-C enzyme, reduced and analyzed by LC/MS. Different oligosaccharide species were quantitated based on the peak intensity detected by mass spectrometry and the relative percentage of different oligosaccharide species was reported. Samples were diluted to 1 mg/mL with Milli-Q water. 100 μL of each sample was mixed with 2 μL of 0.005 mg/mL Lys-C enzyme and incubated at 37° C. for 30 minutes. 1 μL of 1 M DTT was added and incubated at 37° C. for 30 minutes for reduction. 2 μL of sample was injected onto an Agilent 6510 Q-Tof LC/MS system with a diphenyl column and a reduced HPLC gradient was used. The column temperature was set at 60° C. The mass spectrometer was operated at 5 kvolts spray voltage and the scan range was from 600 to 3200 mass to charge ratio.
Example 2.9
Charge Heterogeneity by Weak Cation Exchange Chromatography and Imaged Isoelectric Focusing (icIEF)
Charge heterogeneity was studied using a Propac WCX-10 column for weak cation exchange chromatography analysis. Mobile phase A was 20 mM MES, pH 5.5. Mobile phase B was 20 mM MES, 500 mM NaCl, pH 5.5. Each sample was diluted to 1 mg/mL in mobile phase A. 50 μg of each sample was loaded, and the HPLC gradient is shown in Table 10. The flow rate was 1 mL/minute flow rate and the UV detector was monitored at 280 nm.





TABLE 10



Gradient Used For Weak Cation Exchange Chromatography






Time (minutes)
Mobile phase B









0
20


5
20


25
40


27
100


32
100


34
20


38
20































Imaged isoelectric focusing was performed on an iCE instrument from ProteinSimple. All three samples were diluted to 1 mg/mL with Milli-Q water before mixing with amphalyte and other components as shown in Table 11. Each sample was vortexed briefly and centrifuged for 5 minutes at 10 k RPM before being transferred to glass inserts for analysis. Each sample was pre-focused at 1500 V for 1 minute and focused at 3000 V for 8 minutes.





TABLE 11



Sample Preparation for icIEF






Component
Volume (μL)









1% Methyl cellulose
70


Pharmalyte 3-10
4


Pharmalyte 5-8
4


Diluted pI 5.1 marker
8


Diluted pI 8.2 marker
8


1 mg/mL test sample
50


Water
6


8M Urea
50
































Example 3
Generation of Rat Anti-VEGF-A, Anti-VEGFRII, Rat-Anti-PDGF-BB, Anti-PDGFR-B Monoclonal Antibodies by DNA Immunization and Rat Hybridoma Technology
Example 3.1
DNA Immunization, Hybridoma Fusion and Screening
Genetic immunization enables the development of antibodies against any protein target directly from a cDNA. A cDNA encoding the soluble human VEGFA-165, soluble human PDGF-BB, human VEGFR-II ECD (extracellular domain) or human PDGFR-BB ECD was cloned into a eukaryotic expression vector (Aldevron GmbH, Freiburg, Germany). Wistar rats were immunized by intradermal application of DNA-coated gold-particles using a hand-held device for particle-bombardment (“gene gun”). Antibody-producing splenocytes or lymph node cells were isolated and fused with fusion partner myeloma cells using polyethylene glycol (PEG) according to standard procedures. To help identify positive antisera and hybridomas, screening is done with the use of either cells transfected with screening vector encoding GPI anchored human VEGF-A165, human PDGF-BB, human VEGFR-II ECD or human PDGFR-BB ECD proteins, soluble recombinant human VEGF-A165 and human PDGF-BB protein or peptides. The tables below are the lists of antibodies generated using the rat DNA immunization approach.
Anti-VEGF-A antibodies derived from rat hybridomas were characterized for binding, function and cross-reactivity in a panel of assays. Supernatants were tested for the ability to bind hVEGF 165 (Example 1.3) and block binding of hVEGF 165 to hVEGFR2 in a competition ELISA format (Example 1.4). Select hybridomas were assessed for cross-reactivity by testing for the ability to block human VEGF 111 and rabbit VEGF 165 in a Tyr1054 phosphorylation assay (Example 1.6) and blocking of murine VEGF 164 binding to mVEGFR2 (Example 1.5). Candidate rat IgG was then examined for potency in the hVEGF 165 -induced cell proliferation assay (Example 1.7), reactivity to native hVEGF 165 (Example 1.11) and binding affinity measurement by Biacore analysis (Example 1.1). The data is summarized in Tables 12 and 13 below.





TABLE 12



A List of Anti-VEGF-A Antibodies Generated Using DNA Immunization and Rat

Hybridoma Technology




















huVEGF-










Receptor
A 165







Competition
Neutralization





Phospho-
ELISA
ELISA
Potency in
ELISA
ELISA
Phospho-



ELISA
ELISA
Tyr1054/
Binding to
huVEGF-
hVEGF-
Mouse
Rat
Tyr1054/



huVEGF-
huVEGF-
huVEGF-
Naturally
A 165 /
R2 Over-
VEGF-
VEGF-
Rabbit

Hybridoma

A 165
A 121
A 111
Derived
huVEGF-
expressing
A 164
A 164
VEGF-A 165

Clones
Isotype
Binding
Binding
Neutralization
huVEGF-A
R2 (nM)
Cells (nM)
Binding
Binding
Neutralization















BEW-
IgG2b/κ
+
NT
+
+
0.18
0.09
−
NT
+

164-

C4

BEW-
IgG2b/κ
+
NT
+
+
0.62
0.39
−
NT
+

1E3-

D6

BEW-
IgG2b/κ
+
NT
+
+
0.156
0.88
−
NT
+

5C3-

E7

BEW-
IgG2b/κ
+
NT
+
+
0.197
<0.1
−
NT
+

6C2-

C8

BEW-
IgG2a/κ
+
NT
+
+
0.342
0.41
−
NT
+

8E6-

E4

BEW-
IgG2a/κ
+
NT
+
+
0.249
0.16
−
NT
+

9A8-

E2

BEW-
IgG2a/κ
+
NT
+
+
0.274
0.17
−
NT
+

9E10-

E7

BEW-
IgG2b/κ
+
NT
+
+
0.42
0.42
−
NT
+

10H2-

B9

BEW-
IgG2a/κ
+
NT
+
+
0.124
<0.1
−
NT
+

9E3--

B9

BEW-
IgG2b/κ
+
NT
+
+
0.207
0.14
−
NT
+

9E7-

B4

BEW-
IgG1/κ
+
NT
+
+
0.584
1.46
−
NT
+

1G1-

C2

BEW-
IgG2b/κ
+
NT
+
+
0.155
<0.1
−
NT
+

9C2-

D6

BEW-
IgG2a/κ
+
NT
+
+
0.127
0.09
−
NT
+

9D2-

E8

BEW-
IgG2a/κ
+
NT
+
+
0.326
2.8
−
NT
+

1B10-

B9-C3

BEW-
IgG2b/κ
+
NT
+
+
0.124
0.96
−
NT
+

3A1-

D10-

G9

BED-
IgG2b/κ
+
NT
+
+
0.13
0.38
−
NT
+

4G10-

C8

BDB-
IgG2b/κ
+
NT
+
+
0.13
0.617
−
NT
+

4G8-

D4



NT = not tested























































































TABLE 13



Biacore Binding of Rat Anti-VEGF Antibodies






Antibody
k on (M−1 s−1)
k off (M−1)
K D (M)








BDB-4G8-D4
≧1.0E+07
8.1E−06
≦8.1E−13

BDB-4G8-D4
1.4E+07
1.6E−05
1.2E−12

BED-4G10-C8
1.8E+07
1.1E−03
6.0E−11

BEW-1B4-C4
1.8E+07
1.3E−04
7.4E−12

BEW-1B10-B9-C3
4.4E+06
7.2E−05
1.6E−11

BEW-1E3-D6
1.4E+07
1.4E−04
1.0E−11

BEW-1G1-C2
1.6E+07
3.0E−05
1.9E−12

BEW-3A1-D10-G9
1.0E+07
1.4E−03
1.4E−10

BEW-5C3-E7
1.2E+07
4.8E−05
3.9E−12

BEW-6C2-C8
6.9E+06
8.4E−05
1.2E−11

BEW-8E6-E4
6.9E+06
1.2E−04
1.7E−11

BEW-9A8-E2
7.4E+06
7.1E−06
9.6E−13

BEW-9C2-D6
5.5E+06
≦1.0E−06
≦1.8E−13

BEW-9D2-E8
7.0E+06
9.8E−05
1.4E−11

BEW-9E10-E7
1.3E+07
3.9E−05
3.1E−12

BEW-9E3-B9
6.7E+06
9.5E−05
1.4E−11

BEW-9E7-B4
5.9E+06
2.5E−05
4.3E−12

BEW-10H2-B9
2.4E+07
2.7E−04
1.1E−11









































Anti-PDGF-BB antibodies derived from rat hybridomas were characterized for binding, function and cross-reactivity in a panel of assays. Supernatants were tested for the ability to bind hPDGF-BB (Example 1.12) and block binding of hPDGF-BB to hPDGF-R in a competition ELISA format (Example 1.13). Select hybridomas were assessed for the ability to block human and rat PDGF-BB in a Tyr751 phosphorylation assay (Example 1.14). Candidate rat IgG was then examined for potency in the human, mouse and cynomolgus PDGF-BB-induced cell proliferation assay (Examples 1.15-1.17), reactivity to native hPDGF-BB (Example 1.19) and binding affinity measurement by Biacore analysis (Example 1.1). The data is summarized in Tables 14 and 15 below.





TABLE 14



A List of Anti-PDGF-BB Antibodies Generated using DNA Immunization and Rat

Hybridoma Technology















ELISA
Receptor

huPDGF-

mPDGF-
cynoPDGF-




Binding
Competition

BB
Phospho-
BB
BB




to
ELISA
Phospho-
Neutralization
Tyr751/
Neutralization
Neutralization



ELISA
Naturally
huPDGF-
Tyr751/hPDGF-
Potency
ratPDGF-
Potency
Potency



huPDGF-
Derived
BB/
BB
(nM) in
BB
(nM) in
(nM) in

Hybridoma

BB
huPDGF-
huPDGF
Neutralization
NIH-3T3
Neutralization
NIH-3T3
NIH-3T3

Clones
Isotype
Binding
BB
Rβ (nM)
(nM)
Cells
(nM)
Cells
Cells














BDI-
IgG2b/κ
+
+
1.121
0.629
0.195
0.333
0.026
0.194

9E8-E7

BDI-
IgG2b/κ
+
+
0.528
0.884
0.371
0.319
NT
NT

5H1-F6

BDI-
IgG2b
+
+
>10
>10
>5
>5
NT
NT

7H10-

D8

BDI-
IgG2b/κ
+
NT
>10
1.057
>5
+
NT
NT

1E1-D5

BDI-
IgG2b/λ
+
NT
1.065
0.923
0.741
+
NT
NT

5G2-F9

BDI-
IgG2b/λ
+
NT
3.228
1.618
>5
−
NT
NT

6A3-A9

BDI-
IgG2b
+
NT
>10
>10
>5
−
NT
NT

7F6-D3

BDI-
IgG2b/λ
+
NT
1.035
2.53
>5
−
NT
NT

10E7-

F9

BDI-
IgG2b/λ
+
NT
1.086
3.159
>5
−
NT
NT

8B8-F2

BFF-
IgG2b/κ
+
NT
>50
0.753
>5
NT
NT
NT

5C9-C7-

B5

BFF-
IgG2b/λ
+
NT
>50
1.745
>10
NT
NT
NT

7D7-D3-

E4

BFF-
IgG2b/κ
+
NT
>50
>10
>10
NT
NT
NT

7E9-C3-

B6

BFF-
IgG2b/λ
+
NT
>50
1.896
>10
NT
NT
NT

4G8-B4

BFF-
IgG2b/λ
+
NT
>50
0.739
>10
NT
NT
NT

4E8-E5

BFU-
IgG2b/κ
+
NT
>50
0.642
0.247
NT
NT
NT

3E2-B9-

B8

BFU-
IgG2b/κ
+
NT
7.095
0.736
0.344
NT
NT
NT

11A8-

D6-C3

BFU-
IgG2b
+
NT
2.287
0.639
>10
NT
NT
NT

3H6-D2












































































TABLE 15



Biacore Binding of Rat Anti-PDGF Antibodies






Antibody
k on (M−1 s−1)
k off (M−1)
K D (M)








BDI-1E1-D5
≧1.0E+07
3.7E−04**
≦3.7E−11**

BDI-5G2-F9
≧1.0E+07
≦1.0E−06
≦1.0E−13

BDI-5H1-F6
≧1.0E+07
≦1.0E−06
≦1.0E−13

BDI-6A3-A9
≧1.0E+07
6.7E−03**
≦6.7E−10**

BDI-7F6-D3
≧1.0E+07
6.0E−03
≦6.0E−10

BDI-7H10-D8
≧1.0E+07
≦1.3E−02**
≦1.3E−09**

BDI-8B8-F2
≧1.0E+07*
≦1.0E−06*
≦1.0E−13*

BDI-9E8-E7
≧1.7E+07
≦1.0E−06
≦5.8E−14

BDI-9E8-E7
≧1.0E+07
≦1.0E−06
≦1.0E−13

BDI-10E7-F9
≧1.0E+07*
1.3E−04*
≦1.3E−11*

BFF-4E8-E5
≧1.0E+07
8.3E−03***
≦8.3E−10***

BFF-4G4-B8
≧1.0E+07
8.3E−03**
≦8.3E−10**

BFF-5C9-C7-B5
≧1.0E+07
5.8E−05
≦5.8E−12

BFF-7D7-D3-E4
≧1.0E+07
2.1E−02**
≦2.1E−09**

BFF-7E9-C3-B6
≧1.0E+07
1.2E−03**
≦1.2E−10**

BFU-3E2-B9-B8
≧1.0E+07
1.5E−06
≦1.5E−13

BFU-3H6-D2
≧1.0E+07
2.7E−04**
≦2.7E−11**

BFU-11A8-D6-C3
2.1E+07
≦1.0E−06
≦4.7E−14



*Low Ag response

**Heterogeneous off-rate

***Low Ag response and Heterogeneous off-rate










































Anti-VEGFR2 antibodies derived from rat hybridomas were characterized for binding, function and cross-reactivity in a panel of assays. The subcloned rat antibodies were tested for the ability to bind hVEGFR2 (Example 1.22), block binding of hVEGF-R2 to hVEGF 165 in a competition ELISA format (Example 1.23), and a hVEGF 165 Tyr1054 phosphorylation assay (Example 1.24). Candidate molecules were then characterized for species cross-reactivity by testing their ability to block binding of mVEGFR2 to mVEGF 164 in a competition ELISA format (Example 1.25). The data is summarized in Table 16 below.





TABLE 16



A List of Anti-VEGFR II Antibodies Generated Using

DNA Immunization and Rat Hybridoma Technology





Potency (nM)











hVEGF 165 /
mVEGF 164 /
Tyr1054

Hybridoma

hVEGFR2-
hVEGFR2-Fc
mVEGFR2-Fc
phospho-

Clones
Isotype
Fc Binding
Competition
Competition
assay



BCU-3D6-C9

+
NT
NT
NT

BCU-6B1-G6
IgG2a/κ
+
4.850
1.350
+

BCU-7A6-C2
IgG2b/κ
+
−
−
+






























Anti-PDGF-Rβ antibodies derived from rat hybridomas were characterized for binding and function in a panel of assays. The subcloned rat antibodies were tested for the ability to bind hPDGF-Rβ (Example 1.26). Candidate IgG was also characterized for the ability to block binding of hPDGF-Rβ to hPDGF-BB in a competition ELISA format (Example 1.27) and an hPDGF-BB Tyr751 phosphorylation assay (Example 1.28). The data is summarized in Table 17 below.





TABLE 17



A List of Anti-PDGFR-B Antibodies Generated Using

DNA Immunization and Rat Hybridoma Technology





Potency (nM)










hPDGF-BB/
hPDGF-BB/

Hybridoma

hPDGFRβ-
hPDGFRβ-Fc
Tyr751

Clones
Isotype
Fc Binding
Competition
phospho-assay



BDE-3C9-G4
IgG2b/κ
+
0.832
4.696

BDE-4F2-D4
IgG2a/κ
+
0.527
+

BDE-8H6-F7

+
+
−






























Example 4
Deduction of Variable Region Protein Sequences of Monoclonal Antibodies by DNA Cloning and Sequencing
Total RNA was extracted from hybridoma cell pellets using RNeasy mini kit (Qiagen, catalog #74104) using the following protocol. 600 μl of buffer RLT were added to disrupt cells by pipetting up and down several times. The cell lysate was homogenized by passing it 10 times through a 20-gauge needle fitted to an RNase-free syringe. One volume of 70% ethanol was added to the homogenized lysate and mixed well by pipetting. Up to 700 μl at a time of the sample were added to an RNeasy spin column and spun for 15 seconds at 10,000 rpm, discarding flow through. 700 μl of buffer RW1 were added to the column and spun for 15 seconds at 10,000 rpm, discarding flow through. 500 μl of buffer RPE were added to wash the column membrane and spun for 15 seconds at 10,000 rpm, discarding flow through. The same step was repeated one more time, but the column was centrifuged for 2 minutes. Sample was then centrifuged for 1 minute at 10,000 rpm to eliminate any carryover of buffer RPE. RNA was eluted with 30 μl of RNase-free water by centrifuging for 1 minute at 10,000 rpm. Subsequently, 2 μg of total RNA were used to synthesize first-strand cDNA using SuperScript First-Strand Synthesis System for RT-PCR (Invitrogen, catalog #11904-018) according to following protocol: 2 tag of RNA+2 μl dNTP+2 μl Oligo (dT)+DEPC-H 2 O (to 20 μl) were incubated at 65° C. for 5 minutes, then transferred to ice for at least 1 minute. The sample was then added to the following mixture: 4 μl of 10×RT buffer+8 μl 25 mM MgCl 2 +4 μl 0.1 M DTT+2 μl RNase OUT and incubated at 42° C. for 2 minutes. Then, 2 μl of SuperScript II RT were added to the sample and incubated at 42° C. for 50 minutes. Sample was then incubated at 70° C. for 15 minutes and chilled on ice. 2 μl of RNase H were then added and the sample was incubated at 37° C. for 20 minutes. cDNA was then used as template for PCR amplification of variable regions of antibodies. PCR was performed using first-strand cDNA, primers from Mouse Ig-Primer Set (Novagen, catalog #69831-3) and Platinum Super Mix High Fidelity (Invitrogen, catalog #12532-016). To amplify heavy chain variable regions, PCR samples were assembled as follows: 22.5 μl PCR Super Mix+0.25 μl reverse primer MuIgG V H 3′-2+1 μl cDNA+1.25 μl of one the forward primers (VH-A, VH-B) or 0.5 μl of one of the forward primers (VH-C, VH-D, VH-E, VH-F). To amplify light chain variable regions, PCR samples were assembled as follows: 22.5 μl PCR Super Mix+0.25 μl reverse primer MuIgKV L -3′-1+1 μl cDNA+1.25 μl of one the forward primers (VL-A, VL-B) or 0.5 μl of one of the forward primers (VL-C, VL-D, VL-E, VL-F, VL-G).
For samples with primers VH-A, VH-B, VL-A and VL-B, the following PCR cycles were used (40-45 cycles, steps 2 through 4):
1—Denature 94° C. 2 minutes.

2—Denature 94° C. 30 seconds.

3—Anneal 50° C. 30 seconds.

4—Extend 68° C. 1 minute.

5—Final extension 68° C. 5 minutes.

6—Cool 4° C. forever

For samples with primers VH-C through VH-F, and VL-C through VL-G, the following PCR cycles were used (40-45 cycles, steps 2 through 4):

1—Denature 94° C. 2 minutes.

2—Denature 94° ° C. 30 seconds.

3—Anneal 60° C. 30 seconds.

4—Extend 68° C. 1 minute.

5—Final extension 68° C. 5 minutes.

6—Cool 4° C. forever

PCR products were run on a 1.2% agarose gel, and bands migrating at the expected size (400-500 bp) were excised for DNA extraction. DNA was purified using QIAquick Gel Extraction Kit (Qiagen, catalog #28704) according to the following protocol: gel slices were weighed. 3 volumes of buffer QG to 1 volume of gel were added to each gel slice. Samples were incubated at 50° C. for 10 minutes until gel slices were completely dissolved, mixing every 2-3 minutes. One gel volume of isopropanol was then added to each sample and mixed. Samples were then applied to QIAquick column and centrifuged for 1 minute at 13000 rpm. To wash, 750 μl of buffer PE were added to samples and spun for 1 minute at 13000 rpm. Columns were then centrifuged for an additional minute at 13,000 rpm to completely remove residual ethanol DNA was eluted by adding 30 μl of H 2 O to each column and by spinning 1 minute at 13,000 rpm. Purified PCR products were then sequenced to identify variable region sequences (see Tables below).





TABLE 18



VH and VL Amino Acid Sequences of Rat

Anti-Human VEGFA Monoclonal Antibodies






SEQ ID

Protein
V Region

NO:
Clone
Region
123456789012345678901234567



406
BDB-4G8-D4 VH

QIQLVQSGPELKKPGESVKISCKAS GYTFTNYGMY W




VKQAPGQGLQYMG WINTETGKPTYADDFKG RFVFFL




ETSASTAYLQINNLKNEDMATYFCAR TNYYYRSYIF




YFDY WGQGTMVTVSS



407
BDB-4G8-D4
CDR-H1

GYTFTNYGMY




408
BDB-4G8-D4
CDR-H2

WINTETGKPTYADDFKG




409
BDB-4G8-D4
CDR-H3

TNYYYRSYIFYFDY




410
BDB-4G8-D4 VL

DTVLTQSPALAVSPGERVSISC RASESVSTHMH WYQ




QKPGQQPKLLIY GASNLES GVPARFSGSGSGTDFTL




TIDPVEADDTATYFC QQSWNDPFT FGAVTKLELK



411
BDB-4G8-D4
CDR-L1

RASESVSTHMH




412
BDB-4G8-D4
CDR-L2

GASNLES




413
BDB-4G8-D4
CDR-L3

QQSWNDPFT




414
BED-4G10-C8 VH

QVQLQQSGTELVKPGSSVKISCKAS GYTFTSNYMH W




IRQQPGNGLEWIG WIYPGDGDTNYNHNFNG KATLTA




DKSSSTAYMQLSSLTSEDFAVYFCAS STRAIPGWFT




Y WGQGTLVTVSS



415
BED-4G10-C8
CDR-H1

GYTFTSNYMH




416
BED-4G10-C8
CDR-H2

WIYPGDGDTNYNHNFNG




417
BED-4G10-C8
CDR-H3

STRAIPGWFTY




418
BED-4G10-C8 VL

DTVLTQSPALAVSPGERVSISC WASESVSTLMH WYQ




QKLGQQPKLLIY GASNLES GVPARFRGSGSGTDFTL




TIDPVEADDTATYFC QQSWSDPYT FGAGTKLELK



419
BED-4G10-C8
CDR-L1

WASESVSTLMH




420
BED-4G10-C8
CDR-L2

GASNLES




421
BED-4G10-C8
CDR-L3

QQSWSDPYT




422
BEW-10H2-B9 VH

QIQLVQSGPELKKPGESVKISCKAS GYSFTNFGLY W




VKQAPGQGLQYMG WIDTETGKPTYADDFRG RFVFFL




ETSASTAYLQINNLKNEDMATYFCAR VYGYPSWYFD




F WGPGTMVTVSS



423
BEW-10H2-B9
CDR-H1

GYSFTNFGLY




424
BEW-10H2-B9
CDR-H2

WIDTETGKPTYADDFRG




425
BEW-10H2-B9
CDR-H3

VYGYPSWYFDF




426
BEW-10H2-B9 VL

DIQMTQSPASLSTSLEEIVTITC QASQDIDNYLS WY




QQKPGKSPQLLIH SATSLAD GVPSRFSGSRSGTQFS




LKIHRLQVEDTGIYYC LQHFFPPWT FGGGTKLELK



427
BEW-10H2-B9
CDR-L1

QASQDIDNYLS




428
BEW-10H2-B9
CDR-L2

SATSLAD




429
BEW-10H2-B9
CDR-L3

LQHFFPPWT




430
BEW-1B10-B9-C3 VH

EVQLVESGGGLVQPGRSLKLSCAAS GFSFSKYDMA W




FRQTPTKGLEWVA SITTSGVGTYYRDSVKG RFTVSR




DNAKSTLYLQMDSLRSEDTATYYCAR GYGAMDA WGQ




GTSVTVSS



431
BEW-1B10-B9-C3
CDR-H1

GFSFSKYDMA




432
BEW-1B10-B9-C3
CDR-H2

SITTSGVGTYYRDSVKG




433
BEW-1B10-B9-C3
CDR-H3

GYGAMDA




434
BEW-1B10-B9-C3 VL

DIQMTQSPASLSASLEEIVTITC KASQDIDDYLS WY




QQKPGKSPQLVIY AATRLAD GVPSRFSGSGSGTQYS




LKISRLQVDDSGIYYC LQSSSTPWT FGGGTNLELK



435
BEW-1B10-B9-C3
CDR-L1

KASQDIDDYLS




436
BEW-1B10-B9-C3
CDR-L2

AATRLAD




437
BEW-1B10-B9-C3
CDR-L3

LQSSSTPWT




438
BEW-1B4-C4 VH

QIQLVQSGPELKKPGESVKISCKAS GYSFTNYGMY W




VKQAPGQGLQYMG WIDTETGKPTYTDDFKG RFVFFL




ETSASTAYLQINNLKNEDMATYFCAR WSGDTAGIRG




PWFAY WGQGTLVTVSS



439
BEW-1B4-C4
CDR-H1

GYSFTNYGMY




440
BEW-1B4-C4
CDR-H2

WIDTETGKPTYTDDFKG




441
BEW-1B4-C4
CDR-H3

WSGDTAGIRGPWFAY




442
BEW-1B4-C4 VL

DIRMTQSPASLSASLGETVNIEC LASEDIYSDLA WY




QQKPGKSPQLLIY NANDLQK GVPSRFSGSGSGTQYS




LKINSLQSEDVATYFC QQYNYYPGT FGAGTKLELK



443
BEW-1B4-C4
CDR-L1

LASEDIYSDLA




444
BEW-1B4-C4
CDR-L2

NANDLQK




445
BEW-1B4-C4
CDR-L3

QQYNYYPGT




446
BEW-1C6-D2 VH

QIQLVQSGPELKKPGESVKISCKAS GYTFTNYGMY W




VKQAPGQGLQYMG WINTETGKPTYADDFKG RFVFFL




ETSASTAYFQINNLKNEDLATYFCAR PSDYYDGFWF




PY WGQGTLVTVSS



447
BEW-1C6-D2
CDR-H1

GYTFTNYGMY




448
BEW-1C6-D2
CDR-H2

WINTETGKPTYADDFKG




449
BEW-1C6-D2
CDR-H3

PSDYYDGFWFPY




450
BEW-1C6-D2 VL

DTALTQSPALAVSPGERVSISC RASEGVNSYMH WYQ




QSPGQQPKLLIY KASNLAS GVPARFSGSGSGTDFTL




TIDPVEADDTATYFC QQSWYDPLT FGSGTKLEIK



451
BEW-1C6-D2
CDR-L1

RASEGVNSYMH




452
BEW-1C6-D2
CDR-L2

KASNLAS




453
BEW-1C6-D2
CDR-L3

QQSWYDPLT




454
BEW-1E3-D6 VH

QIQLVQSGPELKKPGESVKISCKAS GYPFTNSGMY W




VKQAPGQGLQYMG WINTEAGKPTYADDFKG RFVFFL




ETSASTAYLQINNLKNEDMATYFCAR WGYISDNSYG




WFDY WGQGTLVTVSS



455
BEW-1E3-D6
CDR-H1

GYPFTNSGMY




456
BEW-1E3-D6
CDR-H2

WINTEAGKPTYADDFKG




457
BEW-1E3-D6
CDR-H3

WGYISDNSYGWFDY




458
BEW-1E3-D6 VL

DTVLTQSPALAVSPGERVSISC RASEGVYSYMH WYQ




QNPGQQPKLLIY KASNLAS GVPARFSGSGSGTDFTL




TIDPVEADDTATYFC HQNWNDPLT FGSGTKLEIK



459
BEW-1E3-D6
CDR-L1

RASEGVYSYMH




460
BEW-1E3-D6
CDR-L2

KASNLAS




461
BEW-1E3-D6
CDR-L3

HQNWNDPLT




462
BEW-3A1-D10-G9 VH

QVQLEQSGAELVKPGTSVKLSCMAS GYTSSSNHMN W




MKQTTGQGLEWIG IINPGSGGTRYNVKFEG KATLTV




DKSSSTAFMQLNSLTPEDSAVYYCAR AGFPGPFSYY




AMGA WGQGTSVTVSS



463
BEW-3A1-D10-G9
CDR-H1

GYTSSSNHMN




464
BEW-3A1-D10-G9
CDR-H2

IINPGSGGTRYNVKFEG




465
BEW-3A1-D10-G9
CDR-H3

AGFPGPFSYYAMGA




466
BEW-3A1-D10-G9 VL

DIQMTQSPPVLSASVGDRVTLSC KASQNIHNNLD WY




QQKHGEAPKLLIF YTNNLQT GIPSRFSGSGSGTDYT




LTISSLQPEDVATYYC YQYNSGYT FGAGTKLELK



467
BEW-3A1-D10-G9
CDR-L1

KASQNIHNNLD




468
BEW-3A1-D10-G9
CDR-L2

YTNNLQT




469
BEW-3A1-D10-G9
CDR-L3

YQYNSGYT




470
BEW-5C3-E7 VH

QIQLVQSGPELKKPGESVKISCKAS GYTFTNYGVY W




VKQAPGQGLQYMG WINTETGKPTYADDFKG RFVFFL




ETSTNTAYLQINNLKNEDMATFFCAR ARQLDWFVY W




GQGTLVTVSS



471
BEW-5C3-E7
CDR-H1

GYTFTNYGVY




472
BEW-5C3-E7
CDR-H2

WINTETGKPTYADDFKG




473
BEW-5C3-E7
CDR-H3

ARQLDWFVY




474
BEW-5C3-E7 VL

DTVLTQSPALTVSPGERVSISC RARESLTTSLC WFQ




QKPGQQPKLLIY GASKLES GVPARFSGSGSGTDFTL




TIDPVEADDTATYFC QQSWYDPPT FGGGTKLELK



475
BEW-5C3-E7
CDR-L1

RARESLTTSLC




476
BEW-5C3-E7
CDR-L2

GASKLES




477
BEW-5C3-E7
CDR-L3

QQSWYDPPT




478
BEW-6C2-C8 VH

EVQLVESGGGLVQPGSSLKLSCAAS GFTFSYYGMH W




IRQAPKKGLEWMA LIYYDSSKMYYADSVKG RFTISR




DNSKNTLYLEMNSLRSEDTAMYYCAA GGTAPVY WGQ




GVMVTVSS



479
BEW-6C2-C8
CDR-H1

GFTFSYYGMH




480
BEW-6C2-C8
CDR-H2

LIYYDSSKMYYADSVKG




481
BEW-6C2-C8
CDR-H3

GGTAPVY




482
BEW-6C2-C8 VL

NIQLTQSPSLLSASVGDRVTLSC KGSQNIANYLA WY




QQKLGEAPKLLIY NTDSLQT GIPSRFSGSGSGTDYT




LTISSLQPEDVATYFC YQSNNGYT FGAGTKLELR



483
BEW-6C2-C8
CDR-L1

KGSQNIANYLA




484
BEW-6C2-C8
CDR-L2

NTDSLQT




485
BEW-6C2-C8
CDR-L3

YQSNNGYT




486
BEW-8E6-E4 VH

QIQLVQSGPELKKPGESVKISCKAS GYTFTDYAMH W




VKQAPGKVLKWMG WINTFTGKPTYIDDFKG RFVFSL




EASASTANLQISDLKNEDTATYFCAR GNYYSGYWYF




DF WGPGTMVTMSS



487
BEW-8E6-E4
CDR-H1

GYTFTDYAMH




488
BEW-8E6-E4
CDR-H2

WINTFTGKPTYIDDFKG




489
BEW-8E6-E4
CDR-H3

GNYYSGYWYFDF




490
BEW-8E6-E4 VL

DIQMTQSPASLSASLGETISIEC RASEDISSNLA WY




QQKSGKSPQLLIF AANRLQD GVPSRFSGSGSGTQFS




LKISGMQPEDEGDYFC LQGSKFYT FGAGTKLELK



491
BEW-8E6-E4
CDR-L1

RASEDISSNLA




492
BEW-8E6-E4
CDR-L2

AANRLQD




493
BEW-8E6-E4
CDR-L3

LQGSKFYT




494
BEW-9A8-E2 VH

QIQLVQSGPELKKPGESVKISCKAS GYTFTNYGMY W




VKQAPGQGLQYMG WINTETGKPIYADDFKG RFVFFL




ETSASTAYLQINNLKNEDMATFFCAR VDYDGSFWFA




Y WGQGTLVTVSS



495
BEW-9A8-E2
CDR-H1

GYTFTNYGMY




496
BEW-9A8-E2
CDR-H2

WINTETGKPIYADDFKG




497
BEW-9A8-E2
CDR-H3

VDYDGSFWFAY




498
BEW-9A8-E2 VL

DTVLTQSPALAVSPGERVSISC RASESVSTVIH WYQ




QKPGQQPKLLIH GASNLES GVPARFSGSGSGTDFTL




TIDPVEADDTATYFC QQHWNDPPT FGAGTKLEMK



499
BEW-9A8-E2
CDR-L1

RASESVSTVIH




500
BEW-9A8-E2
CDR-L2

GASNLES




501
BEW-9A8-E2
CDR-L3

QQHWNDPPT




502
BEW-9C2-D6 VH

QIQLVQSGPELKKPGESVKVSCKAS GYTFTNYGIH W




VKQAPGQGLQYVG WINTETGRPTYADDFKG RFVFFL




ETSASTAYLQINNLKNEDMATYFCAR PLYYGYAHYF




DY WGQGVMVTVSS



503
BEW-9C2-D6
CDR-H1

GYTFTNYGIH




504
BEW-9C2-D6
CDR-H2

WINTETGRPTYADDFKG




505
BEW-9C2-D6
CDR-H3

PLYYGYAHYFDY




506
BEW-9C2-D6 VL

DIQMTQSPASLSASLEEIVTITC QASQDIGNWLA WY




QQKPGKSPQLLIY GATSLAD GVPSRFSGSRSGTQYS




LKISRLQVEDIGIYYC QQASSVTYT FGAGTKLELK



507
BEW-9C2-D6
CDR-L1

QASQDIGNWLA




508
BEW-9C2-D6
CDR-L2

GATSLAD




509
BEW-9C2-D6
CDR-L3

QQASSVTYT




510
BEW-9D2-E8 VH

QIQLVQSGPELKKPGESVKISCKAS GYTFTNYGMY W




VKLAPGQGLQYLG WINTETGKPTYADDFKG RFVFFL




ETSASTAYLQINNLRNEDMATYFCAR PSDYYDGFWF




AY WGQGTLVTVSS



511
BEW-9D2-E8
CDR-H1

GYTFTNYGMY




512
BEW-9D2-E8
CDR-H2

WINTETGKPTYADDFKG




513
BEW-9D2-E8
CDR-H3

PSDYYDGFWFAY




514
BEW-9D2-E8 VL

DTVLTQSPALTVSPGERVSISC RASEWVNSYMH WYQ




QNPGQQPKLLIY KASNLAS GVPARFSGSGSGTDFTL




TLDPVEADDTATYFC QQSWNDPLT FGSGTKLEIK



515
BEW-9D2-E8
CDR-L1

RASEWVNSYMH




516
BEW-9D2-E8
CDR-L2

KASNLAS




517
BEW-9D2-E8
CDR-L3

QQSWNDPLT




518
BEW-9E10-E7 VH

QIQLLQSGPELKKPGESVKISCKAS GYTFTNYGMY W




VKQAPGQGLQYMG WIDTETGRPTYADDFKG RFVFFL




ETSASTAYLQINNLKNEDMATYFCAR WSGDTTGIRG




PWFAY WGQGTLVTVSS



519
BEW-9E10-E7
CDR-H1

GYTFTNYGMY




520
BEW-9E10-E7
CDR-H2

WIDTETGRPTYADDFKG




521
BEW-9E10-E7
CDR-H3

WSGDTTGIRGPWFAY




522
BEW-9E10-E7 VL

DIRMTQSPASLSASLGETVNIEC LASEDIYSDLA WY




QQKPGRSPQLLIY NANGLQN GVPSRFGGSGSGTQYS




LKINSLQSEDVATYFC QQYNYFPGT FGAGTKLELK



523
BEW-9E10-E7
CDR-L1

LASEDIYSDLA




524
BEW-9E10-E7
CDR-L2

NANGLQN




525
BEW-9E10-E7
CDR-L3

QQYNYFPGT




526
BEW-9E3-B9 VH

QIQLVQSGPELKKPGESVKISCKAS GYTFTNYGMY W




VKQAPGQGLQYMG WINTETGKPTYADDFKG RFVFFL




ETSASTAFLQINNLKNEDMATYFCAR PSDYYDGFWF




PY WGQGALVTVSS



527
BEW-9E3-B9
CDR-H1

GYTFTNYGMY




528
BEW-9E3-B9
CDR-H2

WINTETGKPTYADDFKG




529
BEW-9E3-B9
CDR-H3

PSDYYDGFWFPY




530
BEW-9E3-B9 VL

DTILTQSPALAVSPGERISISC RASEGVNSYMH WYQ




QNPGQQPKLLIY KASNLAS GVPARFSGSGSGTDFTL




TIDPVEADDTATYFC QQSWNDPLT FGSGTKLEIK



531
BEW-9E3-B9
CDR-L1

RASEGVNSYMH




532
BEW-9E3-B9
CDR-L2

KASNLAS




533
BEW-9E3-B9
CDR-L3

QQSWNDPLT




534
BEW-9E7-B4 VH

QIQLVQSGPELKKPGESVKISCKAS GYTFTNYGMY W




VKQAPGQGLQYMG WIDTETGKPTYADDFKG RFVFFL




ETSASTAYLQINNLRNEDMATYFCAR WGYTSDYYYG




WFPD WGQGTLVTVST



535
BEW-9E7-B4
CDR-H1

GYTFTNYGMY




536
BEW-9E7-B4
CDR-H2

WIDTETGKPTYADDFKG




537
BEW-9E7-B4
CDR-H3

WGYTSDYYYGWFPD




538
BEW-9E7-B4 VL

DTVLTQSPALAVSPGERVSISC RASEGVNSYMH WYQ




QNPGQQPKLLIY KASNLAS GVPARFSGSGSGTDFTL




NIHPVEADDTATYFC QQNWNVPLT FGSGTKLEIK



539
BEW-9E7-B4
CDR-L1

RASEGVNSYMH




540
BEW-9E7-B4
CDR-L2

KASNLAS




541
BEW-9E7-B4
CDR-L3

QQNWNVPLT
































































































































































































































































































































































































TABLE 19



VH and VL Amino Acid Sequences of Rat Anti-Human PDGF-BB Monoclonal

Antibodies






SEQ ID

Protein
V Region

NO:
Clone
Region
12345678901234567890123456



542
BDI-1E1-D5 VH

EVKLQQSGDELVRPGASVKMSCKAS GYTFTDYVMH W




VKQSPGQGLEWIG TIIPLIDTTSYNQKFKG KATLTA




DKSSNTAYMELSRLTSEDSAVYYCAR TSPYYYSSYD




VMDA WGQGASVTVSS



543
BDI-1E1-D5
CDR-H1

GYTFTDYVMH




544
BDI-1E1-D5
CDR-H2

TIIPLIDTTSYNQKFKG




545
BDI-1E1-D5
CDR-H3

TSPYYYSSYDVMDA




546
BDI-1E1-D5 VL

NIQLTQSPSLLSASVGDRVTLSC KGSQNINNYLA WY




QQKLGEAPKLLIY KTNNLQT GIPSRFSGCGSGTDYT




LTISSLHSEDLATYYC YQYDNGYT FGAGTKLELK



547
BDI-1E1-D5
CDR-L1

KGSQNINNYLA




548
BDI-1E1-D5
CDR-L2

KTNNLQT




549
BDI-1E1-D5
CDR-L3

YQYDNGYT




550
BDI-5G2-F9 VH

QVTLKESGPGILQPSQTLSLTCTFS GFSLSTFGMGV




G WIRQPSGKGLEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSNSQAFLEITNVDTADTATYYCAR ISTGISSYY




VMDA WGQGASVTVSS



551
BDI-5G2-F9
CDR-H1

GFSLSTFGMGVG




552
BDI-5G2-F9
CDR-H2

NIWWDDDKYYNPSLKN




553
BDI-5G2-F9
CDR-H3

ISTGISSYYVMDA




554
BDI-5G2-F9 VL

QFTLTQPKSVSGSLRSTITIPC ERSSGDIGDTYVS W




YQQHLGRPPINVIY GNDQRPS EVSDRFSGSIDSSSN




SASLTITNLQMDDEADYFC QSYDSDIDIV FGGGTKL




TVL



555
BDI-5G2-F9
CDR-L1

ERSSGDIGDTYVS




556
BDI-5G2-F9
CDR-L2

GNDQRPS




557
BDI-5G2-F9
CDR-L3

QSYDSDIDIV




558
BDI-5H1-F6 VH

QVTLKESGPGILQPSQTLSLTCTFS GFSLSTFGMGV




G WIRQPSGKGLEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSNSQAFLEITNVDTADTATYYCAR ISTGISSYY




VMDA WGQGASVTVSS



559
BDI-5H1-F6
CDR-H1

GFSLSTFGMGVG




560
BDI-5H1-F6
CDR-H2

NIWWDDDKYYNPSLKN




561
BDI-5H1-F6
CDR-H3

ISTGISSYYVMDA




562
BDI-5H1-F6 VL

QFTLTQPKSVSGSLRSTITIPC ERSSGDIGDTYVS W




YQQHLGRPPINVIY GNDQRPS EVSDRFSGSIDSSSN




SASLTITNLQMDDEADYFC QSYDSDIDIV FGGGTKL




TVL



563
BDI-5H1-F6
CDR-L1

ERSSGDIGDTYVS




564
BDI-5H1-F6
CDR-L2

GNDQRPS




565
BDI-5H1-F6
CDR-L3

QSYDSDIDIV




566
BDI-6A3-A9 VH

EVQLVESGGGLVQPGRSLKFSCAAS GFSFSDSAMA W




VRQAPKKGLEWVA TIIYDGSGTYYRDSVKG RFTISR




DNAKSTLYLQMDSLRSEDTATYYCAR LGFNYGNYGY




YVMDA WGQGASVTVSS



567
BDI-6A3-A9
CDR-H1

GFSFSDSAMA




568
BDI-6A3-A9
CDR-H2

TIIYDGSGTYYRDSVKG




569
BDI-6A3-A9
CDR-H3

LGFNYGNYGYYVMDA




570
BDI-6A3-A9 VL

QFTLTQPKSVSGSLRNTITIPC ERSSGDIGDSYVS W




YQQHLGRPPINVIF ADDQRPS EVSDRFSGSIDSSSN




SASLTITNLQMDDEADYFC QSYDSNIDINIV FGGGT




KLTVL



571
BDI-6A3-A9
CDR-L1

ERSSGDIGDSYVS




572
BDI-6A3-A9
CDR-L2

ADDQRPS




573
BDI-6A3-A9
CDR-L3

QSYDSNIDINIV




574
BDI-7H10-D8 VH

EVKLQQSGDELVRPGASVKMSCKAS GYTFTDYAMH W




VKQSPGQGLEWIG TIIPLIDTTSYNQKFKG KATLTA




DTSSNTAYMELSRLTSEDSAVYYCAR DWDNNWGYFD




Y WGQGVMVTVSS



575
BDI-7H10-D8
CDR-H1

GYTFTDYAMH




576
BDI-7H10-D8
CDR-H2

TIIPLIDTTSYNQKFKG




577
BDI-7H10-D8
CDR-H3

DWDNNWGYFDY




578
BDI-7H10-D8 VL

DVVLTQTPVSLSVTLGDQASISC RSSQSLEYSDGYT




YLE WYLQKPGQSPQLLIY GVSNRFS GVPDRFIGSGS




GTDFTLKISRVEPEDLGVYYC FQATHDPLT FGSGTK




LEIK



579
BDI-7H10-D8
CDR-L1

RSSQSLEYSDGYTYLE




580
BDI-7H10-D8
CDR-L2

GVSNRFS




581
BDI-7H10-D8
CDR-L3

FQATHDPLT




582
BDI-9E8-E7 VH

QVTLKESGPGILQPSQTLSLTCTFS GFSLSTYGMGV




G WIRQPSGKGLEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSNNQAFLKITNVDTADTATYYCAR IESIGTTYS




FDY WGQGVMVTVSS



583
BDI-9E8-E7
CDR-H1

GFSLSTYGMGVG




584
BDI-9E8-E7
CDR-H2

NIWWDDDKYYNPSLKN




585
BDI-9E8-E7
CDR-H3

IESIGTTYSFDY




586
BDI-9E8-E7 VL

QFTLTQPKSVSGSLRSTITIPC ERSSGDIGDSYVS W




YQQHLGRPPINVIY ADDQRPS EVSDRFSGSIDSSSN




SASLTITNLQMDDEADYFC QSYDINIDIV FGGGTKL




TVL



587
BDI-9E8-E7
CDR-L1

ERSSGDIGDSYVS




588
BDI-9E8-E7
CDR-L2

ADDQRPS




589
BDI-9E8-E7
CDR-L3

QSYDINIDIV




590
BFU-11A8-D6-C3 VH

EVQLQQSGPELQRPGASVKLSCKAS GYTFTESYIY W




VKQRPEQSLELIG RIDPEDGSTDYVEKFKN KATLTA




DTSSNTAYMQLSSLTSEDTATYFCAR FGARSYFYPM




DA WGQGTSVTVSS



591
BFU-11A8-D6-C3
CDR-H1

GYTFTESYIY




592
BFU-11A8-D6-C3
CDR-H2

RIDPEDGSTDYVEKFKN




593
BFU-11A8-D6-C3
CDR-H3

FGARSYFYPMDA




594
BFU-11A8-D6-C3 VL

DTVLTQSPTLAVSPGERVSIPC RASESVSTLMH WYQ




QKPGQQPRLLIY GASNLES GVPARFSGSGSGTDFTL




TIDPVEADDTATYFC QQSWNDPWT FGGGTKLELK



595
BFU-11A8-D6-C3
CDR-L1

RASESVSTLMH




596
BFU-11A8-D6-C3
CDR-L2

GASNLES




597
BFU-11A8-D6-C3
CDR-L3

QQSWNDPWT




598
BFU-3E2-B9-B8 VH

EVQLQQSGPELQRPGASVKLSCKAS GYTFTESYMY W




VKQRPEQSLELIG RIDPEDGSTDYVEKFKN KATLTA




DTSSNTAYMQLSSLTSEDSATYFCAR FGARSYFYPM




DA WGQGTSVTVSS



599
BFU-3E2-B9-B8
CDR-H1

GYTFTESYMY




600
BFU-3E2-B9-B8
CDR-H2

RIDPEDGSTDYVEKFKN




601
BFU-3E2-B9-B8
CDR-H3

FGARSYFYPMDA




602
BFU-3E2-B9-B8 VL

DTVLTQPPALAVSPGERVSISC RASESVSTLMH WYQ




QKPGQQPRLLIY GASNLES GVPARFSGSGSGTDFTL




TIDPVEADDTATYFC QQSWNDPWT FGGGTKLELK



603
BFU-3E2-B9-B8
CDR-L1

RASESVSTLMH




604
BFU-3E2-B9-B8
CDR-L2

GASNLES




605
BFU-3E2-B9-B8
CDR-L3

QQSWNDPWT








































































































































































































TABLE 20



VH and VL Amino Acid Sequences of Rat Anti-Human VEGFR II

Monoclonal Antibodies






SEQ ID

Protein
V Region

NO:
Clone
Region
12345678901234567890123456



606
BCU-3D6-C9 VH

QIQLVQSGPELKKPGESVKISCKAS EYTFTDYAIH W




VKQAPGKGLKWMG WINTYTGKPTYADDFKG RFVFSL




EASASTANLQISNLKNEDTATYFCAR DYGGYGERRD




YFDY WGQGVMVTVSS



607
BCU-3D6-C9
CDR-H1

EYTFTDYAIH




608
BCU-3D6-C9
CDR-H2

WINTYTGKPTYADDFKG




609
BCU-3D6-C9
CDR-H3

DYGGYGERRDYFDY




610
BCU-3D6-C9 VL

DIQMTQSPASLSASLGETVTIEC RVSEDIYNGLA WY




QQKPGKSPQFLIY NANRLHT GVPSRFSGSGSGTQFS




LKINSLQSEDVANYFC QQYYDYPLT FGSATKLEIK



611
BCU-3D6-C9
CDR-L1

RVSEDIYNGLA




612
BCU-3D6-C9
CDR-L2

NANRLHT




613
BCU-3D6-C9
CDR-L3

QQYYDYPLT




614
BCU-6B1-G6 VH

QIQLVQSGPELKKPGESVKISCKAS GYTFTNYGMY W




VKQAPGQALQFMG WINTETGQPTYADDFKG RFVFFL




ETSASTAYLQINNLKNEDMATYFCAR LGNNYGIWFA




Y WGQGTLVTVSS



615
BCU-6B1-G6
CDR-H1

GYTFTNYGMY




616
BCU-6B1-G6
CDR-H2

WINTETGQPTYADDFKG




617
BCU-6B1-G6
CDR-H3

LGNNYGIWFAY




618
BCU-6B1-G6 VL

DIQMTQSPASLSASLGETVTIEC RASDDLYSTLA WY




QQKPGDSPQLLIF DANRLAA GVPSRFSGSGSGTQYS




LKINSLQSEDVASYFC QQYNKFPWT FGGGTKLELK



619
BCU-6B1-G6
CDR-L1

RASDDLYSTLA




620
BCU-6B1-G6
CDR-L2

DANRLAA




621
BCU-6B1-G6
CDR-L3

QQYNKFPWT




622
BCU-7A6-C2 VH

EVQLVESGGGLVQPRGSLKLSCAAS GFDFNSYGMS W




VRQAPGKGLDLVA DISSKSYNYATYYADSVKD RFTI




SRDDSQSMVYLQMDNLKTEDTALYYCTE SLELGGAY




WGQGTLVTVSS



623
BCU-7A6-C2
CDR-H1

GFDFNSYGMS




624
BCU-7A6-C2
CDR-H2

DISSKSYNYATYYADSVKD




625
BCU-7A6-C2
CDR-H3

SLELGGAY




626
BCU-7A6-C2 VL

DIQMTQSPPSLSASLGDEVTITC QASQNINKFIA WY




QQKPGKAPRLLIR YTSTLKS GTPSRFSGSGSGRDYS




FSISNVESEDIASYYC LQYDSLPWT FGGGTKLELK



627
BCU-7A6-C2
CDR-L1

QASQNINKFIA




628
BCU-7A6-C2
CDR-L2

YTSTLKS




629
BCU-7A6-C2
CDR-L3

LQYDSLPWT


























































































TABLE 21



VH and VL Amino Acid Sequences of Rat Anti-Human PDGFR-B

Monoclonal Antibodies






SEQ ID

Protein
V Region

NO:
Clone
Region
12345678901234567890123456



630
BDE-3C9-G4 VH

EVQLVESGGGLVQPGRSLKLSCAAS GFTFSNYGMA




WVRQAPTQGLEWVA SITNSGGNTYYRDSVKG RFTI




SRDSAKNTQYLQMDSLRSEDTATYFCAR HTPGANY




FDY WGQGLMVTVSS



631
BDE-3C9-G4
CDR-H1

GFTFSNYGMA




632
BDE-3C9-G4
CDR-H2

SITNSGGNTYYRDSVKG




633
BDE-3C9-G4
CDR-H3

HTPGANYFDY




634
BDE-3C9-G4 VL

DIQMTQSPPSLSASLGEKVTITC QASQSIKNYIA W




YQLKPGTAPRLLMR YTSTLES GTPSRFSGSGSGRD




YSFSISNVESEDIASYYC VQYANLYT FGGGTKLEL




K



635
BDE-3C9-G4
CDR-L1

QASQSIKNYIA




636
BDE-3C9-G4
CDR-L2

YTSTLES




637
BDE-3C9-G4
CDR-L3

VQYANLYT




638
BDE-4F2-D4 VH

QVQLKESGPGLMQPSQTLSLTCTVS GFSLTNYGVS




WVRQFPGKGLEWIA AISSGGSTYYNSALKS RLSIS




RDTSRSQVFLKMNSLLTEDTAFYFCTR VYYGSNYF




DY WGPGVMVTVSS



639
BDE-4F2-D4
CDR-H1

GFSLTNYGVS




640
BDE-4F2-D4
CDR-H2

AISSGGSTYYNSALKS




641
BDE-4F2-D4
CDR-H3

VYYGSNYFDY




642
BDE-4F2-D4 VL

DIVMTQTPSSQAVSAGEKVTMSC KSSQSLLYGGDQ




KNFLA WYQQKPGQSPKLLIY LASTRES GVPDRFIG




SGSGTDFTLTISSVQAEDLADYYC QQHYGYPFT FG




SGTKLEIK



643
BDE-4F2-D4
CDR-L1

KSSQSLLYGGDQKNFLA




644
BDE-4F2-D4
CDR-L2

LASTRES




645
BDE-4F2-D4
CDR-L3

QQHYGYPFT




646
BDE-8H6-F7 VH

EVQLVESGGGLVQPGSSLKLSCLAS GFTFSNYNMY




WIRQAPKKGLEWIA LIFYDNNNKYYADSVKG RFTI




SRDNSKNTLYLEMNSLRSEDTAMYYCLR DSGPFSY




WGQGTLVTVSS



647
BDE-8H6-F7
CDR-H1

GFTFSNYNMY




648
BDE-8H6-F7
CDR-H2

LIFYDNNNKYYADSVKG




649
BDE-8H6-F7
CDR-H3

DSGPFSY




650
BDE-8H6-F7 VL

DIQMTQSPPSLSASLGDKVTINC QAGQNIKKYIA W




YQQEPGKVPRLLIR YTSKLES DTPSRFSGSGSGRD




YSFSISNVESEDIASYYC LQYDNLPWT FGGGTKLE




LK



651
BDE-8H6-F7
CDR-L1

QAGQNIKKYIA




652
BDE-8H6-F7
CDR-L2

YTSKLES




653
BDE-8H6-F7
CDR-L3

LQYDNLPWT
























































































Example 5
Generation of Chimeric Antibodies
The variable domains of the heavy and light chain of the rat mAbs were cloned in-frame to mutant human IgG1 (L234, 235A) heavy-chain and kappa light-chain constant regions, respectively. The activities of the resulting chimeric antibodies were confirmed in ELISA-based binding and competition assays or Biacore binding assay, and were comparable to their parental rat mAbs.
Chimeric anti-VEGF-A antibodies were characterized for binding, function and cross-reactivity in a panel of assays. Potency for all chimeric molecules was characterized in the hVEGF 165 -induced cell proliferation assay (Example 1.7). Binding affinity of these molecules to hVEGF 165 was measured by Biacore analysis (Example 1.1). Select chimeric molecules were tested for the ability to block binding of hVEGF 165 to hVEGF-R2 in a competition ELISA format (Example 1.4) and a hVEGF 111 Tyr1054 phosphorylation assay (Example 1.6). Candidate molecules were then examined for potency in the HMVEC-d hVEGF 165 -induced proliferation assay (Example 1.10) and species cross-reactivity in the rabVEGF 165 -induced cell proliferation assay (Example 1.9). The data is summarized in Tables 22 and 23 below.





TABLE 22



Characterization of Chimeric Anti-Human VEGF-A Monoclonal Antibodies











Receptor



huVEGF-



Competition

huVEGF-A 165
rabbitVEGF-A 165
A 165



ELISA
Phospho-
Neutralization
Neutralization
Neutralization


ELISA
huVEGF-
Tyr1054/
Potency in
Potency in
Potency


huVEGF-
A 165 /
huVEGF-A 111
hVEGFR2
hVEGFR2
in

Chimeric
A 165
huVEGFR2
Neuterlization
Overexpressing
Overexpressing
HMVEC-d

Clones
Binding
(nM)
(nM)
Cells (nM)
Cells (nM)
cells (nM)











chBEW-1B4
NT
NT
NT
1.428
NT
NT

chBEW-1B4
NT
NT
NT
1.669
NT
NT

half-body

chBEW-1E3
NT
NT
NT
0.657
NT
NT

chBEW-1E3
NT
NT
NT
3.752
NT
NT

half-body

chBEW-5C3
NT
NT
NT
0.244
NT
NT

chBEW-5C3
NT
NT
NT
2.264
NT
NT

half-body

chBEW-6C2
NT
0.148
0.435
>10
0.58
0.031

chBEW-6C2
NT
NT
NT
>10
NT
NT

half-body

chBEW-8E6
NT
NT
NT
0.499
NT
NT

chBEW-8E6
NT
NT
NT
>10
NT
NT

half-body

chBEW-9A8
NT
0.097
0.260
0.416
0.510
0.026

chBEW-9A82
NT
NT
NT
1.584
NT
NT

half-body

chBEW-9E10
NT
NT
NT
0.448
NT
NT

chBEW-9E10
NT
NT
NT
0.598
NT
NT

half-body

chBEW-10H2
NT
NT
NT
0.912
NT
NT

chBEW-
NT
NT
NT
2.562
NT
NT

10H2-B9 half-

body

chBEW-9C2
NT
NT
NT
2.090
NT
NT

chBEW-9C2
NT
NT
NT
2.740
NT
NT

half-body

chBEW-9D2
NT
NT
NT
1.556
0.740
2.150

chBEW-9D2
NT
NT
NT
>10
NT
NT

half-body

chBEW-1B10
NT
NT
NT
0.377
NT
NT

chBEW-3A1
NT
NT
NT
0.680
NT
NT

chBEW-3A1
NT
NT
NT
>10
NT
NT

half-body

chBDB-4G8
NT
0.157
0.575
0.687
NT
0.195

chBEW-1C6
NT
NT
NT
3.595
NT
NT

half-body



NT—Not tested







































































TABLE 23



Biacore Binding of Rat and Rat-Human Chimera Anti-VEGF






Antibody
k on (M−1 s−1)
k off (M−1)
K D (M)








chBDB-4G8
1.7E+07
2.4E−05
1.9E−12

chBDB-4G8
1.2E+07
4.7E−05
3.8E−12

chBED-4G10-C8
1.0E+07
5.9E−03
5.9E−10

chBEW-1B4-C4
1.1E+07
1.2E−04
1.1E−11

chBEW-1B10-B9-C3
5.5E+06
5.2E−05
9.4E−12

chBEW-1E3-D6
7.2E+06
8.0E−05
1.1E−11

chBEW-3A1-D10-G9
3.5E+07
8.0E−04
2.3E−11

chBEW-5C3-E7
6.8E+06
8.2E−05
1.2E−11

chBEW-6C2
4.9E+06
4.3E−05
8.8E−12

chBEW-8E6-E4
6.2E+06
1.0E−04
1.6E−11

chBEW-9A8
8.9E+06
≦1.0E−06
≦1.1E−13

chBEW-10H2-B9
2.8E+07
3.5E−04
1.3E−11



































Chimeric anti-PDGF-BB antibodies were characterized for binding, function and cross-reactivity in a panel of assays. The chimeric molecules were first tested for the ability to bind hPDGF-BB in a direct binding ELISA (Example 1.12). Binding affinity of these molecules to hPDGF-BB was then measured by Biacore analysis (Example 1.1). Functional characterization of these molecules included testing of the ability to block binding of hPDGF-BB to hPDGF-Rβ in a competition ELISA format (Example 1.13) and an hPDGFRβ Tyr751 phosphorylation assay (Example 1.14). Potency was further characterized in the hPDGF-BB-induced cell proliferation assay (Example 1.15). Candidate molecules were advanced and cross-reactivity was determined for mouse and rat/rabbit PDGF-BB in the cell-based proliferation assay (Examples 1.17-1.18). The data is summarized in Tables 24 and 25 below.





TABLE 24



Characterization of Chimeric Anti-Human PDGF-BB Monoclonal Antibodies











Receptor
Phospho-
huPDGF-BB
ratPDGF-BB
mPDGF-BB


ELISA
Competition
Tyr751/hPDGF-
Neutralization
Neutralization
Neutralization


huPDGF-
ELISA
BB
Potency (nM)
Potency (nM)
Potency (nM)

Chimeric
BB
huPDGF-BB/
Neutralization
in NIH-3T3
in NIH-3T3
in NIH-3T3

Molecule
Binding
huPDGFR
(nM)
Cells
Cells B (nM)
Cells











chBDI-9E8
0.38
0.791
0.388
0.058
0.075
0.08

chBDI-9E8
NT
NT
NT
1.84
NT
NT

half-body

chBDI-5H1
0.12
1.039
1.602
0.275
0.17
NT

chBDI-5H1
NT
NT
NT
>10
NT
NT

half-body

chBDI-7H10
>10
10.1
2.476
>10
NT
NT

chBDI-5G2
NT
1.08
NT
0.181
0.118
NT

chBDI-1E1
NT
0.417
NT
>5
NT
NT

chBDI-1E1
NT
NT
NT
>10
NT
NT

half body

chBDI-8B8
NT
0.179
NT
>10
NT
NT

chBFU-3E2
NT
NT
NT
0.099
NT
NT

chBFU-3E2
NT
NT
NT
2.494
NT
NT

half-body

chBFU-11A8
NT
NT
NT
0.086
NT
NT

chBFU-11A8
NT
NT
NT
>10
NT
NT

half-body



NT—Not tested

















































TABLE 25



Biacore Binding Of Rat And Rat-Human Chimera Anti-PDGF






Antibody
k on (M−1 s−1)
k off (M−1)
K D (M)








BFU-11A8-D6-C3
2.1E+07
≦1.0E−06
≦4.7E−14

chBDI-5H1
≧1.0E+07
1.5E−04
≦1.5E−11

chBDI-9E8
≧1.0E+07
1.2E−04
≦1.2E−11

chBFU-3E2-B9-B8
≧1.0E+07
1.9E−04
≦1.9E−11

chBFU-11A8-D6-C3
≧1.0E+07
1.5E−04
≦1.5E−11




























Chimeric anti-VEGFR2 antibodies were tested for the ability to block binding of VEGFR2 to hVEGF 165 in a competition ELISA format, as described in Example 1.22. The data is summarized in Table 26.





TABLE 26



Characterization of Chimeric Anti-Human

VEGFR II Monoclonal Antibodies







hVEGF 165 /hVEGFR2-Fc


Chimeric Molecules
Competition





chBCU-6B1-G6
0.498


chBCU-7A6-C2
NT

























Example 6
Humanization of Rat Monoclonal Antibodies
Below are the humanization designs for the rat monoclonal antibodies, followed by summaries of amino acid sequences and characterization of selected humanized antibodies.
Example 6.1
Humanization of PDGF-BB Antibodies
Example 6.1.1
Humanization Method
Antibody humanization is achieved by grafting CDRs of the rodent antibody onto a “similar” human framework (acceptor) and incorporating minimal number of key framework residues (back-mutation) from the rodent antibody that are selected to maintain the original CDR conformation in order to minimize the immunogenicity while retaining the optimal antigen binding.
Example 6.1.2
Human Germline Sequence Selections for Constructing CDR-Grafted, Humanized PDGF Antibodies
By applying the aforementioned method, the CDR sequences of VH and VL chains of monoclonal antibodies BDI-5H1-F6, BDI-9E8-E7, BDI-7H10-D8, BDI-1E1-D5, BDI-6A3-A9, BFU-3E2 and BFU-11A8 were grafted onto different human heavy and light chain acceptor sequences.
Example 6.1.2.1
BDI-5H1-F6
Based on the alignments with the VH and VL sequences of monoclonal antibody BDI-5H1-F6 of the present invention, the following known human sequences are selected:
1. IGHV2-70*01 and IGHJ6*01 for constructing heavy chain acceptor sequences
2. IGHV2-70*04 and IGHJ6*01 as alternative acceptor sequence for constructing heavy chain
3. IGHV3-66*01 and IGHJ1*01 as alternative acceptor sequence for constructing heavy chain
4. IGLV6-57*01 and IGJL2*01 for constructing light chain acceptor sequences
5. IGKV3-20*01 and IGJK4*01 as alternative acceptor sequences for constructing light chain
6. IGKV4-1*01 and IGJK4*01 as alternative acceptor sequences for constructing light chain
7. IGKV1-39*01 and IGJK1*01 as alternative acceptor sequences for constructing light chain
By grafting the corresponding VH and VL CDRs of BDI-5H1-F6 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.1.2.2
BDI-9E8-E7
Based on the alignments with the VH and VL sequences of monoclonal antibody BDI-9E8-E7 of the present invention, the following known human sequences are selected:
1. IGHV2-70*01 and IGHJ3*01 for constructing heavy chain acceptor sequences
2. IGHV2-70*04 and IGHJ6*01 as alternative acceptor sequence for constructing heavy chain
3. IGHV3-66*01 and IGHJ1*01 as alternative acceptor sequence for constructing heavy chain
4. IGLV6-57*01 and IGJL2*01 for constructing light chain acceptor sequences
5. IGKV3-20*01 and IGJK4*01 as alternative acceptor for constructing light chain sequences
6. IGKV4-1*01 and IGJK4*01 as alternative acceptor sequences for constructing light chain
7. IGKV1-39*01 and IGJK1*01 as alternative acceptor sequences for constructing light chain
By grafting the corresponding VH and VL CDRs of BDI-9E8-E7 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.1.2.3
BDI-7H10-D8
Based on the alignments with the VH and VL sequences of monoclonal antibody BDI-7H10-D8 of the present invention, the following known human sequences are selected:
1. IGHV1-69*01 and IGHJ3*01 for constructing heavy chain acceptor sequences
2. IGKV2-29*02 and IGK2*01 for constructing light chain acceptor sequences
By grafting the corresponding VH and VL CDRs of BDI-7H10-D8 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.1.2.4
BDI-1E1-D5
Based on the alignments with the VH and VL sequences of monoclonal antibody BDI-1E1-D5 of the present invention the following known human sequences are selected:
1. IGHV1-69*06 and IGHJ6*01 for constructing heavy chain acceptor sequences
2. IGKV1D-13*01 and IGKJ2*01 for constructing light chain acceptor sequences
3. IGKV3-11*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain
By grafting the corresponding VH and VL CDRs of BDI-1E1-D5 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.1.2.5
BDI-6A3-A9
Based on the alignments with the VH and VL sequences of monoclonal antibody BDI-6A3-A9 of the present invention the following known human sequences are selected:
1. IGHV3-7*01 and IGHJ6*01 for constructing heavy chain acceptor sequences
2. IGHV1-3*01 and IGHJ6*01 as alternative acceptor sequence for constructing heavy chain
3. IGLV6-57*01 and IGJL2*01 for constructing light chain acceptor sequences
By grafting the corresponding VH and VL CDRs of BDI-6A3-A9 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.1.2.6
BFU-3E2
Based on the alignments with the VH and VL sequences of monoclonal antibody BFU-3E2 of the present invention, the following known human sequences are selected:
1. IGHV1-69*01 and IGHJ6*01 for constructing heavy chain acceptor sequences
2. IGKV3-11*01 and IGKJ4*01 for constructing light chain acceptor sequences
3. IGKV1-13*01 and IGKJ4*01 as alternative acceptor sequence for constructing light chain
By grafting the corresponding VH and VL CDRs of BFU-3E2 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.1.2.7
BFU-11A8
Based on the alignments with the VH and VL sequences of monoclonal antibody BFU-11A8 of the present invention, the following known human sequences are selected:
1. IGHV1-69*01 and IGHJ6*01 for constructing heavy chain acceptor sequences
2. IGKV3-11*01 and IGKJ4*01 for constructing light chain acceptor sequences
3. IGKV1-5*01 and IGKJ4*01 as alternative acceptor sequence for constructing light chain
By grafting the corresponding VH and VL CDRs of BFU-11A8 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.1.3
Introducing Potential Framework Back-Mutations in CDR-Grafted Antibodies
To generate humanized antibody with potential framework back-mutations, the mutations were identified and introduced into the CDR-grafted antibody sequences by de novo synthesis of the variable domain, or mutagenic oligonucleotide primers and polymerase chain reactions, or by methods well known in the art. Different combinations of back mutations and other mutations are constructed for each of the CDR-grafts as follows. Residue numbers for these mutations are based on the Kabat numbering system.
BDI-5H1-F6
When IGHV2-70*01 and IGHJ6*01 selected as BDI-5H1-F6 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, A44→G, K75→N, V78→A, M82→I with or without N65→T (CDR change).
When IGHV2-70*04 and IGHJ6*01 selected as BDI-5H1-F6 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q→1E, K5→R, K75→N, N76→S, V78→A and M82→I.
When IGHV3-66*01 and IGHJ1*01 selected as BDI-5H1-F6 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: A24→F, V37→I, V48→L, S49→A, F67→L, R71→K, N73→T, T77→Q, L78→A, and M82→I.
When IGLV6-57*01 and IGJL2*01 selected as BDI-5H1-F6 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: N1→Q, S22→P, S43→P, T464→N, G57→E, P59→S, and Y87→F.
When IGKV3-20*01 and IGJK4*01 selected as BDI-5H1-F6 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→F, A43→P, L46→N, L47→V, I58→V, G66→I, G68→S, T69→N, F71→A, Y87→F and with or without two residues insertion D66a, S66b and deletion of T10.
When IGKV4-1*01 and IGJK4*01 selected as BDI-5H1-F6 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→F, M4→L, L46→N, L47→V, T69→N, D70→S, F71→A, Y87→F.
When IGKV1-39*01 and IGJK1*01 selected as BDI-5H1-F6 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→F, M4→L, L46→N, L47→V, T69→N, D70→S, F71→A, and Y87→F.
BDI-9E8-E7
When IGHV2-70*01 and IGHJ6*01 selected as BDI-9E8-E7 heavy chain acceptor sequences, one or more of following residues could be back-mutated as follows: Q1→E, A44→G, V78→A M82→I with or without N65→T (CDR change).
When IGHV2-70*04 and IGHJ6*01 selected as BDI-9E8-E7 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, K5→R, V78→A, and M82→I.
When IGHV3-66*01 and IGHJ1*01 selected as BDI-9E8-E7 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: A24→F, V37→I, V48→L, S49→A, F67→L, R71→K, N73→T, T77→Q, L78→A, and M82→I.
When IGLV6-57*01 and IGJL2*01 selected as BDI-9E8-E7 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: S43→P, T46→N and Y87→F.
When IGKV3-20*01 and IGJK4*01 selected as BDI-9E8-E7 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→F, A43→P, L46→N, L47→V, I58→V, G66→I, T69→N, F71→A, Y87→F and W/WO two residues insertion (D66a, S66b) and deletion of T10.
When IGKV4-1*01 and IGJK4*01 selected as BDI-9E8-E7 light chain acceptor sequences, one or more of the following residues could be back mutated as follows: I2→F, M4→L, L46→N, L47→V, T69→N, D70→S, F71→A, T72→S, and Y87→F.
When IGKV1-39*01 and IGJK1*01 selected as BDI-9E8-E7 light chain acceptor sequences, one or more of the following residues could be back mutated as follows: I2→F, M4→L, L46→N, L47→V, T69→N, D70→S, F71→A, and T72→S.
BDI-7H10-D8
When IGHV1-69*01 and IGHJ3*01 selected as BDI-7H10-D8 heavy chain acceptor sequences, one or more of following residues could be back-mutated as follows: Q1→E, M48→I, V67→A, I69→L, E73→T, S76→N, with or without CDR changes Y27→G and T30→S.
When IGKV2-29*02 and IGKJ2*01 selected as BDI-7H10-D8 light chain acceptor sequences, one or more of following residues could be back-mutated as follows: I2→V and M4→L.
BDI-1E1-D5
When IGHV1-69*06 and IGHJ6*01 selected as BDI-1E1-D5 heavy chain acceptor sequence, one or more of the following residues could be back-mutated as follows: Q1→E M48→I, V67→A, I69→L and S76→N.
When IGKV1D-13*01 and IGKJ2*01 selected as BDI-1E1-D5 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V58→I and F71→Y.
When IGKV3-11*01 and IGKJ2*01 selected as BDI-1E1-D5 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: F71→Y and V85→T.
BDI-6A3-A9
When IGHV3-7*01 and IGHJ6*01 selected as BDI-6A3-A9 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: S28→T, R60→V, N76→S.
When IGHV1-3*01 and IGHJ6*01 selected as BDI-6A3-A9 heavy chains acceptor sequences, one or more of following residues could be back-mutated as follows: Q1→E, R44→G, M48→V, G49→A, V67→F, T73→N, A78→L and M80→L.
When IGLV6-57*01 and IGJL2*01 selected as BDI-6A3-A9 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: S43→P, T46→N, Y49→F and Y87→F.
BFU-3E2
When IGHV1-69*01 and IGHJ6*01 selected as BFU-3E2 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: R38-->K, G44-->S, W47-->L, M48-->I, R66-->K, V67-->A, 169-->L, S76-->N, Y91-->F.
When IGKV3-11*01 and IGKJ4*01 selected as BFU-3E2 light chain acceptor sequences, one or more of the following could be back-mutated as follows: I2-->T, A43-->Q, 158-->V, Y87-->F.
When IGKV1-13*01 and IGKJ4*01 selected as BFU-3E2 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2-->T, T22-->S, A43-->Q, K45-->R, Y87-->F.
BFU-11A8
When IGHV1-69*01 and IGHJ6*01 selected as BFU-11A8 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: R38-->K, W47-->L, M48-->I, R66-->K, V67-->A, 169-->L, S76-->N, and Y91-->F.
When IGKV3-11*01 and IGKJ4*01 selected as BFU-11A8 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2-->T, S22-->P, A43-->Q, 158-->V, Y87-->F.
When IGKV1-5*01 and IGKJ4*01 selected as BFU-11A8 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2-->T, M4-->L, T22-->P, A43-->Q, Y87-->F.
Example 6.1.4
Generation of Humanized Antibodies to PDGF Containing Framework Back-Mutations in CDR-Grafted Antibodies
The following humanized variable regions of the murine monoclonal PDGF antibodies were cloned into IgG expression vectors for functional characterization.
Example 6.1.4.1
BDI-5H1-F6






TABLE 1.4.1



Sequences of Humanized BDI-5H1-F6 Variable Regions







Sequence

SEQ ID

12345678901234567890123

NO:
Protein region
4567890



3882
hBDI-5H1-F6VH.1z
QVTLRESGPALVKPTQTLTLTCT



FS GFSLS



TFGMGVG WIRQPPGKALEWLA NI




WWDDDKY




YNPSLKN RLTISKDTSKNQVVLT



MTNMDPV



DTATYYCAR ISTGISSYYVMDA W



GQGTTVT



VSS



3883
hBDI-5H1-F6VH.1
EVTLRESGPALVKPTQTLTLTCT



FS GFSLS



TFGMGVG WIRQPPGKALEWLA NI




WWDDDKY




YNPSLKN RLTISKDTSKNQVVLT



MTNMDPV



DTATYYCAR ISTGISSYYVMDA W



GQGTTVT



VSS



3884
hBDI-5H1-F6VH.1a
EVTLRESGPALVKPTQTLTLTCT



FS GFSLS



TFGMGVG WIRQPPGKGLEWLA NI




WWDDDKY




YNPSLKN RLTISKDTSNNQAVLT



ITNMDPV



DTATYYCAR ISTGISSYYVMDA W



GQGTTVT



VSS



3885
hBDI-5H1-F6VH.1b
EVTLRESGPALVKPTQTLTLTCT



FS GFSLS



TFGMGVG WIRQPPGKGLEWLA NI




WWDDDKY




YNPSLKN RLTISKDTSKNQVVLT



ITNMDPV



DTATYYCAR ISTGISSYYVMDA W



GQGTTVT



VSS



3886
hBDI-5H1-F6VH.1c
EVTLRESGPALVKPTQTLTLTCT



FS GFSLS



TFGMGVG WIRQPPGKGLEWLA NI




WWDDDKY




YNPSLKT RLTISKDTSKNQVVLT



ITNMDPV



DTATYYCAR ISTGISSYYVMDA W



GQGTTVT



VSS



3887
hBDI-5H1-F6VH.2z
QVTLKESGPALVKPTQTLTLTCT



FS GFSLS



TFGMGVG WIRQPPGKALEWLA NI




WWDDDKY




YNPSLKN RLTISKDTSKNQVVLT



MTNMDPV



DTATYYCAR ISTGISSYYVMDA W



GQGTTVT



VSS



3888
hBDI-5H1-F6VH.2
EVTLKESGPALVKPTQTLTLTCT



FS GFSLS



TFGMGVG WIRQPPGKALEWLA NI




WWDDDKY




YNPSLKN RLTISKDTSKNQVVLT



MTNMDPV



DTATYYCAR ISTGISSYYVMDA W



GQGTTVT



VSS



3889
hBDI-5H1-F6VH.2a
EVTLKESGPALVKPTQTLTLTCT



FS GFSLS



TFGMGVG WIRQPPGKGLEWLA NI




WWDDDKY




YNPSLKN RLTISKDTSNSQAVLT



ITNMDPV



DTATYYCAR ISTGISSYYVMDA W



GQGTTVT



VSS



3890
hBDI-5H1-F6VH.2b
EVTLKESGPALVKPTQTLTLTCT



FS GFSLS



TFGMGVG WIRQPPGKALEWLA NI




WWDDDKY




YNPSLKN RLTISKDTSKNQAVLT



ITNMDPV



DTATYYCAR ISTGISSYYVMDA W



GQGTTVT



VSS



3891
hBDI-5H1-F6VH.2c
EVTLRESGPALVKPTQTLTLTCT



FS GFSLS



TFGMGVG WIRQPPGKALEWLA NI




WWDDDKY




YNPSLKN RLTISKDTSKNQAVLT



ITNMDPV



DTATYYCAR ISTGISSYYVMDA W



GQGTTVT



VSS



3892
hBDI-5H1-F6VH.v7
EVQLVESGGGLVQPGGSLRLSCA



FS GFSLS



TFGMGVG WIRQAPGKGLEWLA NI




WWDDDKY




YNPSLKN RLTISKDTSKNQAYLQ



INSLRAE



DTAVYYCAR ISTGISSYYVMDA W



GQGTLVT



VSS



3893
hBDI-5H1-F6VL.1
NFMLTQPHSVSESPGKTVTISC E




RSSGDIG




DTYVS WYQQRPGSSPTTVIY GND



QRPS GVP



DRFSGSIDSSSNSASLTISGLKT



EDEADYY



C QSYDSDIDIV FGGGTKLTVL



3894
hBDI-5H1-F6VL.1a
NFMLTQPHSVSESPGKTVTISC E




RSSGDIG




DTYVS WYQQRPGSPPTNVIY GND



QRPS GVP



DRFSGSIDSSSNSASLTISGLKT



EDEADYF



C QSYDSDIDIV FGGGTKLTVL



3895
hBDI-5H1-F6VL.1b
QFMLTQPHSVSESPGKTVTIPC E




RSSGDIG




DTYVS WYQQRPGSPPTNVIY GND



QRPS EVS



DRFSGSIDSSSNSASLTISGLKT



EDEADYF



C QSYDSDIDIV FGGGTKLTVL



3896
hBDI-5H1-F6VL.1c
QFMLTQPHSVSESPGKTVTISCE




RSSGDIG




DTYVSWYQQRPGSSPTTVIY GND



QRPS GVP



DRFSGSIDSSSNSASLTISGLKT



EDEADYF



C QSYDSDIDIV FGGGTKLTVL



3897
hBDI-5H1-F6VL.2
EIVLTQSPGTLSLSPGERATLSC




ERSSGDI




GDTYVS WYQQKPGQAPRLLIY GN



DQRPS GI



PDRFSGSGSGTDFTLTISRLEPE



DFAVYYC



QSYDSDIDIV FGGGTKVEIK



3898
hBDI-5H1-F6L.2a
EFVLTQSPGLSLSPGERATLSC E




RSSGDIG




DTYVS WYQQKPGQPPRNVIY GND



QRPS GVP



DRFSGSIDSSSNDATLTISRLEP



EDFAVYF



C QSYDSDIDIV FGGGTKVEIK



3899
hBDI-5H1-F6L.2b
EFVLTQSPGTLSLSPGERATLSC




ERSSGDI




GDTYVS WYQQKPGQAPRLVIY GN



DQRPS GI



PDRFSGSGSGTDFTLTISRLEPE



DFAVYYC



QSYDSDIDIV FGGGTKVEIK



3900
hBDI-5H1-F6L.2c
EFVLTQSPGTLSLSPGERATLSC




ERSSGDI




GDTYVS WYQQKPGQPPRNVIY GN



DQRPS GV



PDRFSGSGSGTDFTLTISRLEPE



DFAVYFC



QSYDSDIDIV FGGGTKVEIK



3901
hBDI-5H1-F6VL.v6
DFVLTQSPDSLAVSLGERATINC




ERSSGDI




GDTYVS WYQQKPGQPPKNVIY GN



DQRPS GV



PDRFSGSGSGNSATLTISSLQAE



DVAVYFC



QSYDSDIDIV FGGGTKVEIK



3902
hBDI-5H1-F6VL.v7
DFQLTQSPSSLSASVGDRVTITC




ERSSGDI




GDTYVS WYQQKPGKAPKNVIY GN



DQRPS GV



PSRFSGSGSGNSATLTISSLQPE



DFATYFC



QSYDSDIDIV FGQGTKVEIK





















































































































































































































hBDI-5H1-F6VH.1z is a CDR-grafted, humanized BDI-5H1-F6 VH containing IGHV2-70*01 and IGHJ6 framework sequences.
hBDI-5H1-F6VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
hBDI-5H1-F6VH.1a is a humanized design based on .1 and contains four proposed framework back-mutations (A44G, K75N, V78A and M82I).
hBDI-5H1-F6VH.1b is an intermediate design between .1 and .1a and only has two proposed framework back-mutations (A44G and M82I).
hBDI-5H1-F6VH.1c is based on .1b with additional one CDR germlining change N65T to improve identity to human germline sequence.
hBDI-5H1-F6VH.2z is a CDR-grafted, humanized BDI-5H1-F6 VH containing IGHV2-70*04 and IGHJ6 framework sequences.
hBDI-5H1-F6VH.2 is based on .2z with Q1E change to prevent pyroglutamate formation.
hBDI-5H1-F6VH.2a (hBDI-5H1-F6VH.1d) is based on .2 and contains four proposed framework back-mutations (K75N, N76S, V78A and M82I).
hBDI-5H1-F6VH.2b (hBDI-5H1-F6VH.v2) is an intermediate design between .2 and .2a and only has two proposed framework back-mutations (V78A and M82I).
hBDI-5H1-F6VH.2c (hBDI-5H1-F6VH.v6) is based on .2 and contains three proposed framework back-mutations (K5R, V78A, M82I).
hBDI-5H1-F6VH.v7 is a humanized BDI-5H1-F6 VH containing IGHV3-66*01 and IGHJ1 framework sequences with ten proposed framework back-mutations (A24F, V37I, V48L, S49A, F67L, R71K, N73T, T77Q, L78A, and M82I).
hBDI-5H1-F6VL.1 is a CDR-grafted humanized BDI-5H1-F6 VL containing IGLV6-57*01 and IGJL2*01 framework sequences.
hBDI-5H1-F6VL.1a is a humanized design based on .1 with 3 proposed framework back-mutations (S43P, T46N and Y87F).
hBDI-5H1-F6VL.1b is a humanized design based on .1 with 7 proposed framework back-mutations (N1Q, S22P, S43P, T46N, G57E, P59S, Y87F).
hBDI-5H1-F6VL.1c is an intermediate design between .1 and .1b with 2 back-mutations (N1Q and Y87F).
hBDI-5H1-F6VL.2 is a CDR-grafted humanized BDI-5H1-F6 VL containing IGKV3-20*01 and IGJK4*01 framework sequences.
hBDI-5H1-F6VL.2a is a humanized design based on .2 with 10 proposed framework back-mutations (I2F, A43P, L46N, L47V, I58V, G66I, G68S, T69N, F71A, Y87F) and one residue deletion (T10) and two residues insertion (D66a and S66b).
hBDI-5H1-F6VL.2b is based on .2a only with 2 proposed framework back-mutations (12F, L47V) and without residues deletion (T10) and insertion (D66a, S66b).
hBDI-5H1-F6VL.2c is a humanized design on .2 with 6 proposed framework back-mutations




(I2F, A43P, L46N, L47V, I58V, Y87F) and without residues deletion (T10) and insertion (D66a, S66b).
hBDI-5H1-F6VL.v6 is a humanized BDI-5H1-F6 VL containing IGKV4-1*01 and IGJK4*01 framework sequences with eight proposed framework back-mutations (I2F, M4L, L46N, L47V, T69N, D70S, F71A, Y87F). hBDI-5H1-F6VL.v7 is a humanized BDI-5H1-F6 VL containing IGKV1-39*01 and

IGJK1*01 framework sequences with eight proposed framework back-mutations (I2F, M4L, L46N, L47V, T69N, D70S, F71A, and Y87F).
Example 6.1.4.2
BDI-9E8-E7






TABLE 1.4.2



Sequences of Humanized BDI-9E8-E7 Variable Regions





SEQ
Protein
Sequence

ID NO:
region
123456789012345678901234567890



3903
hBDI-9E8-
QVTLRESGPALVKPTQTLTLTCTFS GFSLS


E7VH.1z
TYGMGVG WIRQPPGKALEWLA NIWWDDDKY



YNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTV



SS



3904
hBDI-9E8-
EVTLRESGPALVKPTQTLTLTCTFS GFSLS


E7VH.1
TYGMGVG WIRQPPGKALEWLA NIWWDDDKY



YNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTV



SS



3905
hBDI-9E8-
EVTLRESGPALVKPTQTLTLTCTFS GFSLS


E7VH.1a
TYGMGVG WIRQPPGKGLEWLA NIWWDDDKY



YNPSLKN RLTISKDTSKNQAVLTITNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTV



SS



3906
hBDI-9E8-
EVTLRESGPALVKPTQTLTLTCTFS GFSLS


E7VH.1b
TYGMGVG WIRQPPGKGLEWLA NIWWDDDKY



YNPSLKN RLTISKDTSKNQVVLTITNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTV



SS



3907
hBDI-9E8-
EVTLRESGPALVKPTQTLTLTCTFS GFSLS


E7VH.1c
TYGMGVG WIRQPPGKGLEWLA NIWWDDDKY



YNPSLKT RLTISKDTSKNQVVLTITNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTV



SS



3908
hBDI-9E8-
EVTLRESGPALVKPTQTLTLTCTFS GFSLS


E7VH.v6
TYGMGVG WIRQPPGKALEWLA NIWWDDDKY



YNPSLKN RLTISKDTSKNQAVLTITNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTTVTV



SS



3909
hBDI-9E8-
EVQLVESGGGLVQPGGSLRLSCAFS GFSLS


E7VH.v7
TYGMGVG WIRQAPGKGLEWLA NIWWDDDKY



YNPSLKN RLTISKDTSKNQAYLQINSLRAE



DTAVYYCAR IESIGTTYSFDY WGQGTLVTV



SS



3910
hBDI-9E8-
NFMLTQPHSVSESPGKTVTISC ERSSGDIG


E7VL.1
DSYVS WYQQRPGSSPTTVIY ADDQRPS GVP



DRFSGSIDSSSNSASLTISGLKTEDEADYY



C QSYDINIDIV FGGGTKLTVL



3911
hBDI-9E8-
NFMLTQPHSVSESPGKTVTISC ERSSGDIG


E7VL.1a
DSYVS WYQQRPGSPPTNVIY ADDQRPS GVP



DRFSGSIDSSSNSASLTISGLKTEDEADYF



C QSYDINIDIV FGGGTKLTVL



3912
hBDI-9E8-
EIVLTQSPGTLSLSPGERATLSC ERSSGDI


E7VL.2
GDSYVS WYQQKPGQAPRLLIY ADDQRPS GI



PDRFSGSGSGTDFTLTISRLEPEDFAVYYC



QSYDINIDIV FGGGTKVEIK



3913
hBDI-9E8-
EFVLTQSPGLSLSPGERATLSC ERSSGDIG


E7VL.2a
DSYVS WYQQKPGQPPRNVIY ADDQRPS GVP



DRFSGSIDSSGNDATLTISRLEPEDFAVYF



C QSYDINIDIV FGGGTKVEIK



3914
hBDI-9E8-
EFVLTQSPGTLSLSPGERATLSC ERSSGDI


E7VL.2b
GDSYVS WYQQKPGQAPRLVIY ADDQRPS GI



PDRFSGSGSGTDFTLTISRLEPEDFAVYYC



QSYDINIDIV FGGGTKVEIK



3915
hBDI-9E8-
DFVLTQSPDSLAVSLGERATINC ERSSGDI


E7VL.v6
GDSYVS WYQQKPGQPPKNVIY ADDQRPS GV



PDRFSGSGSGNSASLTISSLQAEDVAVYFC



QSYDINIDIV FGGGTKVEIK



3916
hBDI-9E8-
DFQLTQSPSSLSASVGDRVTITC ERSSGDI


E7VL.v7
GDSYVS WYQQKPGKAPKNVIY ADDQRPS GV



PSRFSGSGSGNSASLTISSLQPEDFATYYC



QSYDINIDIV FGQGTKVEIK



































































































hBDI-9E8-E7VH.1z is a CDR-grafted, humanized BDI-9E8-E7 VH containing IGHV2-70*01 and IGHJ3*01 framework sequences.
hBDI-9E8-E7VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
hBDI-9E8-E7VH.1a is a humanized design based on .1 and contains three proposed framework back-mutations (A44G, V78A and M82I).
hBDI-9E8-E7VH.1b is an intermediate design between .1 and .1a and only has two proposed framework back-mutations (A44G and M82I).
hBDI-9E8-E7VH.1c is based on .1b with additional one CDR germlining change N65T to improve identity to human germline sequence.
hBDI-9E8-E7VH.v6 is a humanized BDI-9E8-E7 VH containing IGHV2-70*04 and IGHJ6 framework sequences with four proposed framework back-mutations (Q1E, K5R, V78A, and M82I).
hBDI-9E8-E7VH.v7 is a humanized BDI-9E8-E7 VH containing IGHV3-66*01 and IGHJ1 framework sequences with ten proposed framework back-mutations (A24F, V37I, V48L, S49A, F67L, R71K, N73T, T77Q, L78A, and M82I).
hBDI-9E8-E7VL.1 is a CDR-grafted humanized BDI-9E8-E7 VL containing IGLV6-57*01 and IGJL2*01 framework sequences.
hBDI-9E8-E7VL.1a is a humanized design based on .1 with three proposed framework back-mutations (S43P, T46N and Y87F).
hBDI-9E8-E7VL.2 is a CDR-grafted humanized BDI-9E8-E7 VL containing IGKV3-20*01 and IGJK4*01 framework sequences.
hBDI-9E8-E7VL.2a is a humanized design based on .2 with 9 proposed framework back-mutations (I2F, A43P, L46N, L47V, I58V, G66I, T69N, F71A, Y87F) and one residue deletion (T10) and two residues insertion (D66a and S66b).
hBDI-9E8-E7VL.2b is based on .2a only with 2 proposed framework back-mutations (I2F, L47V) and without residues deletion (T10) and insertion (D66a, S66b).
hBDI-9E8-E7VL.v6 is a humanized BDI-9E8-E7 VL containing IGKV4-1*01 and




IGJK4*01 framework sequences with nine proposed framework back-mutations: (I2F, M4L, L46N, L47V, T69N, D70S, F71A, T72S, and Y87F).
hBDI-9E8-E7VL.v7 is a humanized BDI-9E8-E7 VL containing IGKV1-39*01 and

IGJK1*01 framework sequences with eight proposed framework back-mutations: I2F, M4L, L46N, L47V, T69N, D70S, F71A, and T72S.
Example 6.1.4.3
BDI-7H10-D8






TABLE 1.4.3



Sequences of Humanized BDI-7H10-D8 Variable

Regions





SEQ ID
Protein
Sequence

NO:
region
123456789012345678901234567890



3917
hBDI-7H10-
QVQLVQSGAEVKKPGSSVKVSCKAS GYTFT


D8VH.1z
DYAMH WVRQAPGQGLEWMG TIIPLIDTTSY



NQKFKG RVTITADESTSTAYMELSSLRSED



TAVYYCAR DWDNNWGYFDY WGQGTMVTVSS



3918
hBDI-7H10-
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFT


D8VH.1
DYAMH WVRQAPGQGLEWMG TIIPLIDTTSY



NQKFKG PVTITADESTSTAYMELSSLRSED



TAVYYCAR DWDNNWGYFDY WGQGTMVTVSS



3919
hBDI-7H10-
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFT


D8VH.1a
DYAMH WVRQAPGQGLEWIG TIIPLIDTTSY



NQKFKG RATLTADTSTNTAYMELSSLRSED



TAVYYCAR DWDNNWGYFDY WGQGTMVTVSS



3920
hBDI-7H10-
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFT


D8VH.1b
DYAMH WVRQAPGQGLEWIG TIIPLIDTTSY



NQKFKG PVTITADESTSTAYMELSSLRSED



TAVYYCAR DWDNNWGYFDY WGQGTMVTVSS



3921
hBDI-7H10-
EVQLVQSGAEVKKPGSSVKVSCKAS GGTFS


D8VH.1c
DYAMH WVRQAPGQGLEWIG TIIPLIDTTSY



NQKFKG RVTITADESTSTAYMELSSLRSED



TAVYYCAR DWDNNWGYFDY WGQGTMVTVSS



3922
hBDI-7H10-
DIVMTQTPLSLSVTPGQPASISC RSSQSLE


D8VL.1
YSDGYTYLE WYLQKPGQSPQLLIY GVSNRF



S GVPDPFSGSGSGTDFTLKISPVEAEDVGV



YYC FQATHDPLT FGQGTKLEIK



3923
hBDI-7H10-
DVVLTQTPLSLSVTPGQPASISC RSSQSLE


D8VL.1a
YSDGYTYLE WYLQKPGQSPQLLIY GVSNRF



S GVPDPFSGSGSGTDFTLKISPVEAEDVGV



YYC FQATHDPLT FGQGTKLEIK



3924
hBDI-7H10-
DVVMTQTPLSLSVTPGQPASISC RSSQSLE


D8VL.1b
YSDGYTYLE WYLQKPGQSPQLLIY GVSNRF



S GVPDPFSGSGSGTDFTLKISPVEAEDVGV



YYC FQATHDPLT FGQGTKLEIK































































hBDI-7H10-D8VH.1z is a CDR-grafted, humanized BDI-7H10-D8 VH containing IGHV1-69*01 and IGHJ3 framework sequences.
hBDI-7H10-D8VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
hBDI-7H10-D8VH.1a is a humanized design based on .1 and contains five proposed framework back-mutations (M48I, V67A, I69L, E73T and S76N).
hBDI-7H10-D8VH.1b is an intermediate design between .1 and .1a and only has one proposed framework back-mutation M48I.
hBDI-7H10-D8VH.1c is based on .1b with two additional CDR germlining changes Y27G and T30S.
hBDI-7H10-D8VL.1 is a CDR-grafted humanized BDI-7H10-D8 VL containing IGKV2-29*02 and IGKJ2 framework sequences.
hBDI-7H10-D8VL.1a is a humanized design based on .1 with 2 proposed framework back-mutations 12V and M4L.
hBDI-7H10-D8VL.1b is an intermediate design between .1 and .1a with only one proposed framework back-mutation 12V.




Example 6.1.4.4
BDI-1E1-D5






TABLE 1.4.4



Sequences of Humanized BDI-1E1-D5 Variable Regions





SEQ ID
Protein
Sequence

NO:
region
123456789012345678901234567890



3925
hBDI-1E1-
QVQLVQSGAEVKKPGSSVKVSCKAS GYTFT


D5VH.1z
DYVMH WVRQAPGQGLEWMG TIIPLIDTTSY



NQKFKG RVTITADKSTSTAYMELSSLRSED



TAVYYCAR TSPYYYSSYDVMDA WGQGTTVT



VSS



3926
hBDI-1E1-
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFT


D5VH.1
DYVMH WVRQAPGQGLEWMG TIIPLIDTTSY



NQKFKG RVTITADKSTSTAYMELSSLRSED



TAVYYCAR TSPYYYSSYDVMDA WGQGTTVT



VSS



3927
hBDI-1E1-
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFT


D5VH.1a
DYVMH WVRQAPGQGLEWIG TIIPLIDTTSY



NQKFKG RATLTADKSTNTAYMELSSLRSED



TAVYYCAR TSPYYYSSYDVMDA WGQGTTVT



VSS



3928
hBDI-1E1-
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFT


D5VH.1b
DYVMH WVRQAPGQGLEWIG TIIPLIDTTSY



NQKFKG RVTITADKSTSTAYMELSSLRSED



TAVYYCAR TSPYYYSSYDVMDA WGQGTTVT



VSS



3929
hBDI-1E1-
AIQLTQSPSSLSASVGDRVTITC KGSQNIN


D5VL.1
NYLA WYQQKPGKAPKLLIY KTNNLQT GVPS



RFSGSGSGTDFTLTISSLQPEDFATYYC YQ



YDNGYT FGQGTKLEIK



3930
hBDI-
AIQLTQSPSSLSASVGDRVTITC KGSQNIN


1E1-D5VL.1a
NYLA WYQQKPGKAPKLLIY KTNNLQT GIPS



RFSGSGSGTDYTLTISSLQPEDFATYYC YQ



YDNGYT FGQGTKLEIK



3931
hBDI-1E1-
EIVLTQSPATLSLSPGERATLSC KGSQNIN


D5VL.2
NYLA WYQQKPGQAPRLLIY KTNNLQT GIPA



RFSGSGSGTDFTLTISSLEPEDFAVYYC YQ



YDNGYT FGQGTKLEIK



3932
hBDI-
EIVLTQSPATLSLSPGERATLSC KGSQNIN


1E1-D5VL.2a
NYLA WYQQKPGQAPRLLIY KTNNLQT GIPA



RFSGSGSGTDYTLTISSLEPEDFATYYC YQ



YDNGYT FGQGTKLEIK


































































hBDI-1E1-D5VH.1z is a CDR-grafted, humanized BDI-1E1-D5 VH containing IGHV1-69*06 and JH6 framework sequences.
hBDI-1E1-D5VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
hBDI-1E1-D5VH.1a is a humanized design based on .1 and contains four proposed framework back-mutations (M48I, V67A, I69L and S76N).
hBDI-1E1-D5VH.1b is an intermediate design between .1 and .1a and only has one back-mutations M48I. This design eliminates Carter residue back-mutations.
hBDI-1E1-D5VL.1 is a CDR-grafted humanized BDI-1E1-D5 VL containing IGKV1D-13*01 and Jk2 framework sequences.
hBDI-1E1-D5VL.1a is a humanized design based on .1 with 2 proposed framework back-mutations (V58I and F71Y).
hBDI-1E1-D5VL.2 is a CDR-grafted humanized BDI-1E1-D5 VL containing IGKV3-11*01 and Jk2 framework sequences.
hBDI-1E1-D5VL.2a is a humanized design based on .2 with 2 proposed framework back-mutations (F71Y and V85T).




Example 6.1.4.5
BDI-6A3-A9






TABLE 1.4.5



Sequences of Humanized BDI-6A3-A9 Variable Regions





SEQ
Protein
Sequence

ID NO:
region
123456789012345678901234567890



3933
BDI-6A3-
EVQLVESGGGLVQPGGSLRLSCAAS GFSFS


A9VH.1
DSAMA WVRQAPGKGLEWVA TIIYDGSGTYY



RDSVKG RFTISRDNAKNSLYLQMNSLRAED



TAVYYCAR LGFNYGNYGYYVMDA WGQGTTV



TVSS



3934
hBDI-6A3-
EVQLVESGGGLVQPGGSLRLSCAAS GFSFS


A9VH.1a
DSAMA WVRQAPGKGLEWVA TIIYDGSGTYY



RDSVKG RFTISRDNAKSSLYLQMNSLRAED



TAVYYCAR LGFNYGNYGYYVMDA WGQGTTV



TVSS



3935
hBDI-6A3-
EVQLVESGGGLVQPGGSLRLSCAAS GFTFS


A9VH.1b
DSAMA WVRQAPGKGLEWVA TIIYDGSGTYY



VDSVKG RFTISRDNAKNSLYLQMNSLRAED



TAVYYCAR LGFNYGNYGYYVMDA WGQGTTV



TVSS



3936
hBDI-6A3-
QVQLVQSGAEVKKPGASVKVSCKAS GFSFS


A9VH.2z
DSAMA WVRQAPGQRLEWMG TIIYDGSGTYY



RDSVKG RVTITRDTSASTAYMELSSLRSED



TAVYYCAR LGFNYGNYGYYVMDA WGQGTTV



TVSS



3937
hBDI-6A3-
EVQLVQSGAEVKKPGASVKVSCKAS GFSFS


A9VH.2
DSAMA WVRQAPGQRLEWMG TIIYDGSGTYY



RDSVKG RVTITRDTSASTAYMELSSLRSED



TAVYYCAR LGFNYGNYGYYVMDA WGQGTTV



TVSS



3938
hBDI-6A3-
EVQLVQSGAEVKKPGASVKVSCKAS GFSFS


A9VH.2a
DSAMA WVRQAPGQGLEWVA TIIYDGSGTYY



RDSVKG RFTITRDNSASTLYLELSSLRSED



TAVYYCAR LGFNYGNYGYYVMDA WGQGTTV



TVSS



3939
hBDI-6A3-
EVQLVQSGAEVKKPGASVKVSCKAS GFSFS


A9VH.2b
DSAMA WVRQAPGQGLEWVG TIIYDGSGTYY



RDSVKG RVTITRDTSASTAYLELSSLRSED



TAVYYCAR LGFNYGNYGYYVMDA WGQGTTV



TVSS



3940
hBDI-6A3-
NFMLTQPHSVSESPGKTVTISC ERSSGDIG


A9VL.1
DSYVS WYQQRPGSSPTTVIY ADDQRPS GVP



DRFSGSIDSSSNSASLTISGLKTEDEADYY



C QSYDSNIDINIV FGGGTKLTVL



3941
hBDI-6A3-
NFMLTQPHSVSESPGKTVTISC ERSSGDIG


A9VL.1a
DSYVS WYQQRPGSPPTNVIF ADDQRPS GVP



DRFSGSIDSSSNSASLTISGLKTEDEADYF



C QSYDSNIDINIV FGGGTKLTVL



3942
hBDI-6A3-
NFMLTQPHSVSESPGKTVTISC ERSSGDIG


A9VL.1b
DSYVS WYQQRPGSSPTTVIF ADDQRPS GVP



DRFSGSIDSSSNSASLTISGLKTEDEADYY



C QSYDSNIDINIV FGGGTKLTVL















































































hBDI-6A3-A9VH.1 is a CDR-grafted, humanized BDI-6A3-A9 VH containing IGHV3-7*01 and JH6 framework sequences.
hBDI-6A3-A9VH.1a is a humanized design based on .1 and contains one proposed framework back-mutation N76S.
hBDI-6A3-A9VH.1b is based on .1 with additional two CDR germlining changes S28T and R60V to improve identity to human germline sequence.
hBDI-6A3-A9VH.2z is a CDR-grafted, humanized BDI-6A3-A9 VH containing IGHV1-3*01 and JH6 framework sequences.
hBDI-6A3-A9VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
hBDI-6A3-A9VH.2a is a humanized design based on .2 and contains seven proposed framework back-mutations R44G, M48V, G49A, V67F, T73N, A78L and M80L.
hBDI-6A3-A9VH.2b is an intermediate design between .2 and .2a with only three proposed framework back-mutations R44G, M48V and M80L.
hBDI-6A3-A9VL.1 is a CDR-grafted humanized BDI-6A3-A9 VL containing IGLV6-57*01 and JL2 framework sequences.
hBDI-6A3-A9VL.1a is a humanized design based on .1 with 4 proposed framework back-mutations (S43P, T46N, Y49F and Y87F).
hBDI-6A3-A9VL.1b is an intermediate design between .1 and .1a with only 1 proposed framework back-mutation Y49F.




Example 6.1.4.6
BFU-3E2






TABLE 1.4.6



Sequences of Humanized BFU-3E2 Variable Regions





SEQ ID
Protein
Sequence

NO:
region
123456789012345678901234567890







3943
hBFU-3E2VH.1z
QVQLVQSGAEVKKPGSSVKVSCKAS GYTFT



ESYMY WVRQAPGQGLEWMG RIDPEDGSTDY



VEKFKN RVTITADESTSTAYMELSSLRSED



TAVYYCAR FGARSYFYPMDA WGQGTTVTVS



S



3944
hBFU-3E2VH.1
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFT



ESYMY WVRQAPGQGLEWMG RIDPEDGSTDY



VEKFKN RVTITADESTSTAYMELSSLRSED



TAVYYCAR FGARSYFYPMDA WGQGTTVTVS



S



3945
hBFU-3E2VH.1a
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFT



ESYMY WVKQAPGQGLELIG RIDPEDGSTDY



VEKFKN RVTITADESTSTAYMELSSLRSED



TAVYYCAR FGARSYFYPMDA WGQGTTVTVS



S



3946
hBFU-3E2VH.1b
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFT



ESYMY WVRQAPGQGLELIG RIDPEDGSTDY



VEKFKN RVTLTADESTSTAYMELSSLRSED



TAVYYCAR FGARSYFYPMDA WGQGTTVTVS



S



3947
hBFU-3E2VH.1c
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFT



ESYMY WVRQAPGQGLELIG RIDPEDGSTDY



VEKFKN RVTITADESTSTAYMELSSLRSED



TAVYYCAR FGARSYFYPMDA WGQGTTVTVS



S



3948
hBFU-3E2VH.1d
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFT



ESYMY WVKQAPGQSLELIG RIDPEDGSTDY



VEKFKN KATLTADESTNTAYMELSSLRSED



TAVYFCAR FGARSYFYPMDA WGQGTTVTVS



S



3949
hBFU-3E2VL.1
EIVLTQSPATLSLSPGERATLSC RASESVS



TLMH WYQQKPGQAPRLLIY GASNLES GIPA



RFSGSGSGTDFTLTISSLEPEDFAVYYC QQ



SWNDPWT FGGGTKVEIK



3950
hBFU-3E2VL.1a
ETVLTQSPATLSLSPGERATLSC RASESVS



TLMH WYQQKPGQQPRLLIY GASNLES GVPA



RFSGSGSGTDFTLTISSLEPEDFAVYFC QQ



SWNDPWT FGGGTKVEIK



3951
hBFU-3E2VL.1b
ETVLTQSPATLSLSPGERATLSC RASESVS



TLMH WYQQKPGQAPRLLIY GASNLES GVPA



RFSGSGSGTDFTLTISSLEPEDFAVYFC QQ



SWNDPWT FGGGTKVEIK



3952
hBFU-3E2VL.1c
ETVLTQSPATLSLSPGERATLSC RASESVS



TLMH WYQQKPGQAPRLLIY GASNLES GIPA



RFSGSGSGTDFTLTISSLEPEDFAVYYC QQ



SWNDPWT FGGGTKVEIK



3953
hBFU-3E2VL.2
AIQLTQSPSSLSASVGDRVTITC RASESVS



TLMH WYQQKPGKAPKLLIY GASNLES GVPS



RFSGSGSGTDFTLTISSLQPEDFATYYC QQ



SWNDPWT FGGGTKVEIK



3954
hBFU-3E2VL.2a
ATQLTQSPSSLSASVGDRVTISC RASESVS



TLMH WYQQKPGKQPRLLIY GASNLES GVPS



RFSGSGSGTDFTLTISSLQPEDFATYFC QQ



SWNDPWT FGGGTKVEIK



3955
hBFU-3E2VL.2b
ATQLTQSPSSLSASVGDRVTITC RASESVS



TLMH WYQQKPGKAPRLLIY GASNLES GVPS



RFSGSGSGTDFTLTISSLQPEDFATYFC QQ



SWNDPWT FGGGTKVEIK



3956
hBFU-3E2VL.2c
ATQLTQSPSSLSASVGDRVTITC RASESVS



TLMH WYQQKPGKAPRLLIY GASNLES GVPS



RFSGSGSGTDFTLTISSLQPEDFATYYC QQ



SWNDPWT FGGGTKVEIK





































































































hBFU-3E2VH.1z is a CDR-grafted, humanized BFU-3E2 VH containing IGHV1-69*01 and IGHJ6*01 framework sequences.
hBFU-3E2VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
hBFU-3E2VH.1a is a humanized design based on .1 and contains 7 proposed framework back-mutations (R38K, W47L, M48I, R66K, V67A, 169L, Y91F).
hBFU-3E2VH.1b is an intermediate design between .1 and .1a and contains 3 proposed framework back-mutations (W47L, M48I, I69L).
hBFU-3E2VH.1c is an intermediate design between .1 and .1a and contains 2 proposed framework back-mutations (W47L, M48I.)
hBFU-3E2VH.1d is a humanized design based on .1 and contains 9 proposed framework back-mutations (R38K, G44S, W47L, M48I, R66K, V67A, I69L, S76N, Y91F)
hBFU-3E2VL.1 is a CDR-grafted, humanized BFU-3E2 VL containing IGKV3-11*01 and




IGKJ4*01 framework sequences.
hBFU-3E2VL.1a is a humanized design based on .1 and contains 4 proposed framework back-mutations (I2T, A43Q, I58V, Y87F). hBFU-3E2VL.1b is an intermediate design between .1 and .1a. It contains 3 proposed framework back-mutations (I2T, I58V, Y87F). hBFU-3E2VL.1c is a design based on .1b and contains 1 proposed framework back-mutations: I2T. hBFU-3E2VL.2 is a CDR-grafted, humanized BFU-3E2 VL containing IGKV1-13*01 and

IGKJ4*01 framework sequences.
hBFU-3E2VL.2a is a humanized design based on .2 and contains 5 proposed framework back-mutations (I2T, T22S, A43Q, K45R, Y87F). hBFU-3E2VL.2b is an intermediate design between .2 and 2a. It contains 3 proposed framework back-mutations (I2T, K45R, Y87F). hBFU-3E2VL.2c is a design based on .2b and contains 2 proposed framework back-mutations (I2T, K45R).

Example 6.1.4.7
BFU-11A8






TABLE 1.4.7



Sequences of Humanized BFU-11A8 Variable Regions





SEQ



ID
Protein
Sequence

NO:1
region
1234567891234567891234567890







3957
hBFU-11A8VH.1z
QVQLVQSGAEVKKPGSSVKVSCKAS GYTFT



ESYIY WVRQAPGQGLEWMG RIDPEDGSTDY



VEKFKN RVTITADESTSTAYMELSSLRSED



TAVYYCAR FGARSYFYPMDA WGQGTTVTVS



S



3958
hBFU-11A8VH.1
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFT



ESYIY WVRQAPGQGLEWMG RIDPEDGSTDY



VEKFKN RVTITADESTSTAYMELSSLRSED



TAVYYCAR FGARSYFYPMDA WGQGTTVTVS



S



3959
hBFU-11A8VH.1a
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFT



ESYIY WVKQAPGQGLELIG RIDPEDGSTDY



VEKFKN KATLTADESTNTAYMELSSLRSED



TAVYFCAR FGARSYFYPMDA WGQGTTVTVS



S



3960
hBFU-11A8VH.1b
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFT



ESYIY WVRQAPGQGLELIG RIDPEDGSTDY



VEKFKN RVTLTADESTNTAYMELSSLRSED



TAVYYCAR FGARSYFYPMDA WGQGTTVTVS



S



3961
hBFU-11A8VH.1c
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFT



ESYIY WVRQAPGQGLELIG RIDPEDGSTDY



VEKFKN RVTITADESTSTAYMELSSLRSED



TAVYYCAR FGARSYFYPMDA WGQGTTVTVS



S



3962
hBFU-11A8VL.1
EIVLTQSPATLSLSPGERATLSC RASESVS



TLMH WYQQKPGQAPRLLIY GASNLES GIPA



RFSGSGSGTDFTLTISSLEPEDFAVYYC QQ



SWNDPWT FGGGTKVEIK



3963
hBFU-11A8VL.1a
ETVLTQSPATLSLSPGERATLPC RASESVS



TLMH WYQQKPGQQPRLLIY GASNLES GVPA



RFSGSGSGTDFTLTISSLEPEDFAVYFC QQ



SWNDPWT FGGGTKVEIK



3964
hBFU-11A8VL.1b
ETVLTQSPATLSLSPGERATLSC RASESVS



TLMH WYQQKPGQAPRLLIY GASNLES GVPA



RFSGSGSGTDFTLTISSLEPEDFAVYFC QQ



SWNDPWT FGGGTKVEIK



3965
hBFU-11A8VL.1c
ETVLTQSPATLSLSPGERATLSC RASESVS



TLMH WYQQKPGQAPRLLIY GASNLES GIPA



RFSGSGSGTDFTLTISSLEPEDFAVYYC QQ



SWNDPWT FGGGTKVEIK



3966
hBFU-11A8VL.2
DIQMTQSPSTLSASVGDRVTITC RASESVS



TLMH WYQQKPGKAPKLLIY GASNLES GVPS



RFSGSGSGTEFTLTISSLQPDDFATYYC QQ



SWNDPWT FGGGTKVEIK



3967
hBFU-11A8VL.2a
DTQLTQSPSTLSASVGDRVTIPC RASESVS



TLMH WYQQKPGKQPKLLIY GASNLES GVPS



RFSGSGSGTEFTLTISSLQPDDFATYFC QQ



SWNDPWT FGGGTKVEIK



3968
hBFU-11A8VL.2b
DTQLTQSPSTLSASVGDRVTITC RASESVS



TLMH WYQQKPGKAPKLLIY GASNLES GVPS



RFSGSGSGTEFTLTISSLQPDDFATYFC QQ



SWNDPWT FGGGTKVEIK



3969
hBFU-11A8VL.2c
DTQMTQSPSTLSASVGDRVTITC RASESVS



TLMH WYQQKPGKAPKLLIY GASNLES GVPS



RFSGSGSGTEFTLTISSLQPDDFATYYC QQ



SWNDPWT FGGGTKVEIK
































































































hBFU-11A8VH.1z is a CDR-grafted, humanized BFU-11A8 VH containing IGHV1-69*01 and IGHJ6*01 framework sequences.
hBFU-11A8VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
hBFU-11A8VH.1a is a humanized design based on .1 and contains 8 proposed framework back-mutations: R38K, W47L, M48I, R66K, V67A, 169L, S76N, Y91F.
hBFU-11A8VH.1b is an intermediate design between .1 and .1a and contains 4 proposed framework back-mutations: W47L, M48I, I69L, S76N.
hBFU-11A8VH.1c is a design based on .1b and contains 2 proposed framework back-mutations: W47L, M48I.
hBFU-11A8VL.1 is a CDR-grafted, humanized BFU-11A8 VL containing IGKV3-11*01 and




IGKJ4*01 framework sequences.
hBFU-11A8VL.1a is a humanized design based on .1 and contains 5 proposed framework back-mutations: I2T, S22P, A43Q, 158V, Y87F. hBFU-11A8VL.1b is an intermediate design between .1 and .1a. It contains 3 proposed framework back-mutations: I2T, 158V, Y87F. hBFU-11A8VL.1c is a design based on .1b and contains 1 proposed framework back-mutations: I2T. hBFU-11A8VL.2 is a CDR-grafted, humanized BFU-11A8 VL containing IGKV1-5*01 and

IGKJ4*01 framework sequences.
hBFU-11A8VL.2a is a humanized design based on .2 and contains 5 proposed framework back-mutations: I2T, M4L, T22P, A43Q, Y87F. hBFU-11A8VL.2b is an intermediate design between .2 and 2a. It contains 3 proposed framework back-mutations: I2T, M4L, Y87F. hBFU-11A8VL.2c is a design based on .2b and contains 1 proposed framework back-mutations: I2T.

Example 6.2
Humanization of VEGF Antibodies
Example 6.2.1
Humanization Method
Antibody humanization is achieved by grafting CDRs of the rodent antibody onto a “similar” human framework (acceptor) and incorporating minimal number of key framework residues (back-mutation) from the rodent antibody that are selected to maintain the original CDR conformation in order to minimize the immunogenicity while retaining the optimal antigen binding.
Example 6.2.2
Human Germline Sequence Selections for Constructing CDR-Grafted, Humanized VEGF Antibodies
By applying the aforementioned method, the CDR sequences of VH and VL chains of monoclonal antibodies BDB-4G8-D4, BEW-9A8-E2, BEW-6C2-C8, BEW-9D2-E8, BEW-9E3-B9, BEW-5C3, BEW-9E10, BEW-1B10, and BEW-1E3 were grafted onto different human heavy and light chain acceptor sequences.
Example 6.2.2.1
BDB-4G8-D4
Based on the alignments with the VH and VL sequences of monoclonal antibody BDB-4G8-D4 of the present invention, the following known human sequences are selected:
1. IGHV7-4-1*02 and IGHJ3*01 for constructing heavy chain acceptor sequences
2. IGHV1-18*01 and IGHJ3*01 as backup acceptor sequences for constructing heavy chain
3. IGHV5-51*01 and IGHJ3*01 as backup acceptor sequences for constructing heavy chain
4. IGHV3-66*01 and IGHJ1*01 as backup acceptor sequences for constructing heavy chain
5. IGKV1D-13*01 and IGKJ2*01 for constructing light chain acceptor sequences
6. IGKV3-11*01 and IGKJ2*01 as alternative acceptor sequences for constructing light chain
7. IGKV3-15*01 and IGKJ5*01 as alternative acceptor sequences for constructing light chain
8. IGKV3-15*01 and IGKJ1*01 as alternative acceptor sequences for constructing light chain
9. IGKV1-39*01 and IGKJ1*01 as alternative acceptor sequences for constructing light chain.
By grafting the corresponding VH and VL CDRs of BDB-4G8-D4 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.2.2.2
BEW-9A8-E2
Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-9A8-E2 of the present invention the following known human sequences are selected:
1. IGHV7-81*01 and IGHJ1*01 for constructing heavy chain acceptor sequences
2. IGHV1-18*01 and IGHJ1*01 as alternative acceptor sequence for constructing heavy chain
3. IGHV7-4-1*01 and IGHJ1*01 as alternative acceptor sequence for constructing heavy chain
4. IGKV6-21*01 and IGKJ2*01 for constructing light chain acceptor sequences
5. IGKV1-39*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain
6. IGKV3-11*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain
7. IGKV1-13*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain
By grafting the corresponding VH and VL CDRs of BEW-9A8-E2 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.2.2.3
BEW-6C2-C8
Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-6C2-C8 of the present invention the following known human sequences are selected:
1. IGHV3-7*01 and IGHJ3*01 for constructing heavy chain acceptor sequences
2. IGKV3-11*01 and IGKJ2*01 for constructing light chain acceptor sequences
3. IGKV1-39*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain
By grafting the corresponding VH and VL CDRs of BEW-6C2-C8 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.2.2.4
BEW-9D2-E8
Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-9D2-E8 of the present invention the following known human sequences are selected:
1. IGHV7-81*01 and IGHJ4*01 for constructing heavy chain acceptor sequences
2. IGHV1-18*01 and IGHJ4*01 as alternative acceptor sequence for constructing heavy chain
3. IGKV3-11*01 and IGKJ2*01 for constructing light chain acceptor sequences
4. IGKV1-39*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain
By grafting the corresponding VH and VL CDRs of BEW-9D2-E8 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.2.2.5
BEW-9E3-B9
Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-9E3-B9 of the present invention the following known human sequences are selected:
1. IGHV7-81*01 and IGHJ4*01 for constructing heavy chain acceptor sequences
2. IGHV1-18*01 and IGHJ4*01 as alternative acceptor sequence for constructing heavy chain
3. IGKV3-11*01 and IGKJ2*01 for constructing light chain acceptor sequences
4. IGKV1-39*01 and IGKJ2*01 as alternative acceptor sequence for constructing light chain
By grafting the corresponding VH and VL CDRs of BEW-9E3-B9 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.2.2.6
BEW-5C3
Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-5C3 of the present invention, the following known human sequences are selected:
1. IGHV7-4-1*01 and IGHJ1*01 for constructing heavy chain acceptor sequences
2. IGHV1-69*06 and IGHJ1*01 as alternative acceptor for constructing heavy chain
3. IGKV3-11*01 and IGKJ4*01 for constructing light chain acceptor sequences
4. IGKV1-13*01 and IGKJ4*01 as alternative acceptor for constructing light chain
By grafting the corresponding VH and VL CDRs of BEW-5C3 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.2.2.7
BEW-9E10
Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-9E10 of the present invention, the following known human sequences are selected:
1. IGHV7-4-1*01 and IGHJ1*01 for constructing heavy chain acceptor sequences
2. IGHV1-69*06 and IGHJ1*01 as alternative acceptor for constructing heavy chain
3. IGKV1-27*01 and IGKJ2*01 for constructing light chain acceptor sequences
By grafting the corresponding VH and VL CDRs of BEW-9E10 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.2.2.8
BEW-1B10
Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-1B10 of the present invention, the following known human sequences are selected:
1. IGHV3-7*01 and IGHJ6*01 for constructing heavy chain acceptor sequences
2. IGKV1-39*01 and IGKJ4*01 for constructing light chain acceptor sequences
By grafting the corresponding VH and VL CDRs of BEW-1B10 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.2.2.9
BEW-1E3
Based on the alignments with the VH and VL sequences of monoclonal antibody BEW-1E3 of the present invention, the following known human sequences are selected:
1. IGHV7-4-1*01(0-1) and IGHJ1*01 for constructing heavy chain acceptor sequences
2. IGHV1-18*01 and IGHJ1*01 as alternative acceptor for constructing heavy chain
3. IGKV3-11*01 and IGKJ2*01 for constructing light chain acceptor sequences
4. IGKV1-13*01 and IGKJ2*01 as alternative acceptor for constructing light chain
By grafting the corresponding VH and VL CDRs of BEW-1E3 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.2.3
Introducing Potential Framework Back-Mutations in CDR-Grafted Antibodies
To generate humanized antibody with potential framework back-mutations, the mutations were identified and introduced into the CDR-grafted antibody sequences by de novo synthesis of the variable domain, or mutagenic oligonucleotide primers and polymerase chain reactions, or by methods well known in the art. Different combinations of back mutations and other mutations are constructed for each of the CDR-grafts as follows. Residue numbers for these mutations are based on the Kabat numbering system.
Example 6.2.3.1
BDB-4G8-D4
When IGHV7-4-1*02 and IGHJ3*01 selected as BDB-4G8-D4 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→, V2→I, W47→Y, and Y91→F.
When IGHV1-18*01 and IGHJ3*01 selected as BDB-4G8-D4 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, V2→I, W47→Y, V67→F, M69→F, T71→L and Y91→F.
When IGHV5-51*01 and IGHJ3*01 selected as BDB-4G8-D4 heavy chain acceptor sequences, one or more following residues could be back-mutated as follows: V2→I, A9→T, G24→A, R38→K, W47→Y, Q66→R, V67→F, I69→F, A71→L, I75→F, S76→N, Y79→F and Y91→F.
When IGHV3-66*01 and IGHJ1*01 selected as BDB-4G8-D4 heavy chain acceptor sequences, one or more following residues could be back-mutated as follows: V2→I, E6→Q, L11→V, R38→K, W47→Y, V48→M, S49→G, I69→F, R71→L, N73→T, N76→S, L78→A, M82→L and Y91→F.
When IGKV1D-13*01 and IGKJ2*01 selected as BDB-4G8-D4 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, A43→Q and Y87→F with or without one residue deletion (S10).
When IGKV3-11*01 and IGKJ2*01 selected as BDB-4G8-D4 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: E1→D, I2→T, I58→V, and Y87→F.
When IGKV3-15*01 and IGKJ5*01 or IGKJ5*01 selected as BDB-4G8-D4 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: E1→D, I2→T, M4→L, A9→S, L13→A, L21→I, R45→K, I58→V, A60→S, G66→R, E70→D, E79→Q and Y87→F.
When IGKV1-39*01 and IGKJ1*01 selected as BDB-4G8-D4 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, M4→L, T22→S, and Y87→F.
Example 6.2.3.2
BEW-9A8-E2
When IGHV7-81*01 and IGHJ1*01 selected as BEW-9A8-E2 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E V2→I, P38→K, W47→Y, M71→L, Y90→F and Y91→F with or without CDR change T28→S.
When IGHV1-18*01 and IGHJ1*01 selected as BEW-9A8-E2 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, V2→I, R38→K, W47→Y, V67→F, M69→F, T71→L, Y90→F and Y91→F.
When IGHV7-4-1*01 and IGHJ1*01 selected as BEW-9A8-E2 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, V2→I, R38→K, W47→Y, Y90→F, Y91→F.
When IGKV6-21*01 and IGKJ2*01 selected as BEW-9A8-E2 light chain accepter sequences, one or more of the following residues could be back-mutated as follows: I2→T, S434Q, K49→H and Y87→F. Additional mutations include the following: F10 deletion.
When IGKV1-39*01 and IGKJ2*01 selected as BEW-9A8-E2 light chain accepter sequences, one or more of the following residues could be back-mutated as follows: I2→T, M4→L, A43→Q, Y49→H and Y87→F. Additional mutations include the following: S10 deletion.
When IGKV3-11*01 and IGKJ2*01 selected as BEW-9A8-E2 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, Y49→H, I58→V, V85→T, and Y87→F.
When IGKV1-13*01 and IGKJ2*01 selected as BEW-9A8-E2 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, T22→S, Y49→H, Y87→F.
Example 6.2.3.3
BEW-6C2-C8
When IGHV3-7*01 and IGHJ3*01 selected as BEW-6C2-C8 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V37→I, V48→M and R94→A.
When IGKV3-11*01 and IGKJ2*01 selected as BEW-6C2-C8 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: F71→Y and Y87→F.
When IGKV1-39*01 and IGKJ2*01 selected as BEW-6C2-C8 light chain acceptor sequence, one or more of the following residues could be back-mutated as follows: M4→L, V58→I, F71→Y and Y87→F.
Example 6.2.3.4
BEW-9D2-E8
When IGHV7-81*01 and IGHJ4*01 selected as BEW-9D2-E8 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, V2→I, P38→K, Q39→L, W47→Y, M48→L, M71→L and Y91→F with or without CDR change T28→S.
When IGHV1-18*01 and IGHJ4*01 selected as BEW-9D2-E8 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, V2→I, R38→K, Q39→L, W47→Y, M48→L, V67→F, M69→F, T71→L, M80→L and Y91→F.
When IGKV3-11*01 and IGKJ2*01 selected as BEW-9D2-E8 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, A43→Q, I58→V and Y87→F. Additional mutations include the following: T10 deletion.
When IGKV1-39*01 and IGKJ2*01 selected as BEW-9D2-E8 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, M4→L, A43→Q and Y87→F. Additional mutations include the following: T10 deletion.
Example 6.2.3.5
BEW-9E3-B9
When IGHV7-81*01 and IGHJ4*01 selected as BEW-9E3-B9 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1E, V2→I, W47→Y, M71→L and Y91→F with or without CDR change T28→S.
When IGHV1-18*01 and IGHJ4*01 selected as BEW-9E3-B9 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q1→E, V2→I, W47→Y, V67→F, M69→F, T71→L and Y91→F.
When IGKV3-11*01 and IGKJ2*01 selected as BEW-9E3-B9 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, A43→Q, I58→V and Y87→F. Additional mutations include the following: S10 deletion.
When IGKV1-39*01 and IGKJ2*01 selected as BEW-9E3-B9 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I2→T, M4→L, A43→Q and Y87→F. Additional mutations include the following: S10 deletion.
Example 6.2.3.6
BEW-5C3
When IGHV7-4-1*01 and IGHJ1*01 selected as BEW-5C3 heavy chain accepter sequences, one or more of the following residues could be back-mutated as follows: V2→I, R38→K, W47→Y, Y90→F, Y91→F.
When IGHV1-69*01 and IGHJ1*01 selected as BEW-5C3 heavy chain accepter sequences, one or more of the following residues could be back-mutated as follows: V67→F, I69→F, A71→L. Additional mutations include the following: V2→I, R38→K, W47→Y, T68→V, M80→L, Y90→F, Y91→F.
When IGKV3-11*01 and IGKJ4*01 selected as BEW-5C3 light chain accepter sequences, one or more of the following residues could be back-mutated as follows: E1→D, I2→T, Y36→F, Y87→F. Additional mutations include the following: A43→Q, I58→V, C34→S (CDR change).
When IGKV1-13*01 and IGKJ4*01 selected as BEW-5C3 light chain accepter sequences, one or more of the following residues could be back-mutated as follows: A1→D, I2→T, T22→S, Y36→F, A43→Q, Y87→F with CDR change C34→S.
Example 6.2.3.7
BEW-9E10
When IGHV7-4-1*01 and IGHJ1*01 selected as BEW-9E10 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V2→I, R38→K, W47→Y, Y91→F.
When IGHV1-69*06 and IGHJ1*01 selected as BEW-9E10 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V67→F, I69→F. Additional mutations include the following: V2→I, R38→K, W47→Y, Y91→F.
When IGKV1-27*01 and IGKJ2*01 selected as BEW-9E10 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Q3→R, V43→S, F71→Y, Y87→F. Additional mutations include the following: T22→E, T72→S.
Example 6.2.3.8
BEW-1B10
When IGHV3-7*01 and IGHJ6*01 selected as BEW-1B10 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V37→F, I69→V. Additional mutations include the following: N76→S, S77→T.
When IGKV1-39*01 and IGKJ4*01 selected as BEW-1B10 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: A43→S, F71→Y. Additional mutations include the following: L47→V.
Example 6.2.3.9
BEW-1E3
When IGHV7-4-1*01 and IGHJ1*01 selected as BEW-1E3 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V2→I, R38→K, W47→Y, Y91→F.
When IGHV1-18*01 and IGHJ1*01 selected as BEW-1E3 heavy chain acceptor sequences, one or more of the following residues could be back-mutated as follows: V67→F, M69→F, T71→L. Additional mutations include the following: V2→I, R38→K, W47→Y, Y91→F.
When IGKV3-11*01 and IGKJ2*01 selected as BEW-1E3 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: I58→V, Y87→F. Additional mutations include the following: I2→T, A43→Q.
When IGKV1-13*01 and IGKJ2*01 selected as BEW-1E3 light chain acceptor sequences, one or more of the following residues could be back-mutated as follows: Y87→F. Additional mutations include the following: I2→T, T22→S, A43→Q.
Example 6.2.4
Generation of Humanized Antibodies to VEGF Containing Framework Back-Mutations in CDR-Grafted Antibodies
The following humanized variable regions of the murine monoclonal VEGF antibodies were cloned into IgG expression vectors for functional characterization.
Example 6.2.4.1
BDB-4G8-D4






TABLE 2.4.1



Sequences of Humanized BDB-4G8-D4 Variable Regions





SEQ



ID

Sequence

NO:
Protein region
123456789012345678901234567890







654
hBDB-4G8-D4VH.1z
QVQLVQSGSELKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEWMG WINTETGKPTY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYYCAR TNYYYRSYIFYFDY WGQGTMVT



VSS



655
hBDB-4G8-D4VH.1
EVQLVQSGSELKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEWMG WINTETGKPTY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYYCAR TNYYYRSYIFYFDY WGQGTMVT



VSS



656
hBDB-4G8-D4VH.1a
EIQLVQSGSELKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEYMG WINTETGKPTY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYFCAR TNYYYRSYIFYFDY WGQGTMVT



VSS



657
hBDB-4G8-D4VH.1b
EVQLVQSGSELKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEYMG WINTETGKPTY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYYCAR TNYYYRSYIFYFDY WGQGTMVT



VSS



658
hBDB-4G8-D4VH.2z
QVQLVQSGAEVKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEWMG WINTETGKPTY



ADDFKG RVTMTTDTSTSTAYMELRSLRSDD



TAVYYCAR TNYYYRSYIFYFDY WGQGTMVT



VSS



659
hBDB-4G8-D4VH.2
EVQLVQSGAEVKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEWMG WINTETGKPTY



ADDFKG RVTMTTDTSTSTAYMELRSLRSDD



TAVYYCAR TNYYYRSYIFYFDY WGQGTMVT



VSS



660
hBDB-4G8-D4VH.2a
EIQLVQSGAEVKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEYMG WINTETGKPTY



ADDFKG RFTFTLDTSTSTAYMELRSLRSDD



TAVYFCAR TNYYYRSYIFYFDY WGQGTMVT



VSS



661
hBDB-4G8-D4VH.2b
EVQLVQSGAEVKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEYMG WINTETGKPTY



ADDFKG RVTMTLDTSTSTAYMELRSLRSDD



TAVYYCAR TNYYYRSYIFYFDY WGQGTMVT



VSS



662
hBDB-4G8-D4VH.v3
EIQLVQSGTEVKKPGESLKISCKAS GYTFT



NYGMY WVKQMPGKGLEYMC WINTETGKPTY



ADDFKG RFTFSLDKSFNTAFLQWSSLKASD



TAMYFCAR TNYYYRSYIFYFDY WGQGTMVT



VSS



663
hBDB-4G8-D4VH.v4
EIQLVQSGGGVVQPGGSLRLSCAAS GYTFT



NYGMY WVKQAPGKGLEYMC WINTETGKPTY



ADDFKG RFTFSLDTSKSTAYLQLNSLRAED



TAVYFCAR TNYYYRSYIFYFDY WGQGTLVT



VSS



664
hBDB-4G8-D4VH.v5
EVQLVESGGGLVQPGGSLRLSCAAS GYTFT



NYGMY WVKQAPGKGLEYMG WINTETGKPTY



ADDFKG RFTFSLDTSKSTAYLQMNSLRAED



TAVYFCAR TNYYYRSYIFYFDY WGQGTLVT



VSS



665
hBDB-4G8-D4VL.1
AIQLTQSPSSLSASVGDRVTITC RASESVS



THMH WYQQKPGKAPKLLIY GASNLES GVPS



RFSGSGSGTDFTLTISSLQPEDFATYYC QQ



SWNDPFT FGQGTKLEIK



666
hBDB-4G8-D4VL.1a
ATQLTQSPSLSASVGDRVTITC RASESVST



HMH WYQQKPGKQPKLLIY GASNLES GVPSR



FSGSGSGTDFTLTISSLQPEDFATYFC QQS



WNDPFT FGQGTKLEIK



667
hBDB-4G8-D4VL.1b
ATQLTQSPSLSASVGDRVTITC RASESVST



HMH WYQQKPGKAPKLLIY GASNLES GVPSR



FSGSGSGTDFTLTISSLQPEDFATYYC QQS



WNDPFT FGQGTKLEIK



668
hBDB-4G8-D4VL.1c
ATQLTQSPSSLSASVGDRVTITC RASESVS



THMH WYQQKPGKAPKLLIY GASNLES GVPS



RFSGSGSGTDFTLTISSLQPEDFATYYC QQ



SWNDPFT FGQGTKLEIK



669
hBDB-4G8-D4VL.v2
DTVLTQSPATLSLSPGERATLSC RASESVS



THMH WYQQKPGQAPRLLIY GASNLES GVPA



RFSGSGSGTDFTLTISSLEPEDFAVYFC QQ



SWNDPFT FGQGTKLEIK



670
hBDB-4G8-D4VL.v3
ETVLTQSPATLSVSPGERATLSC RASESVS



THMH WYQQKPGQAPRLLIY GASNLES GVPA



RFSGSGSGTDFTLTISSLQSEDFAVYFC QQ



SWNDPFT FGQGTRLEIK



671
hBDB-4G8-D4VL.v4
DTVLTQSPSTLSASPGERATISC RASESVS



THMH WYQQKPGQAPKLLIY GASNLES GVPS



RFSGSRSGTDFTLTISSLQPEDFAVYFC QQ



SWNDPFT FGQGTKVEIK



672
hBDB-4G8-D4VL.v5
DTQLTQSPSSLSASVGDRVTISC RASESVS



THMH WYQQKPGKAPKLLIY GASNLES GVPS



RFSGSGSGTDFTLTISSLQPEDFATYFC QQ



SWNDPFT FGQGTKVEIK




































































































































hBDB-4G8-D4VH.1z is a CDR-grafted, humanized BDB-4G8-D4 VH containing IGHV7-4-1*02 and IGHJ3*01 framework sequences.
hBDB-4G8-D4VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
hBDB-4G8-D4VH.1a is a humanized design based on .1 and contains three proposed framework back-mutations (V2I, W47Y and Y91F).
hBDB-4G8-D4VH.1b is an intermediate design between .1 and .1a and only has one back-mutations W47Y.
hBDB-4G8-D4VH.2z is a CDR-grafted, humanized BDB-4G8-D4 VH containing IGHV1-18*01 and IGHJ3*01 framework sequences.
hBDB-4G8-D4VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
hBDB-4G8-D4VH.2a is a humanized design based on .2 and contains six proposed framework back-mutations (V2I, W47Y, V67F, M69F, T71L and Y91F).
hBDB-4G8-D4VH.2b is an intermediate design between .2 and .2a and only has two proposed framework back-mutations (W47Y and T71L).
hBDB-4G8-D4VH.v3 is a humanized BDB-4G8-D4 VH containing IGHV5-51*01 and




IGHJ3*01 framework sequences with thirteen proposed framework back-mutations (V21, A9T, G24A, R38K, W47Y, Q66R, V67F, 169F, A71L, I75F, S76N, Y79F and Y91F).
hBDB-4G8-D4VH.v4 is a humanized BDB-4G8-D4 VH containing IGHV3-66*01 and

IGHJ1*01 framework sequences with thirteen proposed framework back-mutations (V21, E6Q, L11V, W47Y, V48M, S49G, 169F, R71L, N73T, N76S, L78A, M82L and Y91F).
hBDB-4G8-D4VH.v5 is a humanized BDB-4G8-D4 containing IGHV3-66*01 and IGHJ1*01 framework sequences with ten proposed framework back-mutations (R38K, W47Y, V48M, S49G, 169F, R71L, N73T, N76S, L78A and Y91F). hBDB-4G8-D4VL.1 is a CDR-grafted humanized BDB-4G8-D4 VL containing IGKV1D-13*01 and IGKJ2*01 framework sequences. hBDB-4G8-D4VL.1a is a humanized design based on .1 with 3 proposed framework back-mutations (I2T, A43Q and Y87F) and one residue deletion (S10). hBDB-4G8-D4VL.1b is an intermediate design between .1 and .1a with only one proposed framework back-mutation 12T. hBDB-4G8-D4VL.1c is a humanized design based on .1b with one residue insertion (S10). hBDB-4G8-D4VL.v2 is a humanized BDB-4G8-D4 VL containing IGKV3-11*01 and

IGKJ2*01 framework sequences with four proposed framework back-mutations (E1D, 12T, I58V, and Y87F).
hBDB-4G8-D4VL.v3 is a humanized BDB-4G8-D4 VL design containing IGKV3-15*01 and

IGKJ5*01 framework sequences with five proposed framework back-mutations (I2T, M4L, I58V, E70D, and Y87F).
hBDB-4G8-D4VL.v4 is a humanized BDB-4G8-D4 VL containing IGKV3-15*01 and

IGKJ1*01 framework sequences with eleven proposed framework back-mutations (E1D, 12T, A9S, L13A, L21I, R45K, I58V, A605, G66R, E79Q, and Y87F).
hBDB-4G8-D4VL.v5 is a humanized BDB-4G8-D4 VL containing IGKV1-39*01 and

IGKJ1*01 framework sequences with four proposed framework back-mutations (I2T, M4L, T22S, and Y87F).
Example 6.2.4.2
BEW-9A8-E2






TABLE 2.4.2



Sequences of Humanized BEW-9A8-E2 Variable Regions





SEQ ID
Protein
Sequence

NO:
region
123456789012345678901234567890







673
hBEW-9A8-
QVQLVQSGHEVKQPGASVKVSCKAS GYTFT


E2VH.1z
NYGMY WVPQAPGQGLEWMG WINTETGKPIY



ADDFKG RFVFSMDTSASTAYLQISSLKAED



MAMYYCAR VDYDGSFWFAY WGQGTLVTVSS



674
hBEW-9A8-
EVQLVQSGHEVKQPGASVKVSCKAS GYTFT


E2VH.1
NYGMY WVPQAPGQGLEWMG WINTETGKPIY



ADDFKG RFVFSMDTSASTAYLQISSLKAED



MAMYYCAR VDYDGSFWFAY WGQGTLVTVSS



675
hBEW-9A8-
EIQLVQSGHEVKQPGASVKVSCKAS GYTFT


E2VH.1a
NYGMY WVKQAPGQGLEYMG WINTETGKPIY



ADDFKG RFVFSLDTSASTAYLQISSLKAED



MAMFFCAR VDYDGSFWFAY WGQGTLVTVSS



676
hBEW-9A8-
EVQLVQSGHEVKQPGASVKVSCKAS GYTFT


E2VH.1b
NYGMY WVPQAPGQGLEYMG WINTETGKPIY



ADDFKG RFVFSLDTSASTAYLQISSLKAED



MAMFYCAR VDYDGSFWFAY WGQGTLVTVSS



677
hBEW-9A8-
EVQLVQSGHEVKQPGASVKVSCKAS GYSFT


E2VH.1c
NYGMY WVPQAPGQGLEYMG WINTETGKPIY



ADDFKG RFVFSLDTSASTAYLQISSLKAED



MAMFYCAR VDYDGSFWFAY WGQGTLVTVSS



678
hBEW-9A8-
QVQLVQSGAEVKKPGASVKVSCKAS GYTFT


E2VH.2z
NYGMY WVRQAPGQGLEWMG WINTETGKPIY



ADDFKG RVTMTTDTSTSTAYMELRSLRSDD



TAVYYCAR VDYDGSFWFAY WGQGTLVTVSS



679
hBEW-9A8-
EVQLVQSGAEVKKPGASVKVSCKAS GYTFT


E2VH.2
NYGMY WVRQAPGQGLEWMG WINTETGKPIY



ADDFKG RVTMTTDTSTSTAYMELRSLRSDD



TAVYYCAR VDYDGSFWFAY WGQGTLVTVSS



680
hBEW-9A8-
EIQLVQSGAEVKKPGASVKVSCKAS GYTFT


E2VH.2a
NYGMY WVKQAPGQGLEYMG WINTETGKPIY



ADDFKG RFTFTLDTSTSTAYMELRSLRSDD



TAVFFCAR VDYDGSFWFAY WGQGTLVTVSS



681
hBEW-9A8-
EVQLVQSGAEVKKPGASVKVSCKAS GYTFT


E2VH.2b
NYGMY WVRQAPGQGLEYMG WINTETGKPIY



ADDFKG RVTMTLDTSTSTAYMELRSLRSDD



TAVFYCAR VDYDGSFWFAY WGQGTLVTVSS



682
hBEW-9A8-
EIQLVQSGAEVKKPGASVKVSCKAS GYTFT


E2VH.2c
NYGMY WVKQAPGQGLEYMG WINTETGKPIY



ADDFKG RFTFTLDTSTSTAYMELRSLRSDD



TAVYYCAR VDYDGSFWFAY WGQGTLVTVSS



683
hBEW-9A8-
EIQLVQSGAEVKKPGASVKVSCKAS GYTFT


E2VH.2d
NYGMY WVRQAPGQGLEWMG WINTETGKPIY



ADDFKG RFTFTLDTSTSTAYMELRSLRSDD



TAVYYCAR VDYDGSFWFAY WGQGTLVTVSS



684
hBEW-9A8-
QVQLVQSGSELKKPGASVKVSCKAS GYTFT


E2VH.3z
NYGMY WVRQAPGQGLEWMG WINTETGKPIY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYYCAR VDYDGSFWFAY WGQGTLVTVSS



685
hBEW-9A8-
EVQLVQSGSELKKPGASVKVSCKAS GYTFT


E2VH.3
NYGMY WVRQAPGQGLEWMG WINTETGKPIY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYYCAR VDYDGSFWFAY WGQGTLVTVSS



686
hBEW-9A8-
EIQLVQSGSELKKPGASVKVSCKAS GYTFT


E2VH.3a
NYGMY WVKQAPGQGLEYMG WINTETGKPIY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYYCAR VDYDGSFWFAY WGQGTLVTVSS



687
hBEW-9A8-
EIQLVQSGSELKKPGASVKVSCKAS GYTFT


E2VH.3b
NYGMY WVRQAPGQGLEWMG WINTETGKPIY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYYCAR VDYDGSFWFAY WGQGTLVTVSS



688
hBEW-9A8-
EIQLVQSGSELKKPGASVKVSCKAS GYTFT


E2VH.3c
NYGMY WVKQAPGQGLEYMG WINTETGKPIY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVFFCAR VDYDGSFWFAY WGQGTLVTVSS



689
hBEW-9A8-
EIVLTQSPDFQSVTPKEKVTITC RASESVS


E2VL.1
TVIH WYQQKPDQSPKLLIK GASNLES GVPS



RFSGSGSGTDFTLTINSLEAEDAATYYC QQ



HWNDPPT FGQGTKLEIK



690
hBEW-9A8-
ETVLTQSPDFQSVTPKEKVTITC RASESVS


E2VL.1a
TVIH WYQQKPDQQPKLLIH GASNLES GVPS



RFSGSGSGTDFTLTINSLEAEDAATYFC QQ



HWNDPPT FGQGTKLEIK



691
hBEW-9A8-
ETVLTQSPDFQSVTPKEKVTITC RASESVS


E2VL.1b
TVIH WYQQKPDQSPKLLIH GASNLES GVPS



RFSGSGSGTDFTLTINSLEAEDAATYYC QQ



HWNDPPT FGQGTKLEIK



692
hBEW-9A8-
ETVLTQSPDQSVTPKEKVTITC RASESVST


E2VL.1c
VIH WYQQKPDQSPKLLIH GASNLES GVPSR



FSGSGSGTDFTLTINSLEAEDAATYYC QQH



WNDPPT FGQGTKLEIK



693
hBEW-9A8-
DIQMTQSPSSLSASVGDRVTITC RASESVS


E2VL.2
TVIH WYQQKPGKAPKLLIY GASNLES GVPS



RFSGSGSGTDFTLTISSLQPEDFATYYC QQ



HWNDPPT FGQGTKLEIK



694
hBEW-9A8-
DTQLTQSPSSLSASVGDRVTITC RASESVS


E2VL.2a
TVIH WYQQKPGKQPKLLIH GASNLES GVPS



RFSGSGSGTDFTLTISSLQPEDFATYFC QQ



HWNDPPT FGQGTKLEIK



695
hBEW-9A8-
DTQMTQSPSSLSASVGDRVTITC RASESVS


E2VL.2b
TVIH WYQQKPGKAPKLLIH GASNLES GVPS



RFSGSGSGTDFTLTISSLQPEDFATYYC QQ



HWNDPPT FGQGTKLEIK



696
hBEW-9A8-
DTQMTQSPSLSASVGDRVTITC RASESVST


E2VL.2c
VIH WYQQKPGKAPKLLIH GASNLES GVPSR



FSGSGSGTDFTLTISSLQPEDFATYYC QQH



WNDPPT FGQGTKLEIK



697
hBEW-9A8-
EIVLTQSPATLSLSPGERATLSC RASESVS


E2VL.3
TVIH WYQQKPGQAPRLLIY GASNLES GIPA



RFSGSGSGTDFTLTISSLEPEDFAVYYC QQ



HWNDPPT FGQGTKLEIK



698
hBEW-9A8-
ETVLTQSPATLSLSPGERATLSC RASESVS


E2VL.3a
TVIH WYQQKPGQAPRLLIH GASNLES GVPA



RFSGSGSGTDFTLTISSLEPEDFATYFC QQ



HWNDPPT FGQGTKLEIK



699
hBEW-9A8-
ETVLTQSPATLSLSPGERATLSC RASESVS


E2VL.3b
TVIH WYQQKPGQAPRLLIY GASNLES GIPA



RFSGSGSGTDFTLTISSLEPEDFAVYFC QQ



HWNDPPT FGQGTKLEIK



700
hBEW-9A8-
ETVLTQSPATLSLSPGERATLSC RASESVS


E2VL.3c
TVIH WYQQKPGQAPRLLIY GASNLES GIPA



RFSGSGSGTDFTLTISSLEPEDFAVYYC QQ



HWNDPPT FGQGTKLEIK



701
hBEW-9A8-
AIQLTQSPSSLSASVGDRVTITC RASESVS


E2VL.4
TVIH WYQQKPGKAPKLLIY GASNLES GVPS



RFSGSGSGTDFTLTISSLQPEDFATYYC QQ



HWNDPPT FGQGTKLEIK



702
hBEW-9A8-
ATQLTQSPSSLSASVGDRVTISC RASESVS


E2VL.4a
TVIH WYQQKPGKAPKLLIH GASNLES GVPS



RFSGSGSGTDFTLTISSLQPEDFATYFC QQ



HWNDPPT FGQGTKLEIK



703
hBEW-9A8-
ATQLTQSPSSLSASVGDRVTITC RASESVS


E2VL.4b
TVIH WYQQKPGKAPKLLIY GASNLES GVPS



RFSGSGSGTDFTLTISSLQPEDFATYFC QQ



HWNDPPT FGQGTKLEIK



704
hBEW-9A8-
ATQLTQSPSSLSASVGDRVTITC RASESVS


E2VL.4c
TVIH WYQQKPGKAPKLLIY GASNLES GVPS



RFSGSGSGTDFTLTISSLQPEDFATYYC QQ



HWNDPPT FGQGTKLEIK

























































































































































































hBEW-9A8-E2VH.1z is a CDR-grafted, humanized BEW-9A8-E2 VH containing IGHV7-81*01 and IGHJ1*01 framework sequences.
hBEW-9A8-E2VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
hBEW-9A8-E2VH.1a is a humanized design based on .1 and contains six proposed framework back-mutations (V2I, P38K, W47Y, M71L, Y90F and Y91F).
hBEW-9A8-E2VH.1b is an intermediate design between .1 and .1a and only has three proposed framework back-mutations (W47Y, M71L and Y90F).
hBEW-9A8-E2VH.1c is based on .1b with additional one CDR germlining change T28S to improve identity to human germline sequence.
hBEW-9A8-E2VH.2z is a CDR-grafted, humanized BEW-9A8-E2 VH containing IGHV1-18*01 and IGHJ1*01 framework sequences.
hBEW-9A8-E2VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
hBEW-9A8-E2VH.2a is a humanized design based on .2 and contains eight proposed framework back-mutations (V2I, R38K, W47Y, V67F, M69F, T71L, Y90F and Y91F).
hBEW-9A8-E2VH.2b is an intermediate design between .2 and .2a and contains three back-mutations (W47Y, M71L and Y90F).
hBEW-9A8-E2VH.2c (hBEW-9A8VH.4a) is an intermediate design between .2 and .2a and contains six proposed framework back-mutations (V21, R38K, W47Y, V67F, M69F, and T71L).
hBEW-9A8-E2VH.2d (hBEW-9A8VH.4b) is an intermediate design between .2 and .2a contains four proposed framework back-mutations (V2I, V67F, M69F, and T71L).
hBEW-9A8VH.3z is a CDR-grafted, humanized BEW-9A8 VH containing IGHV7-4-1*01 and IGHJ1*01 framework sequences.
hBEW-9A8VH.3 is based on .3z with a Q1E change to prevent pyroglutamate formation.
hBEW-9A8VH.3a is a humanized design based on .3 and contains 3 proposed framework back-mutations (V2I, R38K, W47Y).
hBEW-9A8VH.3b is an intermediate design between .3 and .3a and contains 1 proposed framework back-mutations: V21.
hBEW-9A8VH.3c is a humanized design based on .3 and contains 5 proposed framework back-mutations (V2I, R38K, W47Y, Y90F, Y91F).
hBEW-9A8-E2VL.1 is a CDR-grafted humanized BEW-9A8-E2 VL containing IGKV6-21*01 and IGKJ2*01 framework sequences.
hBEW-9A8-E2VL.1a is a humanized design based on .1 with four proposed framework back-mutations (I2T, S43Q, K49H and Y87F).
hBEW-9A8-E2VL.1b is an intermediate design between .1 and .1a with only two proposed framework back-mutation (I2T and K49H).
hBEW-9A8-E2VL.1c is based on .1b with one residue deletion of F10.
hBEW-9A8-E2VL.2 is a CDR-grafted humanized BEW-9A8-E2 VL containing IGKV1-39*01 and IGKJ2*01 framework sequences.
hBEW-9A8-E2VL.2a is a humanized design based on .2 with five proposed framework back-mutations (I2T, M4L, A43Q, Y49H and Y87F).
hBEW-9A8-E2VL.2b is an intermediate design between .1 and .1a with only two proposed framework back-mutation (I2T and Y49H).
hBEW-9A8-E2VL.2c is based on .2b with one residue deletion of S10.
hBEW-9A8VL.3 is a CDR-grafted, humanized BEW-9A8 VL containing IGKV3-11*01 and IGKJ2*01 framework sequences.
hBEW-9A8VL.3a is a humanized design based on .3 and contains 5 proposed framework back-mutations: (I2T, Y49H, I58V, V85T, Y87F).
hBEW-9A8VL.3b is an intermediate design between .3 and 3a. It contains 2 proposed framework back-mutations: (I2T, Y87F).
hBEW-9A8VL.3c is a design based on .3b and contains 1 proposed framework back-mutations: I2T.
hBEW-9A8VL.4 is a CDR-grafted, humanized BEW-9A8 VL containing IGKV1-13*01 and IGKJ2*01 framework sequences.
hBEW-9A8VL.4a is a humanized design based on .4 and contains 4 proposed framework back-mutations: I2T, T22S, Y49H, Y87F.
hBEW-9A8VL.4b is an intermediate design between .4 and 4a. It contains 2 proposed framework back-mutations: I2T, Y87F.
hBEW-9A8VL.4c is a design based on .4b and eliminated Carter residue back-mutations. It contains 1 proposed framework back-mutations: I2T.




Example 6.2.4.3
BEW-6C2-C8






TABLE 2.4.3



Sequences of Humanized BEW-6C2-C8 Variable Regions





SEQ



ID
Protein
Sequence

NO:
region
123456789012345678901234567890







705
hBEW-6C2-C8VH.1
EVQLVESGGGLVQPGGSLRLSCAAS GFTFS



YYGMH WVRQAPGKGLEWVA LIYYDSSKMYY



ADSVKG RFTISRDNAKNSLYLQMNSLRAED



TAVYYCAR GGTAPVY WGQGTMVTVSS



706
hBEW-6C2-
EVQLVESGGGLVQPGGSLRLSCAAS GFTFS


C8VH.1a
YYGMH WIRQAPGKGLEWMA LIYYDSSKMYY



ADSVKG RFTISRDNAKNSLYLQMNSLRAED



TAVYYCAA GGTAPVY WGQGTMVTVSS



707
hBEW-6C2-
EVQLVESGGGLVQPGGSLRLSCAAS GFTFS


C8VH.1b
YYGMH WVRQAPGKGLEWMA LIYYDSSKMYY



ADSVKG RFTISRDNAKNSLYLQMNSLRAED



TAVYYCAA GGTAPVY WGQGTMVTVSS



708
hBEW-6C2-C8VL.1
EIVLTQSPATLSLSPGERATLSC KGSQNIA



NYLA WYQQKPGQAPRLLIY NTDSLQT GIPA



RFSGSGSGTDFTLTISSLEPEDFAVYYC YQ



SNNGYT FGQGTKLEIK



709
hBEW-6C2-
EIVLTQSPATLSLSPGERATLSC KGSQNIA


C8VL.1a
NYLA WYQQKPGQAPRLLIY NTDSLQT GIPA



RFSGSGSGTDYTLTISSLEPEDFAVYFC YQ



SNNGYT FGQGTKLEIK



710
hBEW-6C2-C8VL.2
DIQMTQSPSSLSASVGDRVTITC KGSQNIA



NYLA WYQQKPGKAPKLLIY NTDSLQT GVPS



RFSGSGSGTDFTLTISSLQPEDFATYYC YQ



SNNGYT FGQGTKLEIK



711
hBEW-6C2-
DIQLTQSPSSLSASVGDRVTITC KGSQNIA


C8VL.2a
NYLA WYQQKPGKAPKLLIY NTDSLQT GIPS



RFSGSGSGTDYTLTISSLQPEDFATYFC YQ



SNNGYT FGQGTKLEIK





























































hBEW-6C2-C8VH.1 is a CDR-grafted, humanized BEW-6C2-C8 VH containing IGHV3-7*01 and IGHJ3*01 framework sequences.
hBEW-6C2-C8VH.1a is a humanized design based on .1 and contains three proposed framework back-mutations V37I, V48M and R94A.
hBEW-6C2-C8VH.1b is an intermediate design between .1 and .1a and only has two back-mutations V48M and R94A. This design eliminates Carter residue back-mutations.
hBEW-6C2-C8VL.1 is a CDR-grafted humanized BEW-6C2-C8 VL containing IGKV3-11*01 and IGKJ2*01 framework sequences.
hBEW-6C2-C8VL.1a is a humanized design based on .1 with 2 proposed framework back-mutations (F71Y and Y87F).
hBEW-6C2-C8VL.2 is a CDR-grafted humanized BEW-6C2-C8 VL containing IGKV1-39*01 and IGKJ2*01 framework sequences.
hBEW-6C2-C8VL.2a is a humanized design based on .2 with 4 proposed framework back-mutations (M4L, V58I, F71Y and Y87F).




Example 6.2.4.4
BEW-9D2-E8






TABLE 2.4.4



Sequences of Humanized BEW-9D2-E8 Variable Regions





SEQ



ID
Protein
Sequence

NO:
region
123456789012345678901234567890







712
hBEW-9D2-E8VH.1z
QVQLVQSGHEVKQPGASVKVSCKAS GYTFT



NYGMY WVPQAPGQGLEWMG WINTETGKPTY



ADDFKG RFVFSMDTSASTAYLQISSLKAED



MAMYYCAR PSDYYDGFWFAY WGQGTLVTVS



S



713
hBEW-9D2-E8VH.1
EVQLVQSGHEVKQPGASVKVSCKAS GYTFT



NYGMY WVPQAPGQGLEWMG WINTETGKPTY



ADDFKG RFVFSMDTSASTAYLQISSLKAED



MAMYYCAR PSDYYDGFWFAY WGQGTLVTVS



S



714
hBEW-9D2-E8VH.1a
EIQLVQSGHEVKQPGASVKVSCKAS GYTFT



NYGMY WVKLAPGQGLEYLG WINTETGKPTY



ADDFKG RFVFSLDTSASTAYLQISSLKAED



MAMYFCAR PSDYYDGFWFAY WGQGTLVTVS



S



715
hBEW-9D2-E8VH.1b
EVQLVQSGHEVKQPGASVKVSCKAS GYTFT



NYGMY WVKQAPGQGLEYLG WINTETGKPTY



ADDFKG RFVFSLDTSASTAYLQISSLKAED



MAMYYCAR PSDYYDGFWFAY WGQGTLVTVS



S



716
hBEW-9D2-E8VH.1c
EVQLVQSGHEVKQPGASVKVSCKAS GYSFT



NYGMY WVKQAPGQGLEYLG WINTETGKPTY



ADDFKG RFVFSLDTSASTAYLQISSLKAED



MAMYYCAR PSDYYDGFWFAY WGQGTLVTVS



S



717
hBEW-9D2-E8VH.2z
QVQLVQSGAEVKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEWMG WINTETGKPTY



ADDFKG RVTMTTDTSTSTAYMELRSLRSDD



TAVYYCAR PSDYYDGFWFAY WGQGTLVTVS



S



718
hBEW-9D2-E8VH.2
EVQLVQSGAEVKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEWMG WINTETGKPTY



ADDFKG RVTMTTDTSTSTAYMELRSLRSDD



TAVYYCAR PSDYYDGFWFAY WGQGTLVTVS



S



719
hBEW-9D2-E8VH.2a
EIQLVQSGAEVKKPGASVKVSCKAS GYTFT



NYGMY WVKLAPGQGLEYLG WINTETGKPTY



ADDFKG RFTFTLDTSTSTAYLELRSLRSDD



TAVYFCAR PSDYYDGFWFAY WGQGTLVTVS



S



720
hBEW-9D2-E8VH.2B
EVQLVQSGAEVKKPGASVKVSCKAS GYTFT



NYGMY WVKQAPGQGLEYLG WINTETGKPTY



ADDFKG RVTMTLDTSTSTAYLELRSLRSDD



TAVYYCAR PSDYYDGFWFAY WGQGTLVTVS



S



721
hBEW-9D2-E8VL.1
EIVLTQSPATLSLSPGERATLSC RASEWVN



SYMH WYQQKPGQAPRLLIY KASNLAS GIPA



RFSGSGSGTDFTLTISSLEPEDFAVYYC QQ



SWNDPLT FGQGTKLEIK



722
hBEW-9D2-E8VL.1a
ETVLTQSPATLSLSPGERATLSC RASEWVN



SYMH WYQQKPGQQPRLLIY KASNLAS GVPA



RFSGSGSGTDFTLTISSLEPEDFAVYFC QQ



SWNDPLT FGQGTKLEIK



723
hBEW-9D2-E8VL.1b
ETVLTQSPATLSLSPGERATLSC RASEWVN



SYMH WYQQKPGQAPRLLIY KASNLAS GIPA



RFSGSGSGTDFTLTISSLEPEDFAVYYC QQ



SWNDPLT FGQGTKLEIK



724
hBEW-9D2-E8VL.2
DIQMTQSPSSLSASVGDRVTITC RASEWVN



SYMH WYQQKPGKAPKLLIY KASNLAS GVPS



RFSGSGSGTDFTLTISSLQPEDFATYYC QQ



SWNDPLT FGQGTKLEIK



725
hBEW-9D2-E8VL.2a
DTQLTQSPSSLSASVGDRVTITC RASEWVN



SYMH WYQQKPGKQPKLLIY KASNLAS GVPS



RFSGSGSGTDFTLTISSLQPEDFATYFC QQ



SWNDPLT FGQGTKLEIK



726
hBEW-9D2-E8VL.2b
DTQMTQSPSSLSASVGDRVTITC RASEWVN



SYMH WYQQKPGKAPKLLIY KASNLAS GVPS



RFSGSGSGTDFTLTISSLQPEDFATYYC QQ



SWNDPLT FGQGTKLEIK














































































































hBEW-9D2-E8VH.1z is a CDR-grafted, humanized BEW-9D2-E8 VH containing IGHV7-81*01 and IGHJ4*01 framework sequences.
hBEW-9D2-E8VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
hBEW-9D2-E8VH.1a is a humanized design based on .1 and contains seven proposed framework back-mutations (V2I, P38K, Q39L, W47Y, M48L, M71L and Y91F).
hBEW-9D2-E8VH.1b is an intermediate design between .1 and .1a and only has four proposed framework back-mutations (P38K, W47Y, M48L, M71L).
BEW-9D2-E8VH.1c is based on .1b with additional one CDR germlining change T28S to improve identity to human germline sequence.
hBEW-9D2-E8VH.2z is a CDR-grafted, humanized BEW-9D2-E8 VH containing IGHV1-18*01 and IGHJ4*01 framework sequences.
hBEW-9D2-E8VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
hBEW-9D2-E8VH.2a is a humanized design based on .2 and contains ten proposed framework back-mutations (V21, R38K, Q39L, W47Y, M48L, V67F, M69F, T71L, M80L and Y91F).
hBEW-9D2-E8VH.2b is an intermediate design between .2 and .2a and only has five proposed framework back-mutations (R38K, W47Y, M48L, T71L and M80L).
hBEW-9D2-E8VL.1 is a CDR-grafted humanized BEW-9D2-E8 VL containing IGKV3-11*01 and IGKJ2*01 framework sequences.
hBEW-9D2-E8VL.1a is a humanized design based on .1 with four proposed framework back-mutations (I2T, A43Q, I58V and Y87F).
hBEW-9D2-E8VL.1b is an intermediate design between .1 and .1a with one proposed framework back-mutation 12V.
hBEW-9D2-E8VL.2 is a CDR-grafted humanized BEW-9D2-E8 VL containing IGKV1-39*01 and IGKJ2*01 framework sequences.
hBEW-9D2-E8VL.2a is a humanized design based on .2 with four proposed framework back-mutations (I2T, M4L, A43Q and Y87F).
hBEW-9D2-E8VL.2b is an intermediate design between .2 and .2a with one proposed framework back-mutation 12V.




Example 6.2.4.5
BEW-9E3-B9






TABLE 2.4.5



Sequences of Humanized BEW-9E3-B9 Variable Regions





SEQ



ID
Protein
Sequence

NO:
region
123456789012345678901234567890







727
hBEW-9E3-B9VH.1z
QVQLVQSGHEVKQPGASVKVSCKAS GYTFT



NYGMY WVPQAPGQGLEWMG WINTETGKPTY



ADDFKG RFVFSMDTSASTAYLQISSLKAED



MAMYYCAR PSDYYDGFWFPY WGQGTLVTVS



S



728
hBEW-9E3-B9VH.1
EVQLVQSGHEVKQPGASVKVSCKAS GYTFT



NYGMY WVPQAPGQGLEWMG WINTETGKPTY



ADDFKG RFVFSMDTSASTAYLQISSLKAED



MAMYYCAR PSDYYDGFWFPY WGQGTLVTVS



S



729
hBEW-9E3-B9VH.1a
EIQLVQSGHEVKQPGASVKVSCKAS GYTFT



NYGMY WVPQAPGQGLEYMG WINTETGKPTY



ADDFKG RFVFSLDTSASTAYLQISSLKAED



MAMYFCAR PSDYYDGFWFPY WGQGTLVTVS



S



730
hBEW-9E3-B9VH.1b
EVQLVQSGHEVKQPGASVKVSCKAS GYTFT



NYGMY WVPQAPGQGLEYMG WINTETGKPTY



ADDFKG PFVFSLDTSASTAYLQISSLKAED



MAMYYCAR PSDYYDGFWFPY WGQGTLVTVS



S



731
hBEW-9E3-B9VH.1c
EVQLVQSGHEVKQPGASVKVSCKAS GYSFT



NYGMY WVPQAPGQGLEYMG WINTETGKPTY



ADDFKG RFVFSLDTSASTAYLQISSLKAED



MAMYYCAR PSDYYDGFWFPY WGQGTLVTVS



S



732
hBEW-9E3-B9VH.2z
QVQLVQSGAEVKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEWMG WINTETGKPTY



ADDFKG PVTMTTDTSTSTAYMELRSLPSDD



TAVYYCAR PSDYYDGFWFPY WGQGTLVTVS



S



733
hBEW-9E3-B9VH.2
EVQLVQSGAEVKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEWMG WINTETGKPTY



ADDFKG RVTMTTDTSTSTAYMELRSLRSDD



TAVYYCAR PSDYYDGFWFPY WGQGTLVTVS



S



734
hBEW-9E3-B9VH.2a
EIQLVQSGAEVKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEYMG WINTETGKPTY



ADDFKG RFTFTLDTSTSTAYMELRSLRSDD



TAVYFCAR PSDYYDGFWFPY WGQGTLVTVS



S



735
hBEW-9E3-B9VH.2b
EVQLVQSGAEVKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEYMG WINTETGKPTY



ADDFKG RVTMTLDTSTSTAYMELRSLRSDD



TAVYYCAR PSDYYDGFWFPY WGQGTLVTVS



S



736
hBEW-9E3-B9VL.1
EIVLTQSPATLSLSPGERATLSC RASEGVN



SYMH WYQQKPGQAPRLLIY KASNLAS GIPA



RFSGSGSGTDFTLTISSLEPEDFAVYYC QQ



SWNDPLT FGQGTKLEIK



737
hBEW-9E3-B9VL.1a
ETVLTQSPATLSLSPGERATLSC RASEGVN



SYMH WYQQKPGQQPRLLIY KASNLAS GVPA



RFSGSGSGTDFTLTISSLEPEDFAVYFC QQ



SWNDPLT FGQGTKLEIK



738
hBEW-9E3-B9VL.1b
ETVLTQSPATLSLSPGERATLSC RASEGVN



SYMH WYQQKPGQAPRLLIY KASNLAS GIPA



RFSGSGSGTDFTLTISSLEPEDFAVYYC QQ



SWNDPLT FGQGTKLEIK



739
hBEW-9E3-B9VL.2
DIQMTQSPSSLSASVGDRVTITC RASEGVN



SYMH WYQQKPGKAPKLLIY KASNLAS GVPS



RFSGSGSGTDFTLTISSLQPEDFATYYC QQ



SWNDPLT FGQGTKLEIK



740
hBEW-9E3-B9VL.2a
DTQLTQSPSSLSASVGDRVTITC RASEGVN



SYMH WYQQKPGKQPKLLIY KASNLAS GVPS



RFSGSGSGTDFTLTISSLQPEDFATYFC QQ



SWNDPLT FGQGTKLEIK



741
hBEW-9E3-B9VL.2b
DTQMTQSPSSLSASVGDRVTITC RASEGVN



SYMH WYQQKPGKAPKLLIY KASNLAS GVPS



RFSGSGSGTDFTLTISSLQPEDFATYYC QQ



SWNDPLT FGQGTKLEIK














































































































hBEW-9E3-B9VH.1z is a CDR-grafted, humanized BEW-9E3-B9 VH containing IGHV7-81*01 and IGHJ4*01 framework sequences.
hBEW-9E3-B9VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
hBEW-9E3-B9VH.1a is a humanized design based on .1 and contains four proposed framework back-mutations (V2I, W47Y, M71L and Y91F).
hBEW-9E3-B9VH.1b is an intermediate design between .1 and .1a and only has two back-mutations (W47Y and M71L).
hBEW-9E3-B9VH.1c is based on .1b with additional one CDR germlining change T28S to improve identity to human germline sequence.
hBEW-9E3-B9VH.2z is a CDR-grafted, humanized BEW-9E3-B9 VH containing IGHV1-18*01 and IGHJ4*01 framework sequences.
hBEW-9E3-B9VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
hBEW-9E3-B9VH.2a is a humanized design based on .2 and contains six proposed framework back-mutations (V2I, W47Y, V67F, M69F, T71L and Y91F).
hBEW-9E3-B9VH.2b is an intermediate design between .2 and .2a and only has two back-mutations W47Y and T71L.
hBEW-9E3-B9VL.1 is a CDR-grafted humanized BEW-9E3-B9 VL containing IGKV3-11*01 and IGKJ2*01 framework sequences.
hBEW-9E3-B9VL.1a is a humanized design based on .1 with four proposed framework back-mutations (I2T, A43Q, I58V and Y87F).
hBEW-9E3-B9VL.1b is an intermediate design between .1 and .1a with 1 proposed framework back-mutation 12T.
hBEW-9E3-B9VL.2 is a CDR-grafted humanized BEW-9E3-B9 VL containing IGKV1-39*01 and IGKJ2*01 framework sequences.
hBEW-9E3-B9VL.2a is a humanized design based on .1 with four proposed framework back-mutations (I2T, M4L, A43Q and Y87F).
hBEW-9E3-B9VL.2b is an intermediate design between .1 and .1a with 1 proposed framework back-mutation 12T.




Example 6.2.4.6
BEW-5C3






TABLE 2.4.6



Sequences of Humanized BEW-5C3 Variable Regions





SEQ



ID

Sequence

NO:
Protein region
123456789012345678901234567890







742
hBEW-5c3VH.1z
QVQLVQSGSELKKPGASVKVSCKAS GYTFT



NYGVY WVRQAPGQGLEWMG WINTETGKPTY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYYCAR ARQLDWFVY WGQGTLVTVSS



743
hBEW-5C3VH.1
EVQLVQSGSELKKPGASVKVSCKAS GYTFT



NYGVY WVRQAPGQGLEWMG WINTETGKPTY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYYCAR ARQLDWFVY WGQGTLVTVSS



744
hBEW-5C3VH.1a
EIQLVQSGSELKKPGASVKVSCKAS GYTFT



NYGVY WVKQAPGQGLEYMG WINTETGKPTY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYYCAR ARQLDWFVY WGQGTLVTVSS



745
hBEW-5C3VH.1b
EIQLVQSGSELKKPGASVKVSCKAS GYTFT



NYGVY WVKQAPGQGLEYMG WINTETGKPTY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVFFCAR ARQLDWFVY WGQGTLVTVSS



746
hBEW-5C3VH.2z
QVQLVQSGAEVKKPGSSVKVSCKAS GYTFT



NYGVY WVRQAPGQGLEWMG WINTETGKPTY



ADDFKG RVTITADKSTSTAYMELSSLRSED



TAVYYCAR ARQLDWFVY WGQGTLVTVSS



747
hBEW-5C3VH.2
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFT



NYGVY WVRQAPGQGLEWMG WINTETGKPTY



ADDFKG RVTITADKSTSTAYMELSSLRSED



TAVYYCAR ARQLDWFVY WGQGTLVTVSS



748
hBEW-5C3VH.2a
EIQLVQSGAEVKKPGSSVKVSCKAS GYTFT



NYGVY WVKQAPGQGLEYMG WINTETGKPTY



ADDFKG RFTFTLDKSTSTAYMELSSLRSED



TAVYFCAR ARQLDWFVY WGQGTLVTVSS



749
hBEW-5C3VH.2b
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFT



NYGVY WVRQAPGQGLEWMG WINTETGKPTY



ADDFKG RFTFTLDKSTSTAYMELSSLRSED



TAVYYCAR ARQLDWFVY WGQGTLVTVSS



750
hBEW-5C3VH.2C
EIQLVQSGAEVKKPGSSVKVSCKAS GYTFT



NYGVY WVKQAPGQGLEYMG WINTETGKPTY



ADDFKG RFVFTLDKSTSTAYLELSSLRSED



TAVFFCAR ARQLDWFVY WGQGTLVTVSS



751
hBEW-5C3VL.1
EIVLTQSPATLSLSPGERATLSC RARESLT



TSLC WYQQKPGQAPRLLIY GASKLES GIPA



RFSGSGSGTDFTLTISSLEPEDFAVYYC QQ



SWYDPPT FGGGTKVEIK



752
hBEW-5C3VL.1a
DTVLTQSPATLSLSPGERATLSC RARESLT



TSLS WFQQKPGQQPRLLIY GASKLES GVPA



RFSGSGSGTDFTLTISSLEPEDFAVYFC QQ



SWYDPPT FGGGTKVEIK



753
hBEW-5C3VL.1b
DTVLTQSPATLSLSPGERATLSC RARESLT



TSLS WFQQKPGQAPRLLIY GASKLES GIPA



RFSGSGSGTDFTLTISSLEPEDFAVYFC QQ



SWYDPPT FGGGTKVEIK



754
hBEW-5C3VL.1c
DTVLTQSPATLSLSPGERATLSC RARESLT



TSLS WYQQKPGQAPRLLIYgasklesGIPA



RFSGSGSGTDFTLTISSLEPEDFAVYYC QQ



SWYDPPT FGGGTKVEIK



755
hBEW-5C3VL.2
AIQLTQSPSSLSASVGDRVTITC RARESLT



TSLS WYQQKPGKAPKLLIY GASKLES GVPS



RFSGSGSGTDFTLTISSLQPEDFATYYC QQ



SWYDPPT FGGGTKVEIK



756
hBEW-5C3VL.2a
DTQLTQSPSSLSASVGDRVTISC RARESLT



TSLS WFQQKPGKQPKLLIY GASKLES GVPS



RFSGSGSGTDFTLTISSLQPEDFATYFC QQ



SWYDPPT FGGGTKVEIK



757
hBEW-5C3VL.2b
DTQLTQSPSSLSASVGDRVTITC RARESLT



TSLS WFQQKPGKAPKLLIY GASKLES GVPS



RFSGSGSGTDFTLTISSLQPEDFATYFC QQ



SWYDPPT FGGGTKVEIK



758
hBEW-5C3VL.2c
DTQLTQSPSSLSASVGDRVTITC RARESLT



TSLS WYQQKPGKAPKLLIY GASKLES GVPS



RFSGSGSGTDFTLTISSLQPEDFATYYC QQ



SWYDPPT FGGGTKVEIK















































































































hBEW-5C3VH.1z is a CDR-grafted, humanized BEW-5C3 VH containing IGHV7-4-1*01 and IGHJ1*01 framework sequences.
hBEW-5C3VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
hBEW-5C3VH.1a is a humanized design based on .1 and contains three proposed framework back-mutations (V2I, R38K, W47Y).
hBEW-5C3VH.1b is a humanized design based on .1 and contains five proposed framework back-mutations (V2I, R38K, W47Y, Y90F, Y91F).
hBEW-5C3VH.2z is a CDR-grafted, humanized BEW-5C3 VH containing IGHV1-69*06 and IGHJ1*01 framework sequences.
hBEW-5C3VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
hBEW-5C3VH.2a is a humanized design based on .2 and contains seven proposed framework back-mutations (V2I, R38K, W47Y, V67F, I69F, A71L, Y91F).
hBEW-5C3VH.2b is an intermediate design between .2 and .2a and contains three proposed framework back-mutations (V67F, I69F, A71L).
hBEW-5C3VH.2c is a humanized design based on .2 and contains ten proposed framework back-mutations (V2I, R38K, W47Y, V67F, T68V, I69F, A71L, M80L, Y90F, Y91F).
hBEW-5C3VL.1 is a CDR-grafted, humanized BEW-5C3 VL containing IGKV3-11*01 and IGKJ4*01 framework sequences.
hBEW-5C3VL.1a is a humanized design based on .1 and contains six proposed framework back-mutations (E1D, I2T, Y36F, A43Q, I58V, Y87F).
hBEW-5C3VL.1b is an intermediate design between .1 and .1a. It contains four proposed framework back-mutations (E1D, I2T, Y36F, Y87F).
hBEW-5C3VL.1c is a design based on .1b and contains two proposed framework back-mutations (E1D, I2T)
hBEW-5C3VL.2 is a CDR-grafted, humanized BEW-5C3 VL containing IGKV1-13*01 and IGKJ4*01 framework sequences.
hBEW-5C3VL.2a is a humanized design based on .2 and contains six proposed framework back-mutations (A1D, I2T, T22S, Y36F, A43Q, Y87F).
hBEW-5C3VL.2b is an intermediate design between .2 and 2a. It contains four proposed framework back-mutations (A1D, I2T, Y36F, Y87F).
hBEW-5C3VL.2c is a design based on .2b and contains two proposed framework back-mutations (A1D, I2T)




Example 6.2.4.7
BEW-9E10






TABLE 2.4.7



Sequences of Humanized BEW-9E10 Variable Regions





SEQ



ID

Sequence

NO:
Protein region
123456789012345678901234567890







759
hBEW-9E10VH.1z
QVQLVQSGSELKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEWMG WIDTETGRPTY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYYCAR WSGDTTGIRGPWFAY WGQGTLV



TVSS



760
hBEW-9E10VH.1
EVQLVQSGSELKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEWMG WIDTETGRPTY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYYCAR WSGDTTGIRGPWFAY WGQGTLV



TVSS



761
hBEW-9E10VH.1a
EIQLVQSGSELKKPGASVKVSCKAS GYTFT



NYGMY WVKQAPGQGLEYMG WIDTETGRPTY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYFCAR WSGDTTGIRGPWFAY WGQGTLV



TVSS



762
hBEW-9E10VH.2z
QVQLVQSGAEVKKPGSSVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEWMG WIDTETGRPTY



ADDFKG RVTITADKSTSTAYMELSSLRSED



TAVYYCAR WSGDTTGIRGPWFAY WGQGTLV



TVSS



763
hBEW-9E10VH.2
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEWMG WIDTETGRPTY



ADDFKG RVTITADKSTSTAYMELSSLRSED



TAVYYCAR WSGDTTGIRGPWFAY WGQGTLV



TVSS



764
hBEW-9E10VH.2a
EIQLVQSGAEVKKPGSSVKVSCKAS GYTFT



NYGMY WVKQAPGQGLEYMG WIDTETGRPTY



ADDFKG RFTFTADKSTSTAYMELSSLRSED



TAVYFCAR WSGDTTGIRGPWFAY WGQGTLV



TVSS



765
hBEW-9E10VH.2b
EVQLVQSGAEVKKPGSSVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEWMG WIDTETGRPTY



ADDFKG RFTFTADKSTSTAYMELSSLRSED



TAVYYCAR WSGDTTGIRGPWFAY WGQGTLV



TVSS



766
hBEW-9E10VL.1
DIQMTQSPSSLSASVGDRVTITC LASEDIY



SDLA WYQQKPGKVPKLLIY NANGLQN GVPS



RFSGSGSGTDFTLTISSLQPEDVATYYC QQ



YNYFPGT FGQGTKLEIK



767
hBEW-9E10VL.1a
DIRMTQSPSSLSASVGDRVTIEC LASEDIY



SDLA WYQQKPGKSPKLLIY NANGLQN GVPS



RFSGSGSGTDYSLTISSLQPEDVATYFC QQ



YNYFPGT FGQGTKLEIK



768
hBEW-9E10VL.1b
DIRMTQSPSSLSASVGDRVTITC LASEDIY



SDLA WYQQKPGKSPKLLIY NANGLQN GVPS



RFSGSGSGTDYTLTISSLQPEDVATYFC QQ



YNYFPGT FGQGTKLEIK



















































































hBEW-9E10VH.1z is a CDR-grafted, humanized BEW-9E10 VH containing IGHV7-4-1*01 and IGHJ1*01 framework sequences.
hBEW-9E10VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
hBEW-9E10VH.1a is a humanized design based on .1 and contains four proposed framework back-mutations (V2I, R38K, W47Y, Y91F).
hBEW-9E10VH.2z is a CDR-grafted, humanized BEW-9E10 VH containing IGHV1-69*06 and IGHJ1*01 framework sequences.
hBEW-9E10VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
hBEW-9E10VH.2a is a humanized design based on .2 and contains six proposed framework back-mutations (V2I, R38K, W47Y, V67F, I69F, Y91F).
hBEW-9E10VH.2b is an intermediate design between .2 and .2a and contains two proposed framework back-mutations: (V67F, I69F).
hBEW-9E10VL.1 is a CDR-grafted, humanized BEW-9E10 VL containing IGKV1-27*01 and IGKJ2*01 framework sequences.
hBEW-9E10VL.1a is a humanized design based on .1 and contains six proposed framework back-mutations (Q3R, T22E, V43S, F71Y, T72S, Y87F).
hBEW-9E10VL.1b is an intermediate design between .1 and .1a. It contains four proposed framework back-mutations (Q3R, V43S, F71Y, Y87F).




Example 6.2.4.8
BEW-1B10






TABLE 2.4.8



Sequences of Humanized BEW-1B10 Variable Regions





SEQ



ID

Sequence

NO:
Protein region
123456789012345678901234567890







769
hBEW-1B10VH.1
EVQLVESGGGLVQPGGSLRLSCAAS GFSFS



KYDMA WVRQAPGKGLEWVA SITTSGVGTYY



RDSVKG RFTISRDNAKNSLYLQMNSLRAED



TAVYYCAR GYGAMDA WGQGTTVTVSS



770
hBEW-1B10VH.1a
EVQLVESGGGLVQPGGSLRLSCAAS GFSFS



KYDMA WFRQAPGKGLEWVA SITTSGVGTYY



RDSVKG RFTVSRDNAKSTLYLQMNSLRAED



TAVYYCAR GYGAMDA WGQGTTVTVSS



771
hBEW-1B10VH.1b
EVQLVESGGGLVQPGGSLRLSCAAS GFSFS



KYDMA WFRQAPGKGLEWVA SITTSGVGTYY



RDSVKG RFTVSRDNAKNSLYLQMNSLRAED



TAVYYCAR GYGAMDA WGQGTTVTVSS



772
hBEW-1B10VL.1
DIQMTQSPSSLSASVGDRVTITC KASQDID



DYLS WYQQKPGKAPKLLIY AATRLAD GVPS



RFSGSGSGTDFTLTISSLQPEDFATYYC LQ



SSSTPWT FGGGTKVEIK



773
hBEW-1B10VL.1a
DIQMTQSPSSLSASVGDRVTITC KASQDID



DYLS WYQQKPGKSPKLVIY AATRLAD GVPS



RFSGSGSGTDYTLTISSLQPEDFATYYC LQ



SSSTPWT FGGGTKVEIK



774
hBEW-1B10VL.1b
DIQMTQSPSSLSASVGDRVTITC KASQDID



DYLS WYQQKPGKSPKLLIY AATRLAD GVPS



RFSGSGSGTDYTLTISSLQPEDFATYYC LQ



SSSTPWT FGGGTKVEIK
























































hBEW-1B10VH.1 is a CDR-grafted, humanized BEW-1B10 VH containing IGHV3-7*01 and IGHJ6*01 framework sequences.
hBEW-1B10VH.1a is a humanized design based on .1 and contains four proposed framework back-mutations (V37F, I69V, N76S, S77T).
hBEW-1B10VH.1b is an intermediate design between .1 and .1a and contains two proposed framework back-mutations: (V37F, I69V).
hBEW-9E10VH.1z is a CDR-grafted, humanized BEW-9E10 VH containing IGHV7-4-1*01 and IGHJ1*01 framework sequences.
hBEW-9E10VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
hBEW-1B10VL.1 is a CDR-grafted, humanized BEW-1B10 VL containing IGKV1-39*01 and IGKJ4*01 framework sequences.
hBEW-1B10VL.1a is a humanized design based on .1 and contains three proposed framework back-mutations: (A43S, L47V, F71Y).
hBEW-1B10VL.1b is an intermediate design between .1 and .1a. It contains two proposed framework back-mutations (A43S, F71Y).




Example 6.2.4.9
BEW-1E3






TABLE 2.4.9



Sequences of Humanized BEW-1E3 Variable Regions





SEQ



ID

Sequence

NO:
Protein region
123456789012345678901234567890







775
hBEW-1E3VH.1z
QVQLVQSGSELKKPGASVKVSCKAS GYPFT



NSGMY WVRQAPGQGLEWMG WINTEAGKPTY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYYCAR WGYISDNSYGWFDY WGQGTLVT



VSS



776
hBEW-1E3VH.1
EVQLVQSGSELKKPGASVKVSCKAS GYPFT



NSGMY WVRQAPGQGLEWMG WINTEAGKPTY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYYCAR WGYISDNSYGWFDY WGQGTLVT



VSS



777
hBEW-1E3VH.1a
EIQLVQSGSELKKPGASVKVSCKAS GYPFT



NSGMY WVKQAPGQGLEYMG WINTEAGKPTY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYFCAR WGYISDNSYGWFDY WGQGTLVT



VSS



778
hBEW-1E3VH.2z
QVQLVQSGAEVKKPGASVKVSCKAS GYPFT



NSGMY WVRQAPGQGLEWMG WINTEAGKPTY



ADDFKG RVTMTTDTSTSTAYMELRSLRSDD



TAVYYCAR WGYISDNSYGWFDY WGQGTLVT



VSS



779
hBEW-1E3VH.2
EVQLVQSGAEVKKPGASVKVSCKAS GYPFT



NSGMY WVRQAPGQGLEWMG WINTEAGKPTY



ADDFKG RVTMTTDTSTSTAYMELRSLRSDD



TAVYYCAR WGYISDNSYGWFDY WGQGTLVT



VSS



780
hBEW-1E3VH.2a
EIQLVQSGAEVKKPGASVKVSCKAS GYPFT



NSGMY WVKQAPGQGLEYMG WINTEAGKPTY



ADDFKG RFTFTLDTSTSTAYLEIRSLRSDD



TAVYFCAR WGYISDNSYGWFDY WGQGTLVT



VSS



781
hBEW-1E3VH.2b
EVQLVQSGAEVKKPGASVKVSCKAS GYPFT



NSGMY WVRQAPGQGLEWMG WINTEAGKPTY



ADDFKG RFTFTLDTSTSTAYLEIRSLRSDD



TAVYYCAR WGYISDNSYGWFDY WGQGTLVT



VSS



782
hBEW-1E3VL.1
EIVLTQSPATLSLSPGERATLSC RASEGVY



SYMH WYQQKPGQAPRLLIY KASNLAS GIPA



RFSGSGSGTDFTLTISSLEPEDFAVYYC HQ



NWNDPLT FGQGTKLEIK



783
hBEW-1E3VL.1a
ETVLTQSPATLSLSPGERATLSC RASEGVY



SYMH WYQQKPGQQPRLLIY KASNLAS GVPA



RFSGSGSGTDFTLTISSLEPEDFAVYFC HQ



NWNDPLT FGQGTKLEIK



784
hBEW-1E3VL.1b
EIVLTQSPATLSLSPGERATLSC RASEGVY



SYMH WYQQKPGQAPRLLIY KASNLAS GVPA



RFSGSGSGTDFTLTISSLEPEDFAVYFC HQ



NWNDPLT FGQGTKLEIK



785
hBEW-1E3VL.2
AIQLTQSPSSLSASVGDRVTITC RASEGVY



SYMH WYQQKPGKAPKLLIY KASNLAS GVPS



RFSGSGSGTDFTLTISSLQPEDFATYYC HQ



NWNDPLT FGQGTKLEIK



786
hBEW-1E3VL.2a
ATQLTQSPSSLSASVGDRVTISC RASEGVY



SYMH WYQQKPGKQPKLLIY KASNLAS GVPS



RFSGSGSGTDFTLTISSLQPEDFATYFC HQ



NWNDPLT FGQGTKLEIK



787
hBEW-1E3VL.2b
AIQLTQSPSSLSASVGDRVTITC RASEGVY



SYMH WYQQKPGKAPKLLIY KASNLAS GVPS



RFSGSGSGTDFTLTISSLQPEDFATYFC HQ



NWNDPLT FGQGTKLEIK


































































































hBEW-1E3VH.1z is a CDR-grafted, humanized BEW-1E3 VH containing IGHV7-4-1*01 and IGHJ1*01 framework sequences.
hBEW-1E3VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
hBEW-1E3VH.1a is a humanized design based on .1 and contains four proposed framework back-mutations (V2I, R38K, W47Y, Y91F).
hBEW-1E3VH.2z is a CDR-grafted, humanized BEW-1E3 VH containing IGHV1-18*01 and IGHJ1*01 framework sequences.
hBEW-1E3VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
hBEW-1E3VH.2a is a humanized design based on .2 and contains seven proposed framework back-mutations (V2I, R38K, W47Y, V67F, M69F, T71L, Y91F).
hBEW-1E3VH.2b is an intermediate design between .2 and .2a and contains three proposed framework back-mutations (V67F, M69F, T71L).
hBEW-1E3VL.1 is a CDR-grafted, humanized BEW-1E3 VL containing IGKV3-11*01 and IGKJ2*01 framework sequences.
hBEW-1E3VL.1a is a humanized design based on .1 and contains four proposed framework back-mutations (I2T, A43Q, I58V, Y87F).
hBEW-1E3VL.1b is an intermediate design between .1 and .1a. It contains two proposed framework back-mutations (I58V, Y87F).
hBEW-1E3VL.2 is a CDR-grafted, humanized BEW-1E3 VL containing IGKV1-13*01 and IGKJ2*01 framework sequences.
hBEW-1E3VL.2a is a humanized design based on .2 and contains four proposed framework back-mutations (I2T, T22S, A43Q, Y87F).
hBEW-1E3VL.2b is an intermediate design between .2 and 2a. It contains one proposed framework back-mutations Y87F.




Example 6.3
Humanization of VEGFRII Antibodies
Example 6.3.1
Humanization Method
Antibody humanization is achieved by grafting CDRs of the rodent antibody onto a “similar” human framework (acceptor) and incorporating minimal number of key framework residues (back-mutation) from the rodent antibody that are selected to maintain the original CDR conformation in order to minimize the immunogenicity while retaining the optimal antigen binding.
Example 6.3.2
Human Germline Sequence Selections for Constructing CDR-Grafted, Humanized VEGFRII Antibodies
By applying the aforementioned method, the CDR sequences of VH and VL chains of monoclonal antibody BCU-6B1-G6 were grafted onto different human heavy and light chain acceptor sequences.
Example 6.3.2.1
BCU-6B1-G6
Based on the alignments with the VH and VL sequences of monoclonal antibody BCU-6B1-G6 of the present invention, the following known human sequences are selected:
1. IGHV7-4-1*01 and IGHJ1*01 for constructing heavy chain acceptor sequences
2. IGHV1-18*01 and IGHJ1*01 as alternative acceptor for constructing heavy chain
3. IGKV1-27*01 and IGKJ4*01 for constructing light chain acceptor sequences
By grafting the corresponding VH and VL CDRs of BCU-6B1-G6 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.3.3
Introducing Potential Framework Back-Mutations in CDR-Grafted Antibodies
To generate humanized antibody with potential framework back-mutations, the mutations were identified and introduced into the CDR-grafted antibody sequences by de novo synthesis of the variable domain, or mutagenic oligonucleotide primers and polymerase chain reactions, or by methods well known in the art. Different combinations of back mutations and other mutations are constructed for each of the CDR-grafts as follows. Residue numbers for these mutations are based on the Kabat numbering system.
Example 6.3.3.1
BCU-6B1-G6
When IGHV7-4-1*01 and IGHJ1*01 selected as BCU-6B1-G6 heavy chain acceptor sequence, one or more of the following residues could back-mutated as follows: W47→F. Additional mutations include the following: R38→K, Y91→F.
When IGHV1-18*01 and IGHJ1*01 selected as BCU-6B1-G6 heavy chain acceptor sequence, one or more of the following residues could back-mutated as follows: W47→F, V67→F, M69→F, T71→L. Additional mutations include the following: R38→K, Y91→F.
When IGKV1-27*01 and IGKJ4*01 selected as BCU-6B1-G6 light chain acceptor sequence, one or more of the following residues could back-mutated as follows: V43→S, Y49→F, F71→Y, Y87→F. Additional mutations include the following: T22→E, T72→S.
Example 6.3.4
Generation of Humanized Antibodies to VEGFRII Containing Framework Back-Mutations in CDR-Grafted Antibodies
The following humanized variable regions of the murine monoclonal VEGFRII antibodies were cloned into IgG expression vectors for functional characterization.
Example 6.3.4.1
BCU-6B1-G6






TABLE 3.4.1



Sequences of Humanized BCU-6B1-G6 Variable Regions





SEQ



ID
Protein
Sequence

NO:
region
123456789012345678901234567890







788
hBCU-6B1-G6VH.1z
QVQLVQSGSELKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEWMG WINTETGQPTY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYYCAR LGNNYGIWFAY WGQGTLVTVSS



789
hBCU-6B1-G6VH.1
EVQLVQSGSELKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEWMG WINTETGQPTY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYYCAR LGNNYGIWFAY WGQGTLVTVSS



790
hBCU-6B1-G6VH.1a
EVQLVQSGSELKKPGASVKVSCKAS GYTFT



NYGMY WVKQAPGQGLEFMG WINTETGQPTY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYFCAR LGNNYGIWFAY WGQGTLVTVSS



791
hBCU-6B1-G6VH.1b
EVQLVQSGSELKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEFMG WINTETGQPTY



ADDFKG RFVFSLDTSVSTAYLQISSLKAED



TAVYYCAR LGNNYGIWFAY WGQGTLVTVSS



792
hBCU-6B1-G6VH.2z
QVQLVQSGAEVKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEWMG WINTETGQPTY



ADDFKG RVTMTTDTSTSTAYMELRSLRSDD



TAVYYCAR LGNNYGIWFAY WGQGTLVTVSS



793
hBCU-6B1-G6VH.2
EVQLVQSGAEVKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEWMG WINTETGQPTY



ADDFKG RVTMTTDTSTSTAYMELRSLRSDD



TAVYYCAR LGNNYGIWFAY WGQGTLVTVSS



794
hBCU-6B1-G6VH.2a
EVQLVQSGAEVKKPGASVKVSCKAS GYTFT



NYGMY WVKQAPGQGLEFMG WINTETGQPTY



ADDFKG RFTFTLDTSTSTAYMELRSLRSDD



TAVYFCAR LGNNYGIWFAY WGQGTLVTVSS



795
hBCU-6B1-G6VH.2b
EVQLVQSGAEVKKPGASVKVSCKAS GYTFT



NYGMY WVRQAPGQGLEFMG WINTETGQPTY



ADDFKG RFTFTLDTSTSTAYMELRSLRSDD



TAVYYCAR LGNNYGIWFAY WGQGTLVTVSS



796
hBCU-6B1-
DIQMTQSPSSLSASVGDRVTITC RASDDLY


G6VL.1
STLA WYQQKPGKVPKLLIY DANRLAA GVPS



RFSGSGSGTDFTLTISSLQPEDVATYYC QQ



YNKFPWT FGGGTKVEIK



797
hBCU-6B1-
DIQMTQSPSSLSASVGDRVTIEC RASDDLY


G6VL.1a
STLA WYQQKPGKSPKLLIF DANRLAA GVPS



RFSGSGSGTDYSLTISSLQPEDVATYFC QQ



YNKFPWT FGGGTKVEIK



798
hBCU-6B1-
DIQMTQSPSSLSASVGDRVTITC RASDDLY


G6VL.1b
STLA WYQQKPGKSPKLLIF DANRLAA GVPS



RFSGSGSGTDYTLTISSLQPEDVATYFC QQ



YNKFPWT FGGGTKVEIK

















































































hBCU-6B1-G6VH.1z is a CDR-grafted, humanized BCU-6B1-G6 VH containing IGHV7-4-1*01 and IGHJ1*01 framework sequences.
hBCU-6B1-G6VH.1 is based on .1z with a Q1E change to prevent pyroglutamate formation.
hBCU-6B1-G6VH.1a is a humanized design based on .1 and contains 3 proposed framework back-mutations: (R38K, W47F, Y91F).
hBCU-6B1-G6VH.1b is an intermediate design between .1 and .1a and contains 1 proposed framework back-mutations: W47F
hBCU-6B1-G6VH.2z is a CDR-grafted, humanized BCU-6B1-G6 VH containing IGHV1-18*01 and IGHJ1*01 framework sequences.
hBCU-6B1-G6VH.2 is based on .2z with a Q1E change to prevent pyroglutamate formation.
hBCU-6B1-G6VH.2a is a humanized design based on .2 and contains six proposed framework back-mutations (R38K, W47F, V67F, M69F, T71L, Y91F).
hBCU-6B1-G6VH.2b is an intermediate design between .2 and .2a and contains four proposed framework back-mutations: W47F, V67F, M69F, T71L.
hBCU-6B1-G6VL.1 is a CDR-grafted, humanized BCU-6B1-G6 VL containing IGKV1-27*01 and IGKJ4*01 framework sequences.
hBCU-6B1-G6VL.1a is a humanized design based on .1 and contains six proposed framework back-mutations (T22E, V43S, Y49F, F71Y, T72S, Y87F).
hBCU-6B1-G6VL.1b is an intermediate design between .1 and .1a. It contains four proposed framework back-mutations (V43S, Y49F, F71Y, Y87F).




Example 6.4
Humanization of PDGFRB Antibodies
Example 6.4.1
Humanization Method
Antibody humanization is achieved by grafting CDRs of the rodent antibody onto a “similar” human framework (acceptor) and incorporating minimal number of key framework residues (back-mutation) from the rodent antibody that are selected to maintain the original CDR conformation in order to minimize the immunogenicity while retaining the optimal antigen binding.
Example 6.4.2
Human Germline Sequence Selections for Constructing CDR-Grafted, Humanized PDGFRB Antibodies
By applying the aforementioned method, the CDR sequences of VH and VL chains of monoclonal antibody BDE-3C9-G4 was grafted onto different human heavy and light chain acceptor sequences.
Example 6.4.2.1
BDE-3C9-G4
Based on the alignments with the VH and VL sequences of monoclonal antibody BDE-3C9-G4 of the present invention, the following known human sequences are selected:
1. IGHV3-7*01 and IGHJ3*01 for constructing heavy chain acceptor sequences
2. IGKV1-33*01 and IGKJ4*01 for constructing light chain acceptor sequences
By grafting the corresponding VH and VL CDRs of BDE-3C9-G4 into said acceptor sequences, the CDR-grafted, humanized, and modified VH and VL sequences were prepared.
Example 6.4.3
Introducing Potential Framework Back-Mutations in CDR-Grafted Antibodies
To generate humanized antibody with potential framework back-mutations, the mutations were identified and introduced into the CDR-grafted antibody sequences by de novo synthesis of the variable domain, or mutagenic oligonucleotide primers and polymerase chain reactions, or by methods well known in the art. Different combinations of back mutations and other mutations are constructed for each of the CDR-grafts as follows. Residue numbers for these mutations are based on the Kabat numbering system.
Example 6.4.3.1
BDE-3C9-G4
When IGHV3-7*01 and IGHJ3*01 selected as BDE-3C9-G4 heavy chain acceptor sequence, one or more of the following residues could back-mutated as follows: S77→T, L78→Q, Y91→F.
When IGKV1-33*01 and IGKJ4*01 selected as BDE-3C9-G4 light chain acceptor sequence, one or more of the following residues could back-mutated as follows: Q38→L, K45→R, I48→M, Y49→R, T69→R, F71→Y. Additional mutations include the following: V584T.
Example 6.4.4
Generation of Humanized Antibodies to PDGFRB Containing Framework Back-Mutations in CDR-Grafted Antibodies
The following humanized variable regions of the murine monoclonal PDGFRB antibodies were cloned into IgG expression vectors for functional characterization.
Example 6.4.4.1
BDE-3C9-G4






TABLE 4.4.1



Sequences of Humanized BDE-3C9-G4

Variable Regions





SEQ ID
Protein
Sequence

NO:
region
123456789012345678901234567890



799
hBDE-3C9-
EVQLVESGGGLVQPGGSLRLSCAAS GFTFS


G4VH.1
NYGMA WVRQAPGKGLEWVA SITNSGGNTYY



RDSVKG RFTISRDNAKNSLYLQMNSLRAED



TAVYYCAR HTPGANYFDY WGQGTMVTVSS



800
hBDE-3C9-
EVQLVESGGGLVQPGGSLRLSCAAS GFTFS


G4VH.1a
NYGMA WVRQAPGKGLEWVA SITNSGGNTYY



RDSVKG RFTISRDNAKNTQYLQMNSLRAED



TAVYFCAR HTPGANYFDY WGQGTMVTVSS



801
hBDE-3C9-
DIQMTQSPSSLSASVGDRVTITCQ ASQSIK


G4VL.1
NYIA WYQQKPGKAPKLLIY YTSTLES GVPS



RFSGSGSGTDFTFTISSLQPEDIATYYC VQ



YANLYT FGGGTKVEIK



802
hBDE-3C9-
DIQMTQSPSSLSASVGDRVTITC QASQSIK


G4VL.1a
NYIA WYQLKPGKAPRLLMR YTSTLES GTPS



RFSGSGSGRDYTFTISSLQPEDIATYYC VQ



YANLYT FGGGTKVEIK



803
hBDE-3C9-
DIQMTQSPSSLSASVGDRVTITC QASQSIK


G4VL.1b
NYIA WYQQKPGKAPRLLIR YTSTLES GVPS



RFSGSGSGRDYTFTISSLQPEDIATYYC VQ



YANLYT FGGGTKVEIK
















































hBDE-3C9-G4VH.1 is a CDR-grafted, humanized BDE-3C9-G4 VH containing IGHV3-7*01 and IGHJ3*01 framework sequences.
hBDE-3C9-G4VH.1a is a humanized design based on .1 and contains three proposed framework back-mutations (S77T, L78Q, Y91F).
hBDE-3C9-G4VL.1 is a CDR-grafted, humanized BDE-3C9-G4 VL containing IGKV1-33*01 and IGKJ4*01 framework sequences.
hBDE-3C9-G4VL.1a is a humanized design based on .1 and contains seven proposed framework back-mutations (Q38L, K45R, 148M, Y49R, V58T, T69R, F71Y).
hBDE-3C9-G4VL.1b is an intermediate design between .1 and .1a. It contains four proposed framework back-mutations (K45R, Y49R, T69R, F71Y).




Summary of VH and VL Amino Acid Sequences of Humanized Rat Anti-human VEGF-A and Humanized Rat Anti-human PDGF-BB Monoclonal Antibodies






TABLE 27



VH and VL Amino Acid Sequences of Humanized

Rat Anti-Human VEGF-A Monoclonal Antibodies

(CDRs in bold)






SEQ ID

Protein
V Region

NO:
Clone
Region
123456789012345678901234567890








804
hBDB-4G8.1 VH

EVQLVQSGSELKKPGASVKVSCKAS G




YTFTNYGMY WVRQAPGQGLEWMG WIN




TETGKPTYADDFKG RFVFSLDTSVST




AYLQISSLKAEDTAVYYCAR TNYYYR




SYIFYFDY WGQGTMVTVSS



805
hBDB-4G8.1
CDR-H1

GYTFTNYGMY




806
hBDB-4G8.1
CDR-H2

WINTETGKPTYADDFKG




807
hBDB-4G8.1
CDR-H3

TNYYYRSYIFYFDY




808
hBDB-4G8.1 VL

AIQLTQSPSSLSASVGDRVTITC RAS




ESVSTHMH WYQQKPGKAPKLLIY GAS




NLES GVPSRFSGSGSGTDFTLTISSL




QPEDFATYYC QQSWNDPFT FGQGTKL




EIK



809
hBDB-4G8.1
CDR-L1

RASESVSTHMH




810
hBDB-4G8.1
CDR-L2

GASNLES




811
hBDB-4G8.1
CDR-L3

QQSWNDPFT




812
hBDB-4G8.10 VH

EIQLVQSGAEVKKPGASVKVSCKAS G




YTFTNYGMY WVRQAPGQGLEYMG WIN




TETGKPTYADDFKG RFTFTLDTSTST




AYMELRSLRSDDTAVYFCAR TNYYYR




SYIFYFDY WGQGTMVTVSS



813
hBDB-4G8.10
CDR-H1

GYTFTNYGMY




814
hBDB-4G8.10
CDR-H2

WINTETGKPTYADDFKG




815
hBDB-4G8.10
CDR-H3

TNYYYRSYIFYFDY




816
hBDB-4G8.10 VL

AIQLTQSPSSLSASVGDRVTITC RAS




ESVSTHMH WYQQKPGKAPKLLIY GAS




NLES GVPSRFSGSGSGTDFTLTISSL




QPEDFATYYC QQSWNDPFT FGQGTKL




EIK



817
hBDB-4G8.10
CDR-L1

RASESVSTHMH




818
hBDB-4G8.10
CDR-L2

GASNLES




819
hBDB-4G8.10
CDR-L3

QQSWNDPFT




820
hBDB-4G8.11 VH

EIQLVQSGAEVKKPGASVKVSCKAS G




YTFTNYGMY WVRQAPGQGLEYMG WIN




TETGKPTYADDFKG RFTFTLDTSTST




AYMELRSLRSDDTAVYFCAR TNYYYR




SYIFYFDY WGQGTMVTVSS



821
hBDB-4G8.11
CDR-H1

GYTFTNYGMY




822
hBDB-4G8.11
CDR-H2

WINTETGKPTYADDFKG




823
hBDB-4G8.11
CDR-H3

TNYYYRSYIFYFDY




824
hBDB-4G8.11 VL

ATQLTQSPSLSASVGDRVTITC RASE




SVSTHMH WYQQKPGKQPKLLIY GASN




LES GVPSRFSGSGSGTDFTLTISSLQ




PEDFATYFC QQSWNDPFT FGQGTKLE




IK



825
hBDB-4G8.11
CDR-L1

RASESVSTHMH




826
hBDB-4G8.11
CDR-L2

GASNLES




827
hBDB-4G8.11
CDR-L3

QQSWNDPFT




828
hBDB-4G8.12 VH

EIQLVQSGAEVKKPGASVKVSCKAS G




YTFTNYGMY WVRQAPGQGLEYMG WIN




TETGKPTYADDFKG RFTFTLDTSTST




AYMELRSLRSDDTAVYFCAR TNYYYR




SYIFYFDY WGQGTMVTVSS



829
hBDB-4G8.12
CDR-H1

GYTFTNYGMY




830
hBDB-4G8.12
CDR-H2

WINTETGKPTYADDFKG




831
hBDB-4G8.12
CDR-H3

TNYYYRSYIFYFDY




832
hBDB-4G8.12 VL

DTVLTQSPATLSLSPGERATLSC RAS




ESVSTHMH WYQQKPGQAPRLLIY GAS




NLES GVPARFSGSGSGTDFTLTISSL




EPEDFAVYFC QQSWNDPFT FGQGTKL




EIK



833
hBDB-4G8.12
CDR-L1

RASESVSTHMH




834
hBDB-4G8.12
CDR-L2

GASNLES




835
hBDB-4G8.12
CDR-L3

QQSWNDPFT




836
hBDB-4G8.13 VH

EIQLVQSGTEVKKPGESLKISCKAS G




YTFTNYGMY WVKQMPGKGLEYMG WIN




TETGKPTYADDFKG RFTFSLDKSFNT




AFLQWSSLKASDTAMYFCAR TNYYYR




SYIFYFDY WGQGTMVTVSS



837
hBDB-4G8.13
CDR-H1

GYTFTNYGMY




838
hBDB-4G8.13
CDR-H2

WINTETGKPTYADDFKG




839
hBDB-4G8.13
CDR-H3

TNYYYRSYIFYFDY




840
hBDB-4G8.13 VL

ETVLTQSPATLSVSPGERATLSC RAS




ESVSTHMH WYQQKPGQAPRLLIY GAS




NLES GVPARFSGSGSGTDFTLTISSL




QSEDFAVYFC QQSWNDPFT FGQGTRL




EIK



841
hBDB-4G8.13
CDR-L1

RASESVSTHMH




842
hBDB-4G8.13
CDR-L2

GASNLES




843
hBDB-4G8.13
CDR-L3

QQSWNDPFT




844
hBDB-4G8.14 VH

EIQLVQSGGGVVQPGGSLRLSCAAS G




YTFTNYGMY WVKQAPGKGLEYMG WIN




TETGKPTYADDFKG RFTFSLDTSKST




AYLQLNSLRAEDTAVYFCAR TNYYYR




SYIFYFDY WGQGTLVTVSS



845
hBDB-4G8.14
CDR-H1

GYTFTNYGMY




846
hBDB-4G8.14
CDR-H2

WINTETGKPTYADDFKG




847
hBDB-4G8.14
CDR-H3

TNYYYRSYIFYFDY




848
hBDB-4G8.14 VL

DTVLTQSPSTLSASPGERATISC RAS




ESVSTHMH WYQQKPGQAPKLLIY GAS




NLES GVPSRFSGSRSGTDFTLTISSL




QPEDFAVYFC QQSWNDPFT FGQGTKV




EIK



849
hBDB-4G8.14
CDR-L1

RASESVSTHMH




850
hBDB-4G8.14
CDR-L2

GASNLES




851
hBDB-4G8.14
CDR-L3

QQSWNDPFT




852
hBDB-4G8.15 VH

EVQLVESGGGLVQPGGSLRLSCAAS G




YTFTNYGMY WVKQAPGKGLEYMG WIN




TETGKPTYADDFKG RFTFSLDTSKST




AYLQMNSLRAEDTAVYFCAR TNYYYR




SYIFYFDY WGQGTLVTVSS



853
hBDB-4G8.15
CDR-H1

GYTFTNYGMY




854
hBDB-4G8.15
CDR-H2

WINTETGKPTYADDFKG




855
hBDB-4G8.15
CDR-H3

TNYYYRSYIFYFDY




856
hBDB-4G8.15 VL

DTQLTQSPSSLSASVGDRVTISC RAS




ESVSTHMH WYQQKPGKAPKLLIY GAS




NLES GVPSRFSGSGSGTDFTLTISSL




QPEDFATYFC QQSWNDPFT FGQGTKV




EIK



857
hBDB-4G8.15
CDR-L1

RASESVSTHMH




858
hBDB-4G8.15
CDR-L2

GASNLES




859
hBDB-4G8.15
CDR-L3

QQSWNDPFT




860
hBDB-4G8.2 VH

EVQLVQSGSELKKPGASVKVSCKAS G




YTFTNYGMY WVRQAPGQGLEWMG WIN




TETGKPTYADDFKG RFVFSLDTSVST




AYLQISSLKAEDTAVYYCAR TNYYYR




SYIFYFDY WGQGTMVTVSS



861
hBDB-4G8.2
CDR-H1

GYTFTNYGMY




862
hBDB-4G8.2
CDR-H2

WINTETGKPTYADDFKG




863
hBDB-4G8.2
CDR-H3

TNYYYRSYIFYFDY




864
hBDB-4G8.2 VL

ATQLTQSPSLSASVGDRVTITC RASE




SVSTHMH WYQQKPGKQPKLLIY GASN




LES GVPSRFSGSGSGTDFTLTISSLQ




PEDFATYFC QQSWNDPFT FGQGTKLE




IK



865
hBDB-4G8.2
CDR-L1

RASESVSTHMH




866
hBDB-4G8.2
CDR-L2

GASNLES




867
hBDB-4G8.2
CDR-L3

QQSWNDPFT




868
hBDB-4G8.3 VH

EVQLVQSGSELKKPGASVKVSCKAS G




YTFTNYGMY WVRQAPGQGLEWMG WIN




TETGKPTYADDFKG RFVFSLDTSVST




AYLQISSLKAEDTAVYYCAR TNYYYR




SYIFYFDY WGQGTMVTVSS



869
hBDB-4G8.3
CDR-H1

GYTFTNYGMY




870
hBDB-4G8.3
CDR-H2

WINTETGKPTYADDFKG




871
hBDB-4G8.3
CDR-H3

TNYYYRSYIFYFDY




872
hBDB-4G8.3 VL

DTVLTQSPATLSLSPGERATLSC RAS




ESVSTHMH WYQQKPGQAPRLLIY GAS




NLES GVPARFSGSGSGTDFTLTISSL




EPEDFAVYFC QQSWNDPFT FGQGTKL




EIK



873
hBDB-4G8.3
CDR-L1

RASESVSTHMH




874
hBDB-4G8.3
CDR-L2

GASNLES




875
hBDB-4G8.3
CDR-L3

QQSWNDPFT




876
hBDB-4G8.4 VH

EIQLVQSGSELKKPGASVKVSCKAS G




YTFTNYGMY WVRQAPGQGLEYMG WIN




TETGKPTYADDFKG RFVFSLDTSVST




AYLQISSLKAEDTAVYFCAR TNYYYR




SYIFYFDY WGQGTMVTVSS



877
hBDB-4G8.4
CDR-H1

GYTFTNYGMY




878
hBDB-4G8.4
CDR-H2

WINTETGKPTYADDFKG




879
hBDB-4G8.4
CDR-H3

TNYYYRSYIFYFDY




880
hBDB-4G8.4 VL

AIQLTQSPSSLSASVGDRVTITC RAS




ESVSTHMH WYQQKPGKAPKLLIY GAS




NLES GVPSRFSGSGSGTDFTLTISSL




QPEDFATYYC QQSWNDPFT FGQGTKL




EIK



881
hBDB-4G8.4
CDR-L1

RASESVSTHMH




882
hBDB-4G8.4
CDR-L2

GASNLES




883
hBDB-4G8.4
CDR-L3

QQSWNDPFT




884
hBDB-4G8.5 VH

EIQLVQSGSELKKPGASVKVSCKAS G




YTFTNYGMY WVRQAPGQGLEYMG WIN




TETGKPTYADDFKG RFVFSLDTSVST




AYLQISSLKAEDTAVYFCAR TNYYYR




SYIFYFDY WGQGTMVTVSS



885
hBDB-4G8.5
CDR-H1

GYTFTNYGMY




886
hBDB-4G8.5
CDR-H2

WINTETGKPTYADDFKG




887
hBDB-4G8.5
CDR-H3

TNYYYRSYIFYFDY




888
hBDB-4G8.5 VL

ATQLTQSPSLSASVGDRVTITC RASE




SVSTHMH WYQQKPGKQPKLLIY GASN




LES GVPSRFSGSGSGTDFTLTISSLQ




PEDFATYFC QQSWNDPFT FGQGTKLE




IK



889
hBDB-4G8.5
CDR-L1

RASESVSTHMH




890
hBDB-4G8.5
CDR-L2

GASNLES




891
hBDB-4G8.5
CDR-L3

QQSWNDPFT




892
hBDB-4G8.6 VH

EIQLVQSGSELKKPGASVKVSCKAS G




YTFTNYGMY WVRQAPGQGLEYMG WIN




TETGKPTYADDFKG RFVFSLDTSVST




AYLQISSLKAEDTAVYFCAR TNYYYR




SYIFYFDY WGQGTMVTVSS



893
hBDB-4G8.6
CDR-H1

GYTFTNYGMY




894
hBDB-4G8.6
CDR-H2

WINTETGKPTYADDFKG




895
hBDB-4G8.6
CDR-H3

TNYYYRSYIFYFDY




896
hBDB-4G8.6 VL

DTVLTQSPATLSLSPGERATLSC RAS




ESVSTHMH WYQQKPGQAPRLLIY GAS




NLES GVPARFSGSGSGTDFTLTISSL




EPEDFAVYFC QQSWNDPFT FGQGTKL




EIK



897
hBDB-4G8.6
CDR-L1

RASESVSTHMH




898
hBDB-4G8.6
CDR-L2

GASNLES




899
hBDB-4G8.6
CDR-L3

QQSWNDPFT




900
hBDB-4G8.7 VH

EVQLVQSGAEVKKPGASVKVSCKAS G




YTFTNYGMY WVRQAPGQGLEWMG WIN




TETGKPTYADDFKG RVTMTTDTSTST




AYMELRSLRSDDTAVYYCAR TNYYYR




SYIFYFDY WGQGTMVTVSS



901
hBDB-4G8.7
CDR-H1

GYTFTNYGMY




902
hBDB-4G8.7
CDR-H2

WINTETGKPTYADDFKG




903
hBDB-4G8.7
CDR-H3

TNYYYRSYIFYFDY




904
hBDB-4G8.7 VL

AIQLTQSPSSLSASVGDRVTITC RAS




ESVSTHMH WYQQKPGKAPKLLIY GAS




NLES GVPSRFSGSGSGTDFTLTISSL




QPEDFATYYC QQSWNDPFT FGQGTKL




EIK



905
hBDB-4G8.7
CDR-L1

RASESVSTHMH




906
hBDB-4G8.7
CDR-L2

GASNLES




907
hBDB-4G8.7
CDR-L3

QQSWNDPFT




908
hBDB-4G8.8 VH

EVQLVQSGAEVKKPGASVKVSCKAS G




YTFTNYGMY WVRQAPGQGLEWMG WIN




TETGKPTYADDFKG RVTMTTDTSTST




AYMELRSLRSDDTAVYYCAR TNYYYR




SYIFYFDY WGQGTMVTVSS



909
hBDB-4G8.8
CDR-H1

GYTFTNYGMY




910
hBDB-4G8.8
CDR-H2

WINTETGKPTYADDFKG




911
hBDB-4G8.8
CDR-H3

TNYYYRSYIFYFDY




912
hBDB-4G8.8 VL

ATQLTQSPSLSASVGDRVTITC RASE




SVSTHMH WYQQKPGKQPKLLIY GASN




LES GVPSRFSGSGSGTDFTLISSLQ




PEDFATYFC QQSWNDPFT FGQGTKLE




IK



913
hBDB-4G8.8
CDR-L1

RASESVSTHMH




914
hBDB-4G8.8
CDR-L2

GASNLES




915
hBDB-4G8.8
CDR-L3

QQSWNDPFT




916
hBDB-4G8.9 VH

EVQLVQSGAEVKKPGASVKVSCKAS G




YTFTNYGMY WVRQAPGQGLEWMG WIN




TETGKPTYADDFKG RVTMTTDTSTST




AYMELRSLRSDDTAVYYCAR TNYYYR




SYIFYFDY WGQGTMVTVSS



917
hBDB-4G8.9
CDR-H1

GYTFTNYGMY




918
hBDB-4G8.9
CDR-H2

WINTETGKPTYADDFKG




919
hBDB-4G8.9
CDR-H3

TNYYYRSYIFYFDY




920
hBDB-4G8.9 VL

DTVLTQSPATLSLSPGERATLSC RAS




ESVSTHMH WYQQKPGQAPRLLIY GAS




NLES GVPARFSGSGSGTDFTLTISSL




EPEDFAVYFC QQSWNDPFT FGQGTKL




EIK



921
hBDB-4G8.9
CDR-L1

RASESVSTHMH




922
hBDB-4G8.9
CDR-L2

GASNLES




923
hBDB-4G8.9
CDR-L3

QQSWNDPFT




924
hBEW-1B10.1 VH

EVQLVESGGGLVQPGGSLRLSCAAS G




FSFSKYDMA WFRQAPGKGLEWVA SIT




TSGVGTYYRDSVKG RFTVSRDNAKST




LYLQMNSLRAEDTAVYYCAR GYGAMD




A WGQGTTVTVSS



925
hBEW-1B10.1
CDR-H1

GFSFSKYDMA




926
hBEW-1B10.1
CDR-H2

SITTSGVGTYYRDSVKG




927
hBEW-1B10.1
CDR-H3

GYGAMDA




928
hBEW-1B10.1 VL

DIQMTQSPSSLSASVGDRVTITC KAS




QDIDDYLS WYQQKPGKSPKLVIY AAT




RLAD GVPSRFSGSGSGTDYTLTISSL




QPEDFATYYC LQSSSTPWT FGGGTKV




EIK



929
hBEW-1B10.1
CDR-L1

KASQDIDDYLS




930
hBEW-1B10.1
CDR-L2

AATRLAD




931
hBEW-1B10.1
CDR-L3

LQSSSTPWT




932
hBEW-1B10.2 VH

EVQLVESGGGLVQPGGSLRLSCAAS G




FSFSKYDMA WFRQAPGKGLEWVA SIT




TSGVGTYYRDSVKG RFTVSRDNAKNS




LYLQMNSLRAEDTAVYYCAR GYGAMD




A WGQGTTVTVSS



933
hBEW-1B10.2
CDR-H1

GFSFSKYDMA




934
hBEW-1B10.2
CDR-H2

SITTSGVGTYYRDSVKG




935
hBEW-1B10.2
CDR-H3

GYGAMDA




936
hBEW-1B10.2 VL

DIQMTQSPSSLSASVGDRVTITC KAS




QDIDDYLS WYQQKPGKSPKLVIY AAT




RLAD GVPSRFSGSGSGTDYTLTISSL




QPEDFATYYC LQSSSTPWT FGGGTKV




EIK



937
hBEW-1B10.2
CDR-L1

KASQDIDDYLS




938
hBEW-1B10.2
CDR-L2

AATRLAD




939
hBEW-1B10.2
CDR-L3

LQSSSTPWT




940
hBEW-1E3.1 VH

EIQLVQSGSELKKPGASVKVSCKAS G




YPFTNSGMY WVKQAPGQGLEYMG WIN




TEAGKPTYADDFKG RFVFSLDTSVST




AYLQISSLKAEDTAVYFCAR WGYISD




NSYGWFDY WGQGTLVTVSS



941
hBEW-1E3.1
CDR-H1

GYPFTNSGMY




942
hBEW-1E3.1
CDR-H2

WINTEAGKPTYADDFKG




943
hBEW-1E3.1
CDR-H3

WGYISDNSYGWFDY




944
hBEW-1E3.1 VL

ETVLTQSPATLSLSPGERATLSC RAS




EGVYSYMH WYQQKPGQQPRLLIY KAS




NLAS GVPARFSGSGSGTDFTLTISSL




EPEDFAVYFC HQNWNDPLT FGQGTKL




EIK



945
hBEW-1E3.1
CDR-L1

RASEGVYSYMH




946
hBEW-1E3.1
CDR-L2

KASNLAS




947
hBEW-1E3.1
CDR-L3

HQNWNDPLT




948
hBEW-1E3.2 VH

EIQLVQSGAEVKKPGASVKVSCKAS G




YPFTNSGMY WVKQAPGQGLEYMG WIN




TEAGKPTYADDFKG RFTFTLDTSTST




AYLEIRSLRSDDTAVYFCAR WGYISD




NSYGWFDY WGQGTLVTVSS



949
hBEW-1E3.2
CDR-H1

GYPFTNSGMY




950
hBEW-1E3.2
CDR-H2

WINTEAGKPTYADDFKG




951
hBEW-1E3.2
CDR-H3

WGYISDNSYGWFDY




952
hBEW-1E3.2 VL

ETVLTQSPATLSLSPGERATLSC RAS




EGVYSYMH WYQQKPGQQPRLLIY KAS




NLAS GVPARFSGSGSGTDFTLTISSL




EPEDFAVYFC HQNWNDPLT FGQGTKL




EIK



953
hBEW-1E3.2
CDR-L1

RASEGVYSYMH




954
hBEW-1E3.2
CDR-L2

KASNLAS




955
hBEW-1E3.2
CDR-L3

HQNWNDPLT




956
hBEW-1E3.3 VH

EVQLVQSGAEVKKPGASVKVSCKAS G




YPFTNSGMY WVRQAPGQGLEWMG WIN




TEAGKPTYADDFKG RFTFTLDTSTST




AYLEIRSLRSDDTAVYYCAR WGYISD




NSYGWFDY WGQGTLVTVSS



957
hBEW-1E3.3
CDR-H1

GYPFTNSGMY




958
hBEW-1E3.3
CDR-H2

WINTEAGKPTYADDFKG




959
hBEW-1E3.3
CDR-H3

WGYISDNSYGWFDY




960
hBEW-1E3.3 VL

ETVLTQSPATLSLSPGERATLSC RAS




EGVYSYMH WYQQKPGQQPRLLIY KAS




NLAS GVPARFSGSGSGTDFTLTISSL




EPEDFAVYFC HQNWNDPLT FGQGTKL




EIK



961
hBEW-1E3.3
CDR-L1

RASEGVYSYMH




962
hBEW-1E3.3
CDR-L2

KASNLAS




963
hBEW-1E3.3
CDR-L3

HQNWNDPLT




964
hBEW-1E3.4 VH

EIQLVQSGSELKKPGASVKVSCKAS G




YPFTNSGMY WVKQAPGQGLEYMG WIN




TEAGKPTYADDFKG RFVFSLDTSVST




AYLQISSLKAEDTAVYFCAR WGYISD




NSYGWFDY WGQGTLVTVSS



965
hBEW-1E3.4
CDR-H1

GYPFTNSGMY




966
hBEW-1E3.4
CDR-H2

WINTEAGKPTYADDFKG




967
hBEW-1E3.4
CDR-H3

WGYISDNSYGWFDY




968
hBEW-1E3.4 VL

ATQLTQSPSSLSASVGDRVTISC RAS




EGVYSYMH WYQQKPGKQPKLLIY KAS




NLAS GVPSRFSGSGSGTDFTLTISSL




QPEDFATYFC HQNWNDPLT FGQGTKL




EIK



969
hBEW-1E3.4
CDR-L1

RASEGVYSYMH




970
hBEW-1E3.4
CDR-L2

KASNLAS




971
hBEW-1E3.4
CDR-L3

HQNWNDPLT




972
hBEW-1E3.5 VH

EIQLVQSGAEVKKPGASVKVSCKAS G




YPFTNSGMY WVKQAPGQGLEYMG WIN




TEAGKPTYADDFKG RFTFTLDTSTST




AYLEIRSLRSDDTAVYFCAR WGYISD




NSYGWFDY WGQGTLVTVSS



973
hBEW-1E3.5
CDR-H1

GYPFTNSGMY




974
hBEW-1E3.5
CDR-H2

WINTEAGKPTYADDFKG




975
hBEW-1E3.5
CDR-H3

WGYISDNSYGWFDY




976
hBEW-1E3.5 VL

ATQLTQSPSSLSASVGDRVTISC RAS




EGVYSYMH WYQQKPGKQPKLLIY KAS




NLAS GVPSRFSGSGSGTDFTLTISSL




QPEDFATYFC HQNWNDPLT FGQGTKL




EIK



977
hBEW-1E3.5
CDR-L1

RASEGVYSYMH




978
hBEW-1E3.5
CDR-L2

KASNLAS




979
hBEW-1E3.5
CDR-L3

HQNWNDPLT




980
hBEW-5C3.1 VH

EIQLVQSGSELKKPGASVKVSCKAS G




YTFTNYGVY WVKQAPGQGLEYMG WIN




TETGKPTYADDFKG RFVFSLDTSVST




AYLQISSLKAEDTAVYYCAR ARQLDW




FVY WGQGTLVTVSS



981
hBEW-5C3.1
CDR-H1

GYTFTNYGVY




982
hBEW-5C3.1
CDR-H2

WINTETGKPTYADDFKG




983
hBEW-5C3.1
CDR-H3

ARQLDWFVY


984
hBEW-5C3.1 VL

DTVLTQSPATLSLSPGERATLSC RAR




ESLTTSLS WFQQKPGQQPRLLIY GAS




KLES GVPARFSGSGSGTDFTLTISSL




EPEDFAVYFC QQSWYDPPT FGGGTKV




EIK



985
hBEW-5C3.1
CDR-L1

RARESLTTSLS




986
hBEW-5C3.1
CDR-L2

GASKLES




987
hBEW-5C3.1
CDR-L3

QQSWYDPPT




988
hBEW-5C3.2 VH

EIQLVQSGAEVKKPGSSVKVSCKAS G




YTFTNYGVY WVKQAPGQGLEYMG WIN




TETGKPTYADDFKG RFTFTLDKSTST




AYMELSSLRSEDTAVYFCAR ARQLDW




FVY WGQGTLVTVSS



989
hBEW-5C3.2
CDR-H1

GYTFTNYGVY




990
hBEW-5C3.2
CDR-H2

WINTETGKPTYADDFKG




991
hBEW-5C3.2
CDR-H3

ARQLDWFVY




992
hBEW-5C3.2 VL

DTVLTQSPATLSLSPGERATLSC RAR




ESLTTSLS WFQQKPGQQPRLLIY GAS




KLES GVPARFSGSGSGTDFTLTISSL




EPEDFAVYFC QQSWYDPPT FGGGTKV




EIK



993
hBEW-5C3.2
CDR-L1

RARESLTTSLS




994
hBEW-5C3.2
CDR-L2

GASKLES




995
hBEW-5C3.2
CDR-L3

QQSWYDPPT




996
hBEW-5C3.3 VH

EVQLVQSGAEVKKPGSSVKVSCKAS G




YTFTNYGVY WVRQAPGQGLEWMG WIN




TETGKPTYADDFKG RFTFTLDKSTST




AYMELSSLRSEDTAVYYCAR ARQLDW




FVY WGQGTLVTVSS



997
hBEW-5C3.3
CDR-H1

GYTFTNYGVY




998
hBEW-5C3.3
CDR-H2

WINTETGKPTYADDFKG




999
hBEW-5C3.3
CDR-H3

ARQLDWFVY




1000
hBEW-5C3.3 VL

DTVLTQSPATLSLSPGERATLSC RAR




ESLTTSLS WFQQKPGQQPRLLIY GAS




KLES GVPARFSGSGSGTDFTLTISSL




EPEDFAVYFC QQSWYDPPT FGGGTKV




EIK



1001
hBEW-5C3.3
CDR-L1

RARESLTTSLS




1002
hBEW-5C3.3
CDR-L2

GASKLES




1003
hBEW-5C3.3
CDR-L3

QQSWYDPPT




1004
hBEW-5C3.4 VH

EIQLVQSGSELKKPGASVKVSCKAS G




YTFTNYGVY WVKQAPGQGLEYMG WIN




TETGKPTYADDFKG RFVFSLDTSVST




AYLQISSLKAEDTAVYYCAR ARQLDW




FVY WGQGTLVTVSS



1005
hBEW-5C3.4
CDR-H1

GYTFTNYGVY


1006
hBEW-5C3.4
CDR-H2

WINTETGKPTYADDFKG




1007
hBEW-5C3.4
CDR-H3

ARQLDWFVY




1008
hBEW-5C3.4 VL

DTQLTQSPSSLSASVGDRVTISC RAR




ESLTTSLS WFQQKPGKQPKLLIY GAS




KLES GVPSRFSGSGSGTDFTLTISSL




QPEDFATYFC QQSWYDPPT FGGGTKV




EIK



1009
hBEW-5C3.4
CDR-L1

RARESLTTSLS




1010
hBEW-5C3.4
CDR-L2

GASKLES




1011
hBEW-5C3.4
CDR-L3

QQSWYDPPT




1012
hBEW-5C3.5 VH

EIQLVQSGAEVKKPGSSVKVSCKAS G




YTFTNYGVY WVKQAPGQGLEYMG WIN




TETGKPTYADDFKG RFTFTLDKSTST




AYMELSSLRSEDTAVYFCAR ARQLDW




FVY WGQGTLVTVSS



1013
hBEW-5C3.5
CDR-H1

GYTFTNYGVY




1014
hBEW-5C3.5
CDR-H2

WINTETGKPTYADDFKG




1015
hBEW-5C3.5
CDR-H3

ARQLDWFVY




1016
hBEW-5C3.5 VL

DTQLTQSPSSLSASVGDRVTISC RAR




ESLTTSLS WFQQKPGKQPKLLIY GAS




KLES GVPSRFSGSGSGTDFTLTISSL




QPEDFATYFC QQSWYDPPT FGGGTKV




EIK



1017
hBEW-5C3.5
CDR-L1

RARESLTTSLS




1018
hBEW-5C3.5
CDR-L2

GASKLES




1019
hBEW-5C3.5
CDR-L3

QQSWYDPPT




1020
hBEW-5C3.6 VH

EVQLVQSGAEVKKPGSSVKVSCKAS G




YTFTNYGVY WVRQAPGQGLEWMG WIN




TETGKPTYADDFKG RFTFTLDKSTST




AYMELSSLRSEDTAVYYCAR ARQLDW




FVY WGQGTLVTVSS



1021
hBEW-5C3.6
CDR-H1

GYTFTNYGVY




1022
hBEW-5C3.6
CDR-H2

WINTETGKPTYADDFKG




1023
hBEW-5C3.6
CDR-H3

ARQLDWFVY




1024
hBEW-5C3.6 VL

DTQLTQSPSSLSASVGDRVTISC RAR




ESLTTSLS WFQQKPGKQPKLLIY GAS




KLES GVPSRFSGSGSGTDFTLTISSL




QPEDFATYFC QQSWYDPPT FGGGTKV




EIK



1025
hBEW-5C3.6
CDR-L1

RARESLTTSLS




1026
hBEW-5C3.6
CDR-L2

GASKLES




1027
hBEW-5C3.6
CDR-L3

QQSWYDPPT




1028
hBEW-6C2.1 VH

EVQLVESGGGLVQPGGSLRLSCAAS G




FTFSYYGMH WVRQAPGKGLEWVA LIY




YDSSKMYYADSVKG RFTISRDNAKNS




LYLQMNSLRAEDTAVYYCAR GGTAPV




Y WGQGTMVTVSS



1029
hBEW-6C2.1
CDR-H1

GFTFSYYGMH




1030
hBEW-6C2.1
CDR-H2

LIYYDSSKMYYADSVKG




1031
hBEW-6C2.1
CDR-H3

GGTAPVY




1032
hBEW-6C2.1 VL

EIVLTQSPATLSLSPGERATLSC KGS




QNIANYLA WYQQKPGQAPRLLIY NTD




SLQT GIPARFSGSGSGTDFTLTISSL




EPEDFAVYYC YQSNNGYT FGQGTKLE




IK



1033
hBEW-6C2.1
CDR-L1

KGSQNIANYLA




1034
hBEW-6C2.1
CDR-L2

NTDSLQT




1035
hBEW-6C2.1
CDR-L3

YQSNNGYT




1036
hBEW-6C2.2 VH

EVQLVESGGGLVQPGGSLRLSCAAS G




FTFSYYGMH WVRQAPGKGLEWVA LIY




YDSSKMYYADSVKG RFTISRDNAKNS




LYLQMNSLRAEDTAVYYCAR GGTAPV




Y WGQGTMVTVSS



1037
hBEW-6C2.2
CDR-H1

GFTFSYYGMH




1038
hBEW-6C2.2
CDR-H2

LIYYDSSKMYYADSVKG




1039
hBEW-6C2.2
CDR-H3

GGTAPVY




1040
hBEW-6C2.2 VL

EIVLTQSPATLSLSPGERATLSC KGS




QNIANYLA WYQQKPGQAPRLLIY NTD




SLQT GIPARFSGSGSGTDYTLTISSL




EPEDFAVYFC YQSNNGYT FGQGTKLE




IK



1041
hBEW-6C2.2
CDR-L1

KGSQNIANYLA




1042
hBEW-6C2.2
CDR-L2

NTDSLQT




1043
hBEW-6C2.2
CDR-L3

YQSNNGYT




1044
hBEW-6C2.3 VH

EVQLVESGGGLVQPGGSLRLSCAAS G




FTFSYYGMH WVRQAPGKGLEWVA LIY




YDSSKMYYADSVKG RFTISRDNAKNS




LYLQMNSLRAEDTAVYYCAR GGTAPV




Y WGQGTMVTVSS



1045
hBEW-6C2.3
CDR-H1

GFTFSYYGMH




1046
hBEW-6C2.3
CDR-H2

LIYYDSSKMYYADSVKG




1047
hBEW-6C2.3
CDR-H3

GGTAPVY




1048
hBEW-6C2.3 VL

DIQMTQSPSSLSASVGDRVTITC KGS




QNIANYLA WYQQKPGKAPKLLIY NTD




SLQT GVPSRFSGSGSGTDFTLTISSL




QPEDFATYYC YQSNNGYT FGQGTKLE




IK



1049
hBEW-6C2.3
CDR-L1

KGSQNIANYLA




1050
hBEW-6C2.3
CDR-L2

NTDSLQT




1051
hBEW-6C2.3
CDR-L3

YQSNNGYT




1052
hBEW-6C2.4 VH

EVQLVESGGGLVQPGGSLRLSCAAS G




FTFSYYGMH WVRQAPGKGLEWVA LIY




YDSSKMYYADSVKG RFTISRDNAKNS




LYLQMNSLRAEDTAVYYCAR GGTAPV




Y WGQGTMVTVSS



1053
hBEW-6C2.4
CDR-H1

GFTFSYYGMH




1054
hBEW-6C2.4
CDR-H2

LIYYDSSKMYYADSVKG




1055
hBEW-6C2.4
CDR-H3

GGTAPVY




1056
hBEW-6C2.4 VL

DIQLTQSPSSLSASVGDRVTITC KGS




QNIANYLA WYQQKPGKAPKLLIY NTD




SLQT GIPSRFSGSGSGTDYTLTISSL




QPEDFATYFC YQSNNGYT FGQGTKLE




IK



1057
hBEW-6C2.4
CDR-L1

KGSQNIANYLA




1058
hBEW-6C2.4
CDR-L2

NTDSLQT




1059
hBEW-6C2.4
CDR-L3

YQSNNGYT




1060
hBEW-6C2.5 VH

EVQLVESGGGLVQPGGSLRLSCAAS G




FTFSYYGMH WIRQAPGKGLEWMA LIY




YDSSKMYYADSVKG RFTISRDNAKNS




LYLQMNSLRAEDTAVYYCAA GGTAPV




Y WGQGTMVTVSS



1061
hBEW-6C2.5
CDR-H1

GFTFSYYGMH




1062
hBEW-6C2.5
CDR-H2

LIYYDSSKMYYADSVKG




1063
hBEW-6C2.5
CDR-H3

GGTAPVY




1064
hBEW-6C2.5 VL

EIVLTQSPATLSLSPGERATLSC KGS




QNIANYLA WYQQKPGQAPRLLIY NTD




SLQT GIPARFSGSGSGTDFTLTISSL




EPEDFAVYYC YQSNNGYT FGQGTKLE




IK



1065
hBEW-6C2.5
CDR-L1

KGSQNIANYLA




1066
hBEW-6C2.5
CDR-L2

NTDSLQT




1067
hBEW-6C2.5
CDR-L3

YQSNNGYT




1068
hBEW-6C2.6 VH

EVQLVESGGGLVQPGGSLRLSCAAS G




FTFSYYGMH WIRQAPGKGLEWMA LIY




YDSSKMYYADSVKG RFTISRDNAKNS




LYLQMNSLRAEDTAVYYCAA GGTAPV




Y WGQGTMVTVSS



1069
hBEW-6C2.6
CDR-H1

GFTFSYYGMH




1070
hBEW-6C2.6
CDR-H2

LIYYDSSKMYYADSVKG




1071
hBEW-6C2.6
CDR-H3

GGTAPVY




1072
hBEW-6C2.6 VL

EIVLTQSPATLSLSPGERATLSC KGS




QNIANYLA WYQQKPGQAPRLLIY NTD




SLQT GIPARFSGSGSGTDYTLTISSL




EPEDFAVYFC YQSNNGYT FGQGTKLE




IK



1073
hBEW-6C2.6
CDR-L1

KGSQNIANYLA




1074
hBEW-6C2.6
CDR-L2

NTDSLQT




1075
hBEW-6C2.6
CDR-L3

YQSNNGYT




1076
hBEW-6C2.7 VH

EVQLVESGGGLVQPGGSLRLSCAAS G




FTFSYYGMH WIRQAPGKGLEWMA LIY




YDSSKMYYADSVKG RFTISRDNAKNS




LYLQMNSLRAEDTAVYYCAA GGTAPV




Y WGQGTMVTVSS



1077
hBEW-6C2.7
CDR-H1

GFTFSYYGMH




1078
hBEW-6C2.7
CDR-H2

LIYYDSSKMYYADSVKG




1079
hBEW-6C2.7
CDR-H3

GGTAPVY




1080
hBEW-6C2.7 VL

DIQMTQSPSSLSASVGDRVTITC KGS




QNIANYLA WYQQKPGKAPKLLIY NTD




SLQT GVPSRFSGSGSGTDFTLTISSL




QPEDFATYYC YQSNNGYT FGQGTKLE




IK



1081
hBEW-6C2.7
CDR-L1

KGSQNIANYLA




1082
hBEW-6C2.7
CDR-L2

NTDSLQT




1083
hBEW-6C2.7
CDR-L3

YQSNNGYT




1084
hBEW-6C2.8 VH

EVQLVESGGGLVQPGGSLRLSCAAS G




FTFSYYGMH WIRQAPGKGLEWMA LIY




YDSSKMYYADSVKG RFTISRDNAKNS




LYLQMNSLRAEDTAVYYCAA GGTAPV




Y WGQGTMVTVSS



1085
hBEW-6C2.8
CDR-H1

GFTFSYYGMH




1086
hBEW-6C2.8
CDR-H2

LIYYDSSKMYYADSVKG




1087
hBEW-6C2.8
CDR-H3

GGTAPVY




1088
hBEW-6C2.8 VL

DIQLTQSPSSLSASVGDRVTITC KGS




QNIANYLA WYQQKPGKAPKLLIY NTD




SLQT GIPSRFSGSGSGTDYTLTISSL




QPEDFATYFC YQSNNGYT FGQGTKLE




IK



1089
hBEW-6C2.8
CDR-L1

KGSQNIANYLA




1090
hBEW-6C2.8
CDR-L2

NTDSLQT




1091
hBEW-6C2.8
CDR-L3

YQSNNGYT




1092
hBEW-9A8.1 VH

EVQLVQSGHEVKQPGASVKVSCKAS G




YTFTNYGMY WVPQAPGQGLEWMG WIN




TETGKPIYADDFKG RFVFSMDTSAST




AYLQISSLKAEDMAMYYCAR VDYDGS




FWFAY WGQGTLVTVSS



1093
hBEW-9A8.1
CDR-H1

GYTFTNYGMY




1094
hBEW-9A8.1
CDR-H2

WINTETGKPIYADDFKG




1095
hBEW-9A8.1
CDR-H3

VDYDGSFWFAY




1096
hBEW-9A8.1 VL

EIVLTQSPDFQSVTPKEKVTITC RAS




ESVSTVIH WYQQKPDQSPKLLIKP GAS




NLES GVPSRFSGSGSGTDFTLTINSL




EAEDAATYYC QQHWNDPPT FGQGTKL




EIK



1097
hBEW-9A8.1
CDR-L1

RASESVSTVIH




1098
hBEW-9A8.1
CDR-L2

GASNLES




1099
hBEW-9A8.1
CDR-L3

QQHWNDPPT




1100
hBEW-9A8.10 VH

EVQLVQSGAEVKKPGASVKVSCKAS G




YTFTNYGMY WVRQAPGQGLEWMG WIN




TETGKPIYADDFKG RVTMTTDTSTST




AYMELRSLRSDDTAVYYCAR VDYDGS




FWFAY WGQGTLVTVSS



1101
hBEW-9A8.10
CDR-H1

GYTFTNYGMY




1102
hBEW-9A8.10
CDR-H2

WINTETGKPIYADDFKG




1103
hBEW-9A8.10
CDR-H3

VDYDGSFWFAY




1104
hBEW-9A8.10 VL

ETVLTQSPDFQSVTPKEKVTITC RAS




ESVSTVIH WYQQKPDQQPKLLIH GAS




NLES GVPSRFSGSGSGTDFTLTINSL




EAEDAATYFC QQHWNDPPT FGQGTKL




EIK



1105
hBEW-9A8.10
CDR-L1

RASESVSTVIH




1106
hBEW-9A8.10
CDR-L2

GASNLES




1107
hBEW-9A8.10
CDR-L3

QQHWNDPPT




1108
hBEW-9A8.11 VH

EVQLVQSGAEVKKPGASVKVSCKAS G




YTFTNYGMY WVRQAPGQGLEWMG WIN




TETGKPIYADDFKG RVTMTTDTSTST




AYMELRSLRSDDTAVYYCAR VDYDGS




FWFAY WGQGTLVTVSS



1109
hBEW-9A8.11
CDR-H1

GYTFTNYGMY




1110
hBEW-9A8.11
CDR-H2

WINTETGKPIYADDFKG




1111
hBEW-9A8.11
CDR-H3

VDYDGSFWFAY




1112
hBEW-9A8.11 VL

DIQMTQSPSSLSASVGDRVTITC RAS




ESVSTVIH WYQQKPGKAPKLLIY GAS




NLES GVPSRFSGSGSGTDFTLTISSL




QPEDFATYYC QQHWNDPPT FGQGTKL




EIK



1113
hBEW-9A8.11
CDR-L1

RASESVSTVIH




1114
hBEW-9A8.11
CDR-L2

GASNLES




1115
hBEW-9A8.11
CDR-L3

QQHWNDPPT




1116
hBEW-9A8.12 VH

EVQLVQSGAEVKKPGASVKVSCKAS G




YTFTNYGMY WVRQAPGQGLEWMG WIN




TETGKPIYADDFKG RVTMTTDTSTST




AYMELRSLRSDDTAVYYCAR VDYDGS




FWFAY WGQGTLVTVSS



1117
hBEW-9A8.12
CDR-H1

GYTFTNYGMY




1118
hBEW-9A8.12
CDR-H2

WINTETGKPIYADDFKG




1119
hBEW-9A8.12
CDR-H3

VDYDGSFWFAY




1120
hBEW-9A8.12 VL

DTQLTQSPSSLSASVGDRVTITC RAS




ESVSTVIH WYQQKPGKQPKLLIHGAS




NLES GVPSRFSGSGSGTDFTLTISSL




QPEDFATYFC QQHWNDPPT FGQGTKL




EIK



1121
hBEW-9A8.12
CDR-L1

RASESVSTVIH




1122
hBEW-9A8.12
CDR-L2

GASNLES




1123
hBEW-9A8.12
CDR-L3

QQHWNDPPT




1124
hBEW-9A8.13 VH

EIQLVQSGAEVKKPGASVKVSCKAS G




YTFTNYGMY WVKQAPGQGLEYMG WIN




TETGKPIYADDFKG RFTFTLDTSTST




AYMELRSLRSDDTAVFFCAR VDYDGS




FWFAY WGQGTLVTVSS



1125
hBEW-9A8.13
CDR-H1

GYTFTNYGMY




1126
hBEW-9A8.13
CDR-H2

WINTETGKPIYADDFKG




1127
hBEW-9A8.13
CDR-H3

VDYDGSFWFAY




1128
hBEW-9A8.13 VL

EIVLTQSPDFQSVTPKEKVTITC RAS




ESVSTVIH WYQQKPDQSPKLLIK GAS




NLES GVPSRFSGSGSGTDFTLTINSL




EAEDAATYYC QQHWNDPPT FGQGTKL




EIK



1129
hBEW-9A8.13
CDR-L1

RASESVSTVIH




1130
hBEW-9A8.13
CDR-L2

GASNLES




1131
hBEW-9A8.13
CDR-L3

QQHWNDPPT




1132
hBEW-9A8.14 VH

EIQLVQSGAEVKKPGASVKVSCKAS G




YTFTNYGMY WVKQAPGQGLEYMG WIN




TETGKPIYADDFKG RFTFTLDTSTST




AYMELRSLRSDDTAVFFCAR VDYDGS




FWFAY WGQGTLVTVSS



1133
hBEW-9A8.14
CDR-H1

GYTFTNYGMY




1134
hBEW-9A8.14
CDR-H2

WINTETGKPIYADDFKG




1135
hBEW-9A8.14
CDR-H3

VDYDGSFWFAY




1136
hBEW-9A8.14 VL

ETVLTQSPDFQSVTPKEKVTITC RAS




ESVSTVIH WYQQKPDQQPKLLIH GAS




NLES GVPSRFSGSGSGTDFTLTINSL




EAEDAATYFC QQHWNDPPT FGQGTKL




EIK



1137
hBEW-9A8.14
CDR-L1

RASESVSTVIH




1138
hBEW-9A8.14
CDR-L2

GASNLES




1139
hBEW-9A8.14
CDR-L3

QQHWNDPPT




1140
hBEW-9A8.15 VH

EIQLVQSGAEVKKPGASVKVSCKAS G




YTFTNYGMY WVKQAPGQGLEYMG WIN




TETGKPIYADDFKG RFTFTLDTSTST




AYMELRSLRSDDTAVFFCAR VDYDGS




FWFAY WGQGTLVTVSS



1141
hBEW-9A8.15
CDR-H1

GYTFTNYGMY




1142
hBEW-9A8.15
CDR-H2

WINTETGKPIYADDFKG




1143
hBEW-9A8.15
CDR-H3

VDYDGSFWFAY




1144
hBEW-9A8.15 VL

DIQMTQSPSSLSASVGDRVTITC RAS




ESVSTVIH WYQQKPGKAPKLLIY GAS




NLES GVPSRFSGSGSGTDFTLTISSL




QPEDFATYYC QQHWNDPPT FGQGTKL




EIK



1145
hBEW-9A8.15
CDR-L1

RASESVSTVIH




1146
hBEW-9A8.15
CDR-L2

GASNLES




1147
hBEW-9A8.15
CDR-L3

QQHWNDPPT




1148
hBEW-9A8.16 VH

EIQLVQSGAEVKKPGASVKVSCKAS G




YTFTNYGMY WVKQAPGQGLEYMG WIN




TETGKPIYADDFKG RFTFTLDTSTST




AYMELRSLRSDDTAVFFCAR VDYDGS




FWFAY WGQGTLVTVSS



1149
hBEW-9A8.16
CDR-H1

GYTFTNYGMY




1150
hBEW-9A8.16
CDR-H2

WINTETGKPIYADDFKG




1151
hBEW-9A8.16
CDR-H3

VDYDGSFWFAY




1152
hBEW-9A8.16 VL

DTQLTQSPSSLSASVGDRVTITC RAS




ESVSTVIH WYQQKPGKQPKLLIHGAS




NLES GVPSRFSGSGSGTDFTLTISSL




QPEDFATYFC QQHWNDPPT FGQGTKL




EIK



1153
hBEW-9A8.16
CDR-L1

RASESVSTVIH




1154
hBEW-9A8.16
CDR-L2

GASNLES




1155
hBEW-9A8.16
CDR-L3

QQHWNDPPT




1156
hBEW-9A8.17 VH

EIQLVQSGSELKKPGASVKVSCKAS G




YTFTNYGMY WVKQAPGQGLEYMG WIN




TETGKPIYADDFKG RFVFSLDTSVST




AYLQISSLKAEDTAVYYCAR VDYDGS




FWFAY WGQGTLVTVSS



1157
hBEW-9A8.17
CDR-H1

GYTFTNYGMY




1158
hBEW-9A8.17
CDR-H2

WINTETGKPIYADDFKG




1159
hBEW-9A8.17
CDR-H3

VDYDGSFWFAY




1160
hBEW-9A8.17 VL

ETVLTQSPATLSLSPGERATLSG RAS




ESVSTVIH WYQQKPGQQPRLLIH GAS




NLES GVPARFSGSGSGTDFTLTISSL




EPEDFAVYFC QQHWNDPPT FGQGTKL




EIK



1161
hBEW-9A8.17
CDR-L1

RASESVSTVIH




1162
hBEW-9A8.17
CDR-L2

GASNLES




1163
hBEW-9A8.17
CDR-L3

QQHWNDPPT




1164
hBEW-9A8.2 VH

EVQLVQSGHEVKQPGASVKVSCKAS G




YTFTNYGMY WVPQAPGQGLEWMG WIN




TETGKPIYADDFKG RFVFSMDTSAST




AYLQISSLKAEDMAMYYCAR VDYDGS




FWFAY WGQGTLVTVSS



1165
hBEW-9A8.2
CDR-H1

GYTFTNYGMY




1166
hBEW-9A8.2
CDR-H2

WINTETGKPIYADDFKG




1167
hBEW-9A8.2
CDR-H3

VDYDGSFWFAY




1168
hBEW-9A8.2 VL

ETVLTQSPDFQSVTPKEKVTITG RAS




ESVSTVIH WYQQKPDQQPKLLIH GAS




NLES GVPSRFSGSGSGTDFTLTINSL




EAEDAATYFC QQHWNDPPT FGQGTKL




EIK



1169
hBEW-9A8.2
CDR-L1

RASESVSTVIH




1170
hBEW-9A8.2
CDR-L2

GASNLES




1171
hBEW-9A8.2
CDR-L3

QQHWNDPPT




1172
hBEW-9A8.20 VH

EIQLVQSGAEVKKPGASVKVSCKAS G




YTFTNYGMY WVKQAPGQGLEYMG WIN




TETGKPIYADDFKG RFTFTLDTSTST




AYMELRSLRSDDTAVYYCAR VDYDGS




FWFAY WGQGTLVTVSS



1173
hBEW-9A8.20
CDR-H1

GYTFTNYGMY




1174
hBEW-9A8.20
CDR-H2

WINTETGKPIYADDFKG




1175
hBEW-9A8.20
CDR-H3

VDYDGSFWFAY




1176
hBEW-9A8.20 VL

ETVLTQSPATLSLSPGERATLSC RAS




ESVSTVIH WYQQKPGQQPRLLIH GAS




NLES GVPARFSGSGSGTDFTLTISSL




EPEDFAVYFC QQHWNDPPT FGQGTKL




EIK



1177
hBEW-9A8.20
CDR-L1

RASESVSTVIH




1178
hBEW-9A8.20
CDR-L2

GASNLES




1179
hBEW-9A8.20
CDR-L3

QQHWNDPPT




1180
hBEW-9A8.21 VH

EIQLVQSGAEVKKPGASVKVSCKAS G




YTFTNYGMY WVRQAPGQGLEWMG WIN




TETGKPIYADDFKG RFTFTLDTSTST




AYMELRSLRSDDTAVYYCAR VDYDGS




FWFAY WGQGTLVTVSS



1181
hBEW-9A8.21
CDR-H1

GYTFTNYGMY




1182
hBEW-9A8.21
CDR-H2

WINTETGKPIYADDFKG




1183
hBEW-9A8.21
CDR-H3

VDYDGSFWFAY




1184
hBEW-9A8.21 VL

ETVLTQSPATLSLSPGERATLSC RAS




ESVSTVIH WYQQKPGQQPRLLIH GAS




NLES GVPARFSGSGSGTDFTLTISSL




EPEDFAVYFC QQHWNDPPT FGQGTKL




EIK



1185
hBEW-9A8.21
CDR-L1

RASESVSTVIH




1186
hBEW-9A8.21
CDR-L2

GASNLES




1187
hBEW-9A8.21
CDR-L3

QQHWNDPPT




1188
hBEW-9A8.3 VH

EVQLVQSGHEVKQPGASVKVSCKAS G




YTFTNYGMY WVPQAPGQGLEWMG WIN




TETGKPIYADDFKG RFVFSMDTSAST




AYLQISSLKAEDMAMYYCAR VDYDGS




FWFAY WGQGTLVTVSS



1189
hBEW-9A8.3
CDR-H1

GYTFTNYGMY




1190
hBEW-9A8.3
CDR-H2

WINTETGKPIYADDFKG




1191
hBEW-9A8.3
CDR-H3

VDYDGSFWFAY




1192
hBEW-9A8.3 VL

DIQMTQSPSSLSASVGDRVTITC RAS




ESVSTVIH WYQQKPGKAPKLLIY GAS




NLES GVPSRFSGSGSGTDFTLTISSL




QPEDFATYYC QQHWNDPPT FGQGTKL




EIK



1193
hBEW-9A8.3
CDR-L1

RASESVSTVIH




1194
hBEW-9A8.3
CDR-L2

GASNLES




1195
hBEW-9A8.3
CDR-L3

QQHWNDPPT




1196
hBEW-9A8.4 VH

EVQLVQSGHEVKQPGASVKVSCKAS G




YTFTNYGMY WVPQAPGQGLEWMG WIN




TETGKPIYADDFKG RFVFSMDTSAST




AYLQISSLKAEDMAMYYCAR VDYDGS




FWFAY WGQGTLVTVSS



1197
hBEW-9A8.4
CDR-H1

GYTFTNYGMY




1198
hBEW-9A8.4
CDR-H2

WINTETGKPIYADDFKG




1199
hBEW-9A8.4
CDR-H3

VDYDGSFWFAY




1200
hBEW-9A8.4 VL

DTQLTQSPSSLSASVGDRVTITC RAS




ESVSTVIH WYQQKPGKQPKLLIH GAS




NLES GVPSRFSGSGSGTDFTLTISSL




QPEDFATYFC QQHWNDPPT FGQGTKL




EIK



1201
hBEW-9A8.4
CDR-L1

RASESVSTVIH




1202
hBEW-9A8.4
CDR-L2

GASNLES




1203
hBEW-9A8.4
CDR-L3

QQHWNDPPT




1204
hBEW-9A8.5 VH

EIQLVQSGHEVKQPGASVKVSCKAS G




YTFTNYGMY WVKQAPGQGLEYMG WIN




TETGKPIYADDFKG RFVFSLDTSAST




AYLQISSLKAEDMAMFFCAR VDYDGS




FWFAY WGQGTLVTVSS



1205
hBEW-9A8.5
CDR-H1

GYTFTNYGMY




1206
hBEW-9A8.5
CDR-H2

WINTETGKPIYADDFKG




1207
hBEW-9A8.5
CDR-H3

VDYDGSFWFAY




1208
hBEW-9A8.5 VL

EIVLTQSPDFQSVTPKEKVTITC RAS




ESVSTVIH WYQQKPDQSPKLLIK GAS




NLES GVPSRFSGSGSGTDFTLTINSL




EAEDAATYYC QQHWNDPPT FGQGTKL




EIK



1209
hBEW-9A8.5
CDR-L1

RASESVSTVIH




1210
hBEW-9A8.5
CDR-L2

GASNLES




1211
hBEW-9A8.5
CDR-L3

QQHWNDPPT




1212
hBEW-9A8.6 VH

EIQLVQSGHEVKQPGASVKVSCKAS G




YTFTNYGMY WVKQAPGQGLEYMG WIN




TETGKPIYADDFKG RFVFSLDTSAST




AYLQISSLKAEDMAMFFCAR VDYDGS




FWFAY WGQGTLVTVSS



1213
hBEW-9A8.6
CDR-H1

GYTFTNYGMY




1214
hBEW-9A8.6
CDR-H2

WINTETGKPIYADDFKG




1215
hBEW-9A8.6
CDR-H3

VDYDGSFWFAY




1216
hBEW-9A8.6 VL

ETVLTQSPDFQSVTPKEKVTITC RAS




ESVSTVIH WYQQKPDQQPKLLIH GAS




NLES GVPSRFSGSGSGTDFTLTINSL




EAEDAATYFC QQHWNDPPT FGQGTKL




EIK



1217
hBEW-9A8.6
CDR-L1

RASESVSTVIH




1218
hBEW-9A8.6
CDR-L2

GASNLES




1219
hBEW-9A8.6
CDR-L3

QQHWNDPPT




1220
hBEW-9A8.7 VH

EIQLVQSGHEVKQPGASVKVSCKAS G




YTFTNYGMY WVKQAPGQGLEYMG WIN




TETGKPIYADDFKG RFVFSLDTSAST




AYLQISSLKAEDMAMFFCAR VDYDGS




FWFAY WGQGTLVTVSS



1221
hBEW-9A8.7
CDR-H1

GYTFTNYGMY




1222
hBEW-9A8.7
CDR-H2

WINTETGKPIYADDFKG




1223
hBEW-9A8.7
CDR-H3

VDYDGSFWFAY




1224
hBEW-9A8.7 VL

DIQMTQSPSSLSASVGDRVTITC RAS




ESVSTVIH WYQQKPGKAPKLLIY GAS




NLES GVPSRFSGSGSGTDFTLTISSL




QPEDFATYYC QQHWNDPPT FGQGTKL




EIK



1225
hBEW-9A8.7
CDR-L1

RASESVSTVIH




1226
hBEW-9A8.7
CDR-L2

GASNLES




1227
hBEW-9A8.7
CDR-L3

QQHWNDPPT




1228
hBEW-9A8.8 VH

EIQLVQSGHEVKQPGASVKVSCKAS G




YTFTNYGMY WVKQAPGQGLEYMG WIN




TETGKPIYADDFKG RFVFSLDTSAST




AYLQISSLKAEDMAMFFCAR VDYDGS




FWFAY WGQGTLVTVSS



1229
hBEW-9A8.8
CDR-H1

GYTFTNYGMY




1230
hBEW-9A8.8
CDR-H2

WINTETGKPIYADDFKG




1231
hBEW-9A8.8
CDR-H3

VDYDGSFWFAY




1232
hBEW-9A8.8 VL

DTQLTQSPSSLSASVGDRVTITC RAS




ESVSTVIH WYQQKPGKQPKLLIH GAS




NLES GVPSRFSGSGSGTDFTLTISSL




QPEDFATYFC QQHWNDPPT FGQGTKL




EIK



1233
hBEW-9A8.8
CDR-L1

RASESVSTVIH




1234
hBEW-9A8.8
CDR-L2

GASNLES




1235
hBEW-9A8.8
CDR-L3

QQHWNDPPT




1236
hBEW-9A8.9 VH

EVQLVQSGAEVKKPGASVKVSCKAS G




YTFTNYGMY WVRQAPGQGLEWMG WIN




TETGKPIYADDFKG RVTMTTDTSTST




AYMELRSLRSDDTAVYYCAR VDYDGS




FWFAY WGQGTLVTVSS



1237
hBEW-9A8.9
CDR-H1

GYTFTNYGMY




1238
hBEW-9A8.9
CDR-H2

WINTETGKPIYADDFKG




1239
hBEW-9A8.9
CDR-H3

VDYDGSFWFAY




1240
hBEW-9A8.9 VL

EIVLTQSPDFQSVTPKEKVTITC RAS




ESVSTVIH WYQQKPDQSPKLLIK GAS




NLES GVPSRFSGSGSGTDFTLTINSL




EAEDAATYYC QQHWNDPPT FGQGTKL




EIK



1241
hBEW-9A8.9
CDR-L1

RASESVSTVIH




1242
hBEW-9A8.9
CDR-L2

GASNLES




1243
hBEW-9A8.9
CDR-L3

QQHWNDPPT




1244
hBEW-9E10.1 VH

EIQLVQSGSELKKPGASVKVSCKAS G




YTFTNYGMY WVKQAPGQGLEYMG WID




TETGRPTYADDFKG RFVFSLDTSVST




AYLQISSLKAEDTAVYFCAR WSGDTT




GIRGPWFAY WGQGTLVTVSS



1245
hBEW-9E10.1
CDR-H1

GYTFTNYGMY




1246
hBEW-9E10.1
CDR-H2

WIDTETGRPTYADDFKG




1247
hBEW-9E10.1
CDR-H3

WSGDTTGIRGPWFAY




1248
hBEW-9E10.1 VL

DIRMTQSPSSLSASVGDRVTIEC LAS




EDIYSDLA WYQQKPGKSPKLLIY NAN




GLQN GVPSRFSGSGSGTDYSLTISSL




QPEDVATYFC QQYNYFPGT FGQGTKL




EIK



1249
hBEW-9E10.1
CDR-L1

LASEDIYSDLA




1250
hBEW-9E10.1
CDR-L2

NANGLQN




1251
hBEW-9E10.1
CDR-L3

QQYNYFPGT




1252
hBEW-9E10.2 VH

EIQLVQSGAEVKKPGSSVKVSCKAS G




YTFTNYGMY WVKQAPGQGLEYMG WID




TETGRPTYADDFKG RFTFTADKSTST




AYMELSSLRSEDTAVYFCAR WSGDTT




GIRGPWFAY WGQGTLVTVSS



1253
hBEW-9E10.2
CDR-H1

GYTFTNYGMY




1254
hBEW-9E10.2
CDR-H2

WIDTETGRPTYADDFKG




1255
hBEW-9E10.2
CDR-H3

WSGDTTGIRGPWFAY




1256
hBEW-9E10.2 VL

DIRMTQSPSSLSASVGDRVTIEC LAS




EDIYSDLA WYQQKPGKSPKLLIY NAN




GLQN GVPSRFSGSGSGTDYSLTISSL




QPEDVATYFC QQYNYFPGT FGQGTKL




EIK



1257
hBEW-9E10.2
CDR-L1

LASEDIYSDLA




1258
hBEW-9E10.2
CDR-L2

NANGLQN




1259
hBEW-9E10.2
CDR-L3

QQYNYFPGT




1260
hBEW-9E10.3 VH

EVQLVQSGAEVKKPGSSVKVSCKAS G




YTFTNYGMY WVRQAPGQGLEWMG WID




TETGRPTYADDFKG RFTFTADKSTST




AYMELSSLRSEDTAVYYCAR WSGDTT




GIRGPWFAY WGQGTLVTVSS



1261
hBEW-9E10.3
CDR-H1

GYTFTNYGMY




1262
hBEW-9E10.3
CDR-H2

WIDTETGRPTYADDFKG




1263
hBEW-9E10.3
CDR-H3

WSGDTTGIRGPWFAY




1264
hBEW-9E10.3 VL

DIRMTQSPSSLSASVGDRVTIEC LAS




EDIYSDLA WYQQKPGKSPKLLTY NAN




GLQN GVPSRFSGSGSGTDYSLTISSL




QPEDVATYFC QQYNYFPGT FGQGTKL




EIK



1265
hBEW-9E10.3
CDR-L1

LASEDIYSDLA




1266
hBEW-9E10.3
CDR-L2

NANGLQN




1267
hBEW-9E10.3
CDR-L3

QQYNYFPGT




1268
hBEW-9E10.4 VH

EIQLVQSGSELKKPGASVKVSCKAS G




YTFTNYGMY WVKQAPGQGLEYMG WID




TETGRPTYADDFKG RFVFSLDTSVST




AYLQISSLKAEDTAVYFCAR WSGDTT




GIRGPWFAY WGQGTLVTVSS



1269
hBEW-9E10.4
CDR-H1

GYTFTNYGMY




1270
hBEW-9E10.4
CDR-H2

WIDTETGRPTYADDFKG




1271
hBEW-9E10.4
CDR-H3

WSGDTTGIRGPWFAY




1272
hBEW-9E10.4 VL

DIRMTQSPSSLSASVGDRVTITC LAS




EDIYSDLA WYQQKPGKSPKLLTY NAN




GLQN GVPSRFSGSGSGTDYTLTISSL




QPEDVATYFC QQYNYFPGT FGQGTKL




EIK



1273
hBEW-9E10.4
CDR-L1

LASEDIYSDLA




1274
hBEW-9E10.4
CDR-L2

NANGLQN




1275
hBEW-9E10.4
CDR-L3

QQYNYFPGT




1276
hBEW-9E10.5 VH

EIQLVQSGAEVKKPGSSVKVSCKAS G




YTFTNYGMY WVKQAPGQGLEYMG WID




TETGRPTYADDFKG RFTFTADKSTST




AYMELSSLRSEDTAVYFCAR WSGDTT




GIRGPWFAY WGQGTLVTVSS



1277
hBEW-9E10.5
CDR-H1

GYTFTNYGMY




1278
hBEW-9E10.5
CDR-H2

WIDTETGRPTYADDFKG




1279
hBEW-9E10.5
CDR-H3

WSGDTTGIRGPWFAY




1280
hBEW-9E10.5 VL

DIRMTQSPSSLSASVGDRVTITC LAS




EDIYSDLA WYQQKPGKSPKLLTY NAN




GLQN GVPSRFSGSGSGTDYTLTISSL




QPEDVATYFC QQYNYFPGT FGQGTKL




EIK



1281
hBEW-9E10.5
CDR-L1

LASEDIYSDLA




1282
hBEW-9E10.5
CDR-L2

NANGLQN




1283
hBEW-9E10.5
CDR-L3

QQYNYFPGT




1284
hBEW-9E10.6 VH

EVQLVQSGAEVKKPGSSVKVSCKAS G




YTFTNYGMY WVRQAPGQGLEWMG WID




TETGRPTYADDFKG RFTFTADKSTST




AYMELSSLRSEDTAVYYCAR WSGDTT




GIRGPWFAY WGQGTLVTVSS



1285
hBEW-9E10.6
CDR-H1

GYTFTNYGMY




1286
hBEW-9E10.6
CDR-H2

WIDTETGRPTYADDFKG




1287
hBEW-9E10.6
CDR-H3

WSGDTTGIRGPWFAY




1288
hBEW-9E10.6 VL

DIRMTQSPSSLSASVGDRVTITC LAS




EDIYSDLA WYQQKPGKSPKLLIY NAN




GLQN GVPSRFSGSGSGTDYTLTISSL




QPEDVATYFC QQYNYFPGT FGQGTKL




EIK



1289
hBEW-9E10.6
CDR-L1

LASEDIYSDLA




1290
hBEW-9E10.6
CDR-L2

NANGLQN




1291
hBEW-9E10.6
CDR-L3

QQYNYFPGT




1292
AB014 VH

EVQLVESGGGLVQPGGSLR




LSCAAS GYTFTNYGMN WVR




QAPGKGLEWVG WINTYTGE




PTYAADFKR RFTFSLDTSK




STAYLQMNSLRAEDTAVYY




CAK YPHYYGSSHWYFDV WG




QGTLVTVSS



1293
AB014
CDR-H1

GYTFTNYGMN




1294
AB014
CDR-H2

WINTYTGEPTYAADFKR




1295
AB014
CDR-H3

YPHYYGSSHWYFDV




1296
AB014 VL

DIQMTQSPSSLSASVGDRV




TITC SASQDISNYLN WYQQ




KPGKAPKVLIY FTSSLHS G




VPSRFSGSGSGTDFTLTIS




SLQPEDFATYYC QQYSTVP




WT FGQGTKVEIK



1297
AB014
CDR-L1

SASQDISNYLN




1298
AB014
CDR-L2

FTSSLHS




1299
AB014
CDR-L3

QQYSTVPWT
















































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































TABLE 28



VH and VL Amino Acid Sequences of Humanized Versions of

Rat Anti-Human PDGF-BB Monoclonal Antibodies (CDRs in bold)






SEQ ID

Protein
V Region

NO:
Clone
Region
123456789012345678901234567890



1300
hBDI-1E1.1 VH

EVQLVQSGAEVKKPGSSVKVSCKAS GYTFTDYVMH W




VRQAPGQGLEWMG TIIPLIDTTSYNQKFKG RVTITA




DKSTSTAYMELSSLRSEDTAVYYCAR TSPYYYSSYD




VMDA WGQGTTVTVSS



1301
hBDI-1E1.1
CDR-H1

GYTFTDYVMH




1302
hBDI-1E1.1
CDR-H2

TIIPLIDTTSYNQKFKG




1303
hBDI-1E1.1
CDR-H3

TSPYYYSSYDVMDA




1304
hBDI-1E1.1 VL

AIQLTQSPSSLSASVGDRVTITC KGSQNINNYLA WY




QQKPGKAPKLLIY KTNNLQT GVPSRFSGSGSGTDFT




LTISSLQPEDFATYYC YQYDNGYT FGQGTKLEIK



1305
hBDI-1E1.1
CDR-L1

KGSQNINNYLA




1306
hBDI-1E1.1
CDR-L2

KTNNLQT




1307
hBDI-1E1.1
CDR-L3

YQYDNGYT




1308
hBDI-1E1.10 VH

EVQLVQSGAEVKKPGSSVKVSCKAS GYTFTDYVMH W




VRQAPGQGLEWIG TIIPLIDTTSYNQKFKG RVTITA




DKSTSTAYMELSSLRSEDTAVYYCAR TSPYYYSSYD




VMDA WGQGTTVTVSS



1309
hBDI-1E1.10
CDR-H1

GYTFTDYVMH




1310
hBDI-1E1.10
CDR-H2

TIIPLIDTTSYNQKFKG




1311
hBDI-1E1.10
CDR-H3

TSPYYYSSYDVMDA




1312
hBDI-1E1.10 VL

AIQLTQSPSSLSASVGDRVTITC KGSQNINNYLA WY




QQKPGKAPKLLIY KTNNLQT GIPSRFSGSGSGTDYT




LTISSLQPEDFATYYC YQYDNGYT FGQGTKLEIK



1313
hBDI-1E1.10
CDR-L1

KGSQNINNYLA




1314
hBDI-1E1.10
CDR-L2

KTNNLQT




1315
hBDI-1E1.10
CDR-L3

YQYDNGYT




1316
hBDI-1E1.11 VH

EVQLVQSGAEVKKPGSSVKVSCKAS GYTFTDYVMH W




VRQAPGQGLEWIG TIIPLIDTTSYNQKFKG RVTITA




DKSTSTAYMELSSLRSEDTAVYYCAR TSPYYYSSYD




VMDA WGQGTTVTVSS



1317
hBDI-1E1.11
CDR-H1

GYTFTDYVMH




1318
hBDI-1E1.11
CDR-H2

TIIPLIDTTSYNQKFKG




1319
hBDI-1E1.11
CDR-H3

TSPYYYSSYDVMDA




1320
hBDI-1E1.11 VL

EIVLTQSPATLSLSPGERATLSC KGSQNINNYLA WY




QQKPGQAPRLLIY KTNNLQT GIPARFSGSGSGTDFT




LTISSLEPEDFAVYYC YQYDNGYT FGQGTKLEIK



1321
hBDI-1E1.11
CDR-L1

KGSQNINNYLA




1322
hBDI-1E1.11
CDR-L2

KTNNLQT




1323
hBDI-1E1.11
CDR-L3

YQYDNGYT




1324
hBDI-1E1.12 VH

EVQLVQSGAEVKKPGSSVKVSCKAS GYTFTDYVMH W




VRQAPGQGLEWIG TIIPLIDTTSYNQKFKG RVTITA




DKSTSTAYMELSSLRSEDTAVYYCAR TSPYYYSSYD




VMDA WGQGTTVTVSS



1325
hBDI-1E1.12
CDR-H1

GYTFTDYVMH




1326
hBDI-1E1.12
CDR-H2

TIIPLIDTTSYNQKFKG




1327
hBDI-1E1.12
CDR-H3

TSPYYYSSYDVMDA




1328
hBDI-1E1.12 VL

EIVLTQSPATLSLSPGERATLSC KGSQNINNYLA WY




QQKPGQAPRLLIY KTNNLQT GIPARFSGSGSGTDYT




LTISSLEPEDFATYYC YQYDNGYT FGQGTKLEIK



1329
hBDI-1E1.12
CDR-L1

KGSQNINNYLA




1330
hBDI-1E1.12
CDR-L2

KTNNLQT




1331
hBDI-1E1.12
CDR-L3

YQYDNGYT




1332
hBDI-1E1.2 VH

EVQLVQSGAEVKKPGSSVKVSCKAS GYTFTDYVMH W




VRQAPGQGLEWMG TIIPLIDTTSYNQKFKG RVTITA




DKSTSTAYMELSSLRSEDTAVYYCAR TSPYYYSSYD




VMDA WGQGTTVTVSS



1333
hBDI-1E1.2
CDR-H1

GYTFTDYVMH




1334
hBDI-1E1.2
CDR-H2

TIIPLIDTTSYNQKFKG




1335
hBDI-1E1.2
CDR-H3

TSPYYYSSYDVMDA




1336
hBDI-1E1.2 VL

AIQLTQSPSSLSASVGDRVTITC KGSQNINNYLA WY




QQKPGKAPKLLIY KTNNLQT GIPSRFSGSGSGTDYT




LTISSLQPEDFATYYC YQYDNGYT FGQGTKLEIK



1337
hBDI-1E1.2
CDR-L1

KGSQNINNYLA




1338
hBDI-1E1.2
CDR-L2

KTNNLQT




1339
hBDI-1E1.2
CDR-L3

YQYDNGYT




1340
hBDI-1E1.3 VH

EVQLVQSGAEVKKPGSSVKVSCKAS GYTFTDYVMH W




VRQAPGQGLEWMG TIIPLIDTTSYNQKFKG RVTITA




DKSTSTAYMELSSLRSEDTAVYYCAR TSPYYYSSYD




VMDA WGQGTTVTVSS



1341
hBDI-1E1.3
CDR-H1

GYTFTDYVMH




1342
hBDI-1E1.3
CDR-H2

TIIPLIDTTSYNQKFKG




1343
hBDI-1E1.3
CDR-H3

TSPYYYSSYDVMDA




1344
hBDI-1E1.3 VL

EIVLTQSPATLSLSPGERATLSC KGSQNINNYLA WY




QQKPGQAPRLLIY KTNNLQT GIPARFSGSGSGTDFT




LTISSLEPEDFAVYYC YQYDNGYT FGQGTKLEIK



1345
hBDI-1E1.3
CDR-L1

KGSQNINNYLA




1346
hBDI-1E1.3
CDR-L2

KTNNLQT




1347
hBDI-1E1.3
CDR-L3

YQYDNGYT




1348
hBDI-1E1.4 VH

EVQLVQSGAEVKKPGSSVKVSCKAS GYTFTDYVMH W




VRQAPGQGLEWMG TIIPLIDTTSYNQKFKG RVTITA




DKSTSTAYMELSSLRSEDTAVYYCAR TSPYYYSSYD




VMDA WGQGTTVTVSS



1349
hBDI-1E1.4
CDR-H1

GYTFTDYVMH




1350
hBDI-1E1.4
CDR-H2

TIIPLIDTTSYNQKFKG




1351
hBDI-1E1.4
CDR-H3

TSPYYYSSYDVMDA




1352
hBDI-1E1.4 VL

EIVLTQSPATLSLSPGERATLSC KGSQNINNYLA WY




QQKPGQAPRLLIY KTNNLQT GIPARFSGSGSGTDYT




LTISSLEPEDFATYYC YQYDNGYT FGQGTKLEIK



1353
hBDI-1E1.4
CDR-L1

KGSQNINNYLA




1354
hBDI-1E1.4
CDR-L2

KTNNLQT




1355
hBDI-1E1.4
CDR-L3

YQYDNGYT




1356
hBDI-1E1.5 VH

EVQLVQSGAEVKKPGSSVKVSCKAS GYTFTDYVMH W




VRQAPGQGLEWIG TIIPLIDTTSYNQKFKG RATLTA




DKSTNTAYMELSSLRSEDTAVYYCAR TSPYYYSSYD




VMDA WGQGTTVTVSS



1357
hBDI-1E1.5
CDR-H1

GYTFTDYVMH




1358
hBDI-1E1.5
CDR-H2

TIIPLIDTTSYNQKFKG




1359
hBDI-1E1.5
CDR-H3

TSPYYYSSYDVMDA




1360
hBDI-1E1.5 VL

AIQLTQSPSSLSASVGDRVTITC KGSQNINNYLA WY




QQKPGKAPKLLIY KTNNLQT GVPSRFSGSGSGTDFT




LTISSLQPEDFATYYC YQYDNGYT FGQGTKLEIK



1361
hBDI-1E1.5
CDR-L1

KGSQNINNYLA




1362
hBDI-1E1.5
CDR-L2

KTNNLQT




1363
hBDI-1E1.5
CDR-L3

YQYDNGYT




1364
hBDI-1E1.6 VH

EVQLVQSGAEVKKPGSSVKVSCKAS GYTFTDYVMH W




VRQAPGQGLEWIG TIIPLIDTTSYNQKFKG RATLTA




DKSTNTAYMELSSLRSEDTAVYYCAR TSPYYYSSYD




VMDA WGQGTTVTVSS



1365
hBDI-1E1.6
CDR-H1

GYTFTDYVMH




1366
hBDI-1E1.6
CDR-H2

TIIPLIDTTSYNQKFKG




1367
hBDI-1E1.6
CDR-H3

TSPYYYSSYDVMDA




1368
hBDI-1E1.6 VL

AIQLTQSPSSLSASVGDRVTITC KGSQNINNYLA WY




QQKPGKAPKLLIY KTNNLQT GIPSRFSGSGSGTDYT




LTISSLQPEDFATYYC YQYDNGYT FGQGTKLEIK



1369
hBDI-1E1.6
CDR-L1

KGSQNINNYLA




1370
hBDI-1E1.6
CDR-L2

KTNNLQT




1371
hBDI-1E1.6
CDR-L3

YQYDNGYT




1372
hBDI-1E1.7 VH

EVQLVQSGAEVKKPGSSVKVSCKAS GYTFTDYVMH W




VRQAPGQGLEWIG TIIPLIDTTSYNQKFKG RATLTA




DKSTNTAYMELSSLRSEDTAVYYCAR TSPYYYSSYD




VMDA WGQGTTVTVSS



1373
hBDI-1E1.7
CDR-H1

GYTFTDYVMH




1374
hBDI-1E1.7
CDR-H2

TIIPLIDTTSYNQKFKG




1375
hBDI-1E1.7
CDR-H3

TSPYYYSSYDVMDA




1376
hBDI-1E1.7 VL

EIVLTQSPATLSLSPGERATLSC KGSQNINNYLA WY




QQKPGQAPRLLIY KTNNLQT GIPARFSGSGSGTDFT




LTISSLEPEDFAVYYC YQYDNGYT FGQGTKLEIK



1377
hBDI-1E1.7
CDR-L1

KGSQNINNYLA




1378
hBDI-1E1.7
CDR-L2

KTNNLQT




1379
hBDI-1E1.7
CDR-L3

YQYDNGYT




1380
hBDI-1E1.8 VH

EVQLVQSGAEVKKPGSSVKVSCKAS GYTFTDYVMH W




VRQAPGQGLEWIG TIIPLIDTTSYNQKFKG RATLTA




DKSTNTAYMELSSLRSEDTAVYYCAR TSPYYYSSYD




VMDA WGQGTTVTVSS



1381
hBDI-1E1.8
CDR-H1

GYTFTDYVMH




1382
hBDI-1E1.8
CDR-H2

TIIPLIDTTSYNQKFKG




1383
hBDI-1E1.8
CDR-H3

TSPYYYSSYDVMDA




1384
hBDI-1E1.8 VL

EIVLTQSPATLSLSPGERATLSC KGSQNINNYLA WY




QQKPGQAPRLLIY KTNNLQT GIPARFSGSGSGTDYT




LTISSLEPEDFATYYC YQYDNGYT FGQGTKLEIK



1385
hBDI-1E1.8
CDR-L1

KGSQNINNYLA




1386
hBDI-1E1.8
CDR-L2

KTNNLQT




1387
hBDI-1E1.8
CDR-L3

YQYDNGYT




1388
hBDI-1E1.9 VH

EVQLVQSGAEVKKPGSSVKVSCKAS GYTFTDYVMH W




VRQAPGQGLEWIG TIIPLIDTTSYNQKFKG RVTITA




DKSTSTAYMELSSLRSEDTAVYYCAR TSPYYYSSYD




VMDA WGQGTTVTVSS



1389
hBDI-1E1.9
CDR-H1

GYTFTDYVMH




1390
hBDI-1E1.9
CDR-H2

TIIPLIDTTSYNQKFKG




1391
hBDI-1E1.9
CDR-H3

TSPYYYSSYDVMDA




1392
hBDI-1E1.9 VL

AIQLTQSPSSLSASVGDRVTITC KGSQNINNYLA WY




QQKPGKAPKLLIY KTNNLQT GVPSRFSGSGSGTDFT




LTISSLQPEDFATYYC YQYDNGYT FGQGTKLEIK



1393
hBDI-1E1.9
CDR-L1

KGSQNINNYLA




1394
hBDI-1E1.9
CDR-L2

KTNNLQT




1395
hBDI-1E1.9
CDR-L3

YQYDNGYT




1396
hBDI-5H1.1 VH

EVTLRESGPALVKPTQTLTLTCTFS GFSLSTFGMGV




G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQVVLTMTNMDPVDTATYYCAR ISTGISSYY




VMDA WGQGTTVTVSS



1397
hBDI-5H1.1
CDR-H1

GFSLSTFGMGVG




1398
hBDI-5H1.1
CDR-H2

NIWWDDDKYYNPSLKN




1399
hBDI-5H1.1
CDR-H3

ISTGISSYYVMDA




1400
hBDI-5H1.1 VL

NFMLTQPHSVSESPGKTVTISC ERSSGDIGDTYVS W




YQQRPGSSPTTVIY GNDQRPS GVPDRFSGSIDSSSN




SASLTISGLKTEDEADYYC QSYDSDIDIV FGGGTKL




TVL



1401
hBDI-5H1.1
CDR-L1

ERSSGDIGDTYVS




1402
hBDI-5H1.1
CDR-L2

GNDQRPS




1403
hBDI-5H1.1
CDR-L3

QSYDSDIDIV




1404
hBDI-5H1.10 VH

EVTLRESGPALVKPTQTLTLTCTFS GFSLSTFGMGV




G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQAVLTITNMDPVDTATYYCAR ISTGISSYY




VMDA WGQGTTVTVSS



1405
hBDI-5H1.10
CDR-H1

GFSLSTFGMGVG




1406
hBDI-5H1.10
CDR-H2

NIWWDDDKYYNPSLKN




1407
hBDI-5H1.10
CDR-H3

ISTGISSYYVMDA




1408
hBDI-5H1.10 VL

DFQLTQSPSSLSASVGDRVTITC ERSSGDIGDTYVS




WYQQKPGKAPKNVIY GNDQRPS GVPSRFSGSGSGNS




ATLTISSLQPEDFATYFC QSYDSDIDIV FGQGTKVE




IK



1409
hBDI-5H1.10
CDR-L1

ERSSGDIGDTYVS




1410
hBDI-5H1.10
CDR-L2

GNDQRPS




1411
hBDI-5H1.10
CDR-L3

QSYDSDIDIV




1412
hBDI-5H1.11 VH

EVQLVESGGGLVQPGGSLRLSCAFS GFSLSTFGMGV




G WIRQAPGKGLEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQAYLQINSLRAEDTAVYYCAR ISTGISSYY




VMDA WGQGTLVTVSS



1413
hBDI-5H1.11
CDR-H1

GFSLSTFGMGVG




1414
hBDI-5H1.11
CDR-H2

NIWWDDDKYYNPSLKN




1415
hBDI-5H1.11
CDR-H3

ISTGISSYYVMDA




1416
hBDI-5H1.11 VL

DFVLTQSPDSLAVSLGERATINC ERSSGDIGDTYVS




WYQQKPGQPPKNVIY GNDQRPS GVPDRFSGSGSGNS




ATLTISSLQAEDVAVYFC QSYDSDIDIV FGGGTKVE




IK



1417
hBDI-5H1.11
CDR-L1

ERSSGDIGDTYVS




1418
hBDI-5H1.11
CDR-L2

GNDQRPS




1419
hBDI-5H1.11
CDR-L3

QSYDSDIDIV




1420
hBDI-5H1.12 VH

EVQLVESGGGLVQPGGSLRLSCAFS GFSLSTFGMGV




G WIRQAPGKGLEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQAYLQINSLRAEDTAVYYCAR ISTGISSYY




VMDA WGQGTLVTVSS



1421
hBDI-5H1.12
CDR-H1

GFSLSTFGMGVG




1422
hBDI-5H1.12
CDR-H2

NIWWDDDKYYNPSLKN




1423
hBDI-5H1.12
CDR-H3

ISTGISSYYVMDA




1424
hBDI-5H1.12 VL

DFQLTQSPSSLSASVGDRVTITC ERSSGDIGDTYVS




WYQQKPGKAPKNVIY GNDQRPS GVPSRFSGSGSGNS




ATLTISSLQPEDFATYFC QSYDSDIDIV FGQGTKVE




IK



1425
hBDI-5H1.12
CDR-L1

ERSSGDIGDTYVS




1426
hBDI-5H1.12
CDR-L2

GNDQRPS




1427
hBDI-5H1.12
CDR-L3

QSYDSDIDIV




1428
hBDI-5H1.13 VH

EVTLKESGPALVKPTQTLTLTCTFS GFSLSTFGMGV




G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQAVLTITNMDPVDTATYYCAR ISTGISSYY




VMDA WGQGTTVTVSS



1429
hBDI-5H1.13
CDR-H1

GFSLSTFGMGVG




1430
hBDI-5H1.13
CDR-H2

NIWWDDDKYYNPSLKN




1431
hBDI-5H1.13
CDR-H3

ISTGISSYYVMDA




1432
hBDI-5H1.13 VL

DFQLTQSPSSLSASVGDRVTITC ERSSGDIGDTYVS




WYQQKPGKAPKNVIY GNDQRPS GVPSRFSGSGSGNS




ATLTISSLQPEDFATYFC QSYDSDIDIV FGQGTKVE




IK



1433
hBDI-5H1.13
CDR-L1

ERSSGDIGDTYVS




1434
hBDI-5H1.13
CDR-L2

GNDQRPS




1435
hBDI-5H1.13
CDR-L3

QSYDSDIDIV




1436
hBDI-5H1.16 VH

EVTLKESGPALVKPTQTLTLTCTFS GFSLSTFGMGV




G WIRQPPGKGLEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSNSQAVLTITNMDPVDTATYYCAR ISTGISSYY




VMDA WGQGTTVTVSS



1437
hBDI-5H1.16
CDR-H1

GFSLSTFGMGVG




1438
hBDI-5H1.16
CDR-H2

NIWWDDDKYYNPSLKN




1439
hBDI-5H1.16
CDR-H3

ISTGISSYYVMDA




1440
hBDI-5H1.16 VL

EFVLTQSPGTLSLSPGERATLSC ERSSGDIGDTYVS




WYQQKPGQPPRNVIY GNDQRPS GVPDRFSGSGSGTD




FTLTISRLEPEDFAVYFC QSYDSDIDIV FGGGTKVE




IK



1441
hBDI-5H1.16
CDR-L1

ERSSGDIGDTYVS




1442
hBDI-5H1.16
CDR-L2

GNDQRPS




1443
hBDI-5H1.16
CDR-L3

QSYDSDIDIV




1444
hBDI-5H1.17 VH

EVTLKESGPALVKPTQTLTLTCTFS GFSLSTFGMGV




G WIRQPPGKGLEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSNSQAVLTITNMDPVDTATYYCAR ISTGISSYY




VMDA WGQGTTVTVSS



1445
hBDI-5H1.17
CDR-H1

GFSLSTFGMGVG




1446
hBDI-5H1.17
CDR-H2

NIWWDDDKYYNPSLKN




1447
hBDI-5H1.17
CDR-H3

ISTGISSYYVMDA




1448
hBDI-5H1.17 VL

EFVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS




WYQQKPGQAPRLVIY ADDQRPS GIPDRFSGSGSGTD




FTLTISRLEPEDFAVYYC QSYDINIDIV FGGGTKVE




IK



1449
hBDI-5H1.17
CDR-L1

ERSSGDIGDSYVS




1450
hBDI-5H1.17
CDR-L2

ADDQRPS




1451
hBDI-5H1.17
CDR-L3

QSYDINIDIV




1452
hBDI-5H1.2 VH

EVTLRESGPALVKPTQTLTLTCTFS GFSLSTFGMGV




G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQVVLTMTNMDPVDTATYYCAR ISTGISSYY




VMDA WGQGTTVTVSS



1453
hBDI-5H1.2
CDR-H1

GFSLSTFGMGVG




1454
hBDI-5H1.2
CDR-H2

NIWWDDDKYYNPSLKN




1455
hBDI-5H1.2
CDR-H3

ISTGISSYYVMDA




1456
hBDI-5H1.2 VL

NFMLTQPHSVSESPGKTVTISC ERSSGDIGDTYVS W




YQQRPGSPPTNVIY GNDQRPS GVPDRFSGSIDSSSN




SASLTISGLKTEDEADYFC QSYDSDIDIV FGGGTKL




TVL



1457
hBDI-5H1.2
CDR-L1

ERSSGDIGDTYVS




1458
hBDI-5H1.2
CDR-L2

GNDQRPS




1459
hBDI-5H1.2
CDR-L3

QSYDSDIDIV




1460
hBDI-5H1.3 VH

EVTLRESGPALVKPTQTLTLTCTFS GFSLSTFGMGV




G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQVVLTMTNMDPVDTATYYCAR ISTGISSYY




VMDA WGQGTTVTVSS



1461
hBDI-5H1.3
CDR-H1

GFSLSTFGMGVG




1462
hBDI-5H1.3
CDR-H2

NIWWDDDKYYNPSLKN




1463
hBDI-5H1.3
CDR-H3

ISTGISSYYVMDA




1464
hBDI-5H1.3 VL

EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDTYVS




WYQQKPGQAPRLLIY GNDQRPS GIPDRFSGSGSGTD




FTLTISRLEPEDFAVYYC QSYDSDIDIV FGGGTKVE




IK



1465
hBDI-5H1.3
CDR-L1

ERSSGDIGDTYVS




1466
hBDI-5H1.3
CDR-L2

GNDQRPS




1467
hBDI-5H1.3
CDR-L3

QSYDSDIDIV




1468
hBDI-5H1.4 VH

EVTLRESGPALVKPTQTLTLTCTFS GFSLSTFGMGV




G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQVVLTMTNMDPVDTATYYCAR ISTGISSYY




VMDA WGQGTTVTVSS



1469
hBDI-5H1.4
CDR-H1

GFSLSTFGMGVG




1470
hBDI-5H1.4
CDR-H2

NIWWDDDKYYNPSLKN




1471
hBDI-5H1.4
CDR-H3

ISTGISSYYVMDA




1472
hBDI-5H1.4 VL

EFVLTQSPGTLSLSPGERATLSC ERSSGDIGDTYVS




WYQQKPGQAPRLVIY GNDQRPS GIPDRFSGSGSGTD




FTLTISRLEPEDFAVYYC QSYDSDIDIV FGGGTKVE




IK



1473
hBDI-5H1.4
CDR-L1

ERSSGDIGDTYVS




1474
hBDI-5H1.4
CDR-L2

GNDQRPS




1475
hBDI-5H1.4
CDR-L3

QSYDSDIDIV




1476
hBDI-5H1.5 VH

EVTLKESGPALVKPTQTLTLTCTFS GFSLSTFGMGV




G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQAVLTITNMDPVDTATYYCAR ISTGISSYY




VMDA WGQGTTVTVSS



1477
hBDI-5H1.5
CDR-H1

GFSLSTFGMGVG




1478
hBDI-5H1.5
CDR-H2

NIWWDDDKYYNPSLKN




1479
hBDI-5H1.5
CDR-H3

ISTGISSYYVMDA




1480
hBDI-5H1.5 VL

NFMLTQPHSVSESPGKTVTISC ERSSGDIGDTYVS W




YQQRPGSSPTTVIY GNDQRPS GVPDRFSGSIDSSSN




SASLTISGLKTEDEADYYC QSYDSDIDIV FGGGTKL




TVL



1481
hBDI-5H1.5
CDR-L1

ERSSGDIGDTYVS




1482
hBDI-5H1.5
CDR-L2

GNDQRPS




1483
hBDI-5H1.5
CDR-L3

QSYDSDIDIV




1484
hBDI-5H1.6 VH

EVTLKESGPALVKPTQTLTLTCTFS GFSLSTFGMGV




G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQAVLTITNMDPVDTATYYCAR ISTGISSYY




VMDA WGQGTTVTVSS



1485
hBDI-5H1.6
CDR-H1

GFSLSTFGMGVG




1486
hBDI-5H1.6
CDR-H2

NIWWDDDKYYNPSLKN




1487
hBDI-5H1.6
CDR-H3

ISTGISSYYVMDA




1488
hBDI-5H1.6 VL

NFMLTQPHSVSESPGKTVTISC ERSSGDIGDTYVS W




YQQRPGSPPTNVIY GNDQRPS GVPDRFSGSIDSSSN




SASLTISGLKTEDEADYFC QSYDSDIDIV FGGGTKL




TVL



1489
hBDI-5H1.6
CDR-L1

ERSSGDIGDTYVS




1490
hBDI-5H1.6
CDR-L2

GNDQRPS




1491
hBDI-5H1.6
CDR-L3

QSYDSDIDIV




1492
hBDI-5H1.7 VH

EVTLKESGPALVKPTQTLTLTCTFS GFSLSTFGMGV




G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQAVLTITNMDPVDTATYYCAR ISTGISSYY




VMDA WGQGTTVTVSS



1493
hBDI-5H1.7
CDR-H1

GFSLSTFGMGVG




1494
hBDI-5H1.7
CDR-H2

NIWWDDDKYYNPSLKN




1495
hBDI-5H1.7
CDR-H3

ISTGISSYYVMDA




1496
hBDI-5H1.7 VL

EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDTYVS




WYQQKPGQAPRLLIY GNDQRPS GIPDRFSGSGSGTD




FTLTISRLEPEDFAVYYC QSYDSDIDIV FGGGTKVE




IK



1497
hBDI-5H1.7
CDR-L1

ERSSGDIGDTYVS




1498
hBDI-5H1.7
CDR-L2

GNDQRPS




1499
hBDI-5H1.7
CDR-L3

QSYDSDIDIV




1500
hBDI-5H1.8 VH

EVTLKESGPALVKPTQTLTLTCTFS GFSLSTFGMGV




G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQAVLTITNMDPVDTATYYCAR ISTGISSYY




VMDA WGQGTTVTVSS



1501
hBDI-5H1.8
CDR-H1

GFSLSTFGMGVG




1502
hBDI-5H1.8
CDR-H2

NIWWDDDKYYNPSLKN




1503
hBDI-5H1.8
CDR-H3

ISTGISSYYVMDA




1504
hBDI-5H1.8 VL

EFVLTQSPGTLSLSPGERATLSC ERSSGDIGDTYVS




WYQQKPGQAPRLVIY GNDQRPS GIPDRFSGSGSGTD




FTLTISRLEPEDFAVYYC QSYDSDIDIV FGGGTKVE




IK



1505
hBDI-5H1.8
CDR-L1

ERSSGDIGDTYVS




1506
hBDI-5H1.8
CDR-L2

GNDQRPS




1507
hBDI-5H1.8
CDR-L3

QSYDSDIDIV




1508
hBDI-5H1.9 VH

EVTLRESGPALVKPTQTLTLTCTFS GFSLSTFGMGV




G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQAVLTITNMDPVDTATYYCAR ISTGISSYY




VMDA WGQGTTVTVSS



1509
hBDI-5H1.9
CDR-H1

GFSLSTFGMGVG




1510
hBDI-5H1.9
CDR-H2

NIWWDDDKYYNPSLKN




1511
hBDI-5H1.9
CDR-H3

ISTGISSYYVMDA




1512
hBDI-5H1.9 VL

DFVLTQSPDSLAVSLGERATINC ERSSGDIGDTYVS




WYQQKPGQPPKNVIY GNDQRPS GVPDRFSGSGSGNS




ATLTISSLQAEDVAVYFC QSYDSDIDIV FGGGTKVE




IK



1513
hBDI-5H1.9
CDR-L1

ERSSGDIGDTYVS




1514
hBDI-5H1.9
CDR-L2

GNDQRPS




1515
hBDI-5H1.9
CDR-L3

QSYDSDIDIV




1516
hBDI-9E8.1 VH

EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGV




G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQVVLTMTNMDPVDTATYYCAR IESIGTTYS




FDY WGQGTMVTVSS



1517
hBDI-9E8.1
CDR-H1

GFSLSTYGMGVG




1518
hBDI-9E8.1
CDR-H2

NIWWDDDKYYNPSLKN




1519
hBDI-9E8.1
CDR-H3

IESIGTTYSFDY




1520
hBDI-9E8.1 VL

NFMLTQPHSVSESPGKTVTISC ERSSGDIGDSYVS W




YQQRPGSSPTTVIY ADDQRPS GVPDRFSGSIDSSSN




SASLTISGLKTEDEADYYC QSYDINIDIV FGGGTKL




TVL



1521
hBDI-9E8.1
CDR-L1

ERSSGDIGDSYVS




1522
hBDI-9E8.1
CDR-L2

ADDQRPS




1523
hBDI-9E8.1
CDR-L3

QSYDINIDIV




1524
hBDI-9E8.10 VH

EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGV




G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQAVLTITNMDPVDTATYYCAR IESIGTTYS




FDY WGQGTTVTVSS



1525
hBDI-9E8.10
CDR-H1

GFSLSTYGMGVG




1526
hBDI-9E8.10
CDR-H2

NIWWDDDKYYNPSLKN




1527
hBDI-9E8.10
CDR-H3

IESIGTTYSFDY




1528
hBDI-9E8.10 VL

DFQLTQSPSSLSASVGDRVTITC ERSSGDIGDSYVS




WYQQKPGKAPKNVIY ADDQRPS GVPSRFSGSGSGNS




ASLTISSLQPEDFATYYC QSYDINIDIV FGQGTKVE




IK



1529
hBDI-9E8.10
CDR-L1

ERSSGDIGDSYVS




1530
hBDI-9E8.10
CDR-L2

ADDQRPS




1531
hBDI-9E8.10
CDR-L3

QSYDINIDIV




1532
hBDI-9E8.11 VH

EVQLVESGGGLVQPGGSLRLSCAFS GFSLSTYGMGV




G WIRQAPGKGLEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQAYLQINSLRAEDTAVYYCAR IESIGTTYS




FDY WGQGTLVTVSS



1533
hBDI-9E8.11
CDR-H1

GFSLSTYGMGVG




1534
hBDI-9E8.11
CDR-H2

NIWWDDDKYYNPSLKN




1535
hBDI-9E8.11
CDR-H3

IESIGTTYSFDY




1536
hBDI-9E8.11 VL

DFVLTQSPDSLAVSLGERATINC ERSSGDIGDSYVS




WYQQKPGQPPKNVIY ADDQRPS GVPDRFSGSGSGNS




ASLTISSLQAEDVAVYFC QSYDINIDIV FGGGTKVE




IK



1537
hBDI-9E8.11
CDR-L1

ERSSGDIGDSYVS




1538
hBDI-9E8.11
CDR-L2

ADDQRPS




1539
hBDI-9E8.11
CDR-L3

QSYDINIDIV




1540
hBDI-9E8.12 VH

EVQLVESGGGLVQPGGSLRLSCAFS GFSLSTYGMGV




G WIRQAPGKGLEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQAYLQINSLRAEDTAVYYCAR IESIGTTYS




FDY WGQGTLVTVSS



1541
hBDI-9E8.12
CDR-H1

GFSLSTYGMGVG




1542
hBDI-9E8.12
CDR-H2

NIWWDDDKYYNPSLKN




1543
hBDI-9E8.12
CDR-H3

IESIGTTYSFDY




1544
hBDI-9E8.12 VL

DFQLTQSPSSLSASVGDRVTITC ERSSGDIGDSYVS




WYQQKPGKAPKNVIY ADDQRPS GVPSRFSGSGSGNS




ASLTISSLQPEDFATYYC QSYDINIDIV FGQGTKVE




IK



1545
hBDI-9E8.12
CDR-L1

ERSSGDIGDSYVS




1546
hBDI-9E8.12
CDR-L2

ADDQRPS




1547
hBDI-9E8.12
CDR-L3

QSYDINIDIV




1548
hBDI-9E8.13 VH

EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGV




G WIRQPPGKGLEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQAVLTITNMDPVDTATYYCAR IESIGTTYS




FDY WGQGTMVTVSS



1549
hBDI-9E8.13
CDR-H1

GFSLSTYGMGVG




1550
hBDI-9E8.13
CDR-H2

NIWWDDDKYYNPSLKN




1551
hBDI-9E8.13
CDR-H3

IESIGTTYSFDY




1552
hBDI-9E8.13 VL

DFQLTQSPSSLSASVGDRVTITC ERSSGDIGDSYVS




WYQQKPGKAPKNVIY ADDQRPS GVPSRFSGSGSGNS




ASLTISSLQPEDFATYYC QSYDINIDIV FGQGTKVE




IK



1553
hBDI-9E8.13
CDR-L1

ERSSGDIGDSYVS




1554
hBDI-9E8.13
CDR-L2

ADDQRPS




1555
hBDI-9E8.13
CDR-L3

QSYDINIDIV




1556
hBDI-9E8.2 VH

EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGV




G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQVVLTMTNMDPVDTATYYCAR IESIGTTYS




FDY WGQGTMVTVSS



1557
hBDI-9E8.2
CDR-H1

GFSLSTYGMGVG




1558
hBDI-9E8.2
CDR-H2

NIWWDDDKYYNPSLKN




1559
hBDI-9E8.2
CDR-H3

IESIGTTYSFDY




1560
hBDI-9E8.2 VL

NFMLTQPHSVSESPGKTVTISC ERSSGDIGDSYVS W




YQQRPGSPPTNVIY ADDQRPS GVPDRFSGSIDSSSN




SASLTISGLKTEDEADYFC QSYDINIDIV FGGGTKL




TVL



1561
hBDI-9E8.2
CDR-L1

ERSSGDIGDSYVS




1562
hBDI-9E8.2
CDR-L2

ADDQRPS




1563
hBDI-9E8.2
CDR-L3

QSYDINIDIV




1564
hBDI-9E8.3 VH

EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGV




G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQVVLTMTNMDPVDTATYYCAR IESIGTTYS




FDY WGQGTMVTVSS



1565
hBDI-9E8.3
CDR-H1

GFSLSTYGMGVG




1566
hBDI-9E8.3
CDR-H2

NIWWDDDKYYNPSLKN




1567
hBDI-9E8.3
CDR-H3

IESIGTTYSFDY




1568
hBDI-9E8.3 VL

EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS




WYQQKPGQAPRLLIY ADDQRPS GIPDRFSGSGSGTD




FTLTISRLEPEDFAVYYC QSYDINIDIV FGGGTKVE




IK



1569
hBDI-9E8.3
CDR-L1

ERSSGDIGDSYVS




1570
hBDI-9E8.3
CDR-L2

ADDQRPS




1571
hBDI-9E8.3
CDR-L3

QSYDINIDIV




1572
hBDI-9E8.4 VH

EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGV




G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQVVLTMTNMDPVDTATYYCAR IESIGTTYS




FDY WGQGTMVTVSS



1573
hBDI-9E8.4
CDR-H1

GFSLSTYGMGVG




1574
hBDI-9E8.4
CDR-H2

NIWWDDDKYYNPSLKN




1575
hBDI-9E8.4
CDR-H3

IESIGTTYSFDY




1576
hBDI-9E8.4 VL

EFVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS




WYQQKPGQAPRLVIY ADDQRPS GIPDRFSGSGSGTD




FTLTISRLEPEDFAVYYC QSYDINIDIV FGGGTKVE




IK



1577
hBDI-9E8.4
CDR-L1

ERSSGDIGDSYVS




1578
hBDI-9E8.4
CDR-L2

ADDQRPS




1579
hBDI-9E8.4
CDR-L3

QSYDINIDIV




1580
hBDI-9E8.5 VH

EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGV




G WIRQPPGKGLEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQAVLTITNMDPVDTATYYCAR IESIGTTYS




FDY WGQGTMVTVSS



1581
hBDI-9E8.5
CDR-H1

GFSLSTYGMGVG




1582
hBDI-9E8.5
CDR-H2

NIWWDDDKYYNPSLKN




1583
hBDI-9E8.5
CDR-H3

IESIGTTYSFDY




1584
hBDI-9E8.5 VL

NFMLTQPHSVSESPGKTVTISC ERSSGDIGDSYVS W




YQQRPGSSPTTVIY ADDQRPS GVPDRFSGSIDSSSN




SASLTISGLKTEDEADYYC QSYDINIDIV FGGGTKL




TVL



1585
hBDI-9E8.5
CDR-L1

ERSSGDIGDSYVS




1586
hBDI-9E8.5
CDR-L2

ADDQRPS




1587
hBDI-9E8.5
CDR-L3

QSYDINIDIV




1588
hBDI-9E8.6 VH

EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGV




G WIRQPPGKGLEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQAVLTITNMDPVDTATYYCAR IESIGTTYS




FDY WGQGTMVTVSS



1589
hBDI-9E8.6
CDR-H1

GFSLSTYGMGVG




1590
hBDI-9E8.6
CDR-H2

NIWWDDDKYYNPSLKN




1591
hBDI-9E8.6
CDR-H3

IESIGTTYSFDY




1592
hBDI-9E8.6 VL

NFMLTQPHSVSESPGKTVTISC ERSSGDIGDSYVS W




YQQRPGSPPTNVIY ADDQRPS GVPDRFSGSIDSSSN




SASLTISGLKTEDEADYFC QSYDINIDIV FGGGTKL




TVL



1593
hBDI-9E8.6
CDR-L1

ERSSGDIGDSYVS




1594
hBDI-9E8.6
CDR-L2

ADDQRPS




1595
hBDI-9E8.6
CDR-L3

QSYDINIDIV




1596
hBDI-9E8.7 VH

EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGV




G WIRQPPGKGLEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQAVLTITNMDPVDTATYYCAR IESIGTTYS




FDY WGQGTMVTVSS



1597
hBDI-9E8.7
CDR-H1

GFSLSTYGMGVG




1598
hBDI-9E8.7
CDR-H2

NIWWDDDKYYNPSLKN




1599
hBDI-9E8.7
CDR-H3

IESIGTTYSFDY




1600
hBDI-9E8.7 VL

EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS




WYQQKPGQAPRLLIY ADDQRPS GIPDRFSGSGSGTD




FTLTISRLEPEDFAVYYC QSYDINIDIV FGGGTKVE




IK



1601
hBDI-9E8.7
CDR-L1

ERSSGDIGDSYVS




1602
hBDI-9E8.7
CDR-L2

ADDQRPS




1603
hBDI-9E8.7
CDR-L3

QSYDINIDIV




1604
hBDI-9E8.8 VH

EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGV




G WIRQPPGKGLEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQAVLTITNMDPVDTATYYCAR IESIGTTYS




FDY WGQGTMVTVSS



1605
hBDI-9E8.8
CDR-H1

GFSLSTYGMGVG




1606
hBDI-9E8.8
CDR-H2

NIWWDDDKYYNPSLKN




1607
hBDI-9E8.8
CDR-H3

IESIGTTYSFDY




1608
hBDI-9E8.8 VL

EFVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS




WYQQKPGQAPRLVIY ADDQRPS GIPDRFSGSGSGTD




FTLTISRLEPEDFAVYYC QSYDINIDIV FGGGTKVE




IK



1609
hBDI-9E8.8
CDR-L1

ERSSGDIGDSYVS




1610
hBDI-9E8.8
CDR-L2

ADDQRPS




1611
hBDI-9E8.8
CDR-L3

QSYDINIDIV




1612
hBDI-9E8.9 VH

EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGV




G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQAVLTITNMDPVDTATYYCAR IESIGTTYS




FDY WGQGTTVTVSS



1613
hBDI-9E8.9
CDR-H1

GFSLSTYGMGVG




1614
hBDI-9E8.9
CDR-H2

NIWWDDDKYYNPSLKN




1615
hBDI-9E8.9
CDR-H3

IESIGTTYSFDY




1616
hBDI-9E8.9 VL

DFVLTQSPDSLAVSLGERATINC ERSSGDIGDSYVS




WYQQKPGQPPKNVIY ADDQRPS GVPDRFSGSGSGNS




ASLTISSLQAEDVAVYFC QSYDINIDIV FGGGTKVE




IK



1617
hBDI-9E8.9
CDR-L1

ERSSGDIGDSYVS




1618
hBDI-9E8.9
CDR-L2

ADDQRPS




1619
hBDI-9E8.9
CDR-L3

QSYDINIDIV




1620
hBDI-9E8.4E VH

EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGV




G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTIS




KDTSKNQVVLTMTNMDPVDTATYYCAR IESIGTTYS




FDY WGQGTMVTVSS



1621
hBDI-9E8.4E
CDR-H1

GFSLSTYGMGVG




1622
hBDI-9E8.4E
CDR-H2

NIWWDDDKYYNPSLKN




1623
hBDI-9E8.4E
CDR-H3

IESIGTTYSFDY




1624
hBDI-9E8.4E VL

EFVLTQSPGTLSLSPGERATLSC ERSSGDIGESYVS




WYQQKPGQAPRLVIY ADDQRPS GIPDRFSGSGSGTD




FTLTISRLEPEDFAVYYC QSYDINIDIV FGGGTKVE




IK



1625
hBDI-9E8.4E
CDR-L1

ERSSGDIGESYVS




1626
hBDI-9E8.4E
CDR-L2

ADDQRPS




1627
hBDI-9E8.4E
CDR-L3

QSYDINIDIV




1628
hBFU-3E2.1 VH

EVQLVQSGAEVKKPGSSVKVSCKAS GYTFTESYMY W




VKQAPGQGLELIG RIDPEDGSTDYVEKFKN KATLTA




DKSTSTAYMELSSLRSEDTAVYFCAR FGARSYFYPM




DA WGQGTTVTVSS



1629
hBFU-3E2.1
CDR-H1

GYTFTESYMY




1630
hBFU-3E2.1
CDR-H2

RIDPEDGSTDYVEKFKN




1631
hBFU-3E2.1
CDR-H3

FGARSYFYPMDA




1632
hBFU-3E2.1 VL

ETVLTQSPATLSLSPGERATLSC RASESVSTLMH WY




QQKPGQQPRLLIY GASNLES GVPARFSGSGSGTDFT




LTISSLEPEDFAVYFC QQSWNDPWT FGGGTKVEIK



1633
hBFU-3E2.1
CDR-L1

RASESVSTLMH




1634
hBFU-3E2.1
CDR-L2

GASNLES




1635
hBFU-3E2.1
CDR-L3

QQSWNDPWT




1636
hBFU-3E2.2 VH

EVQLVQSGAEVKKPGSSVKVSCKAS GYTFTESYMY W




VRQAPGQGLELIG RIDPEDGSTDYVEKFKN RVTLTA




DKSTSTAYMELSSLRSEDTAVYYCAR FGARSYFYPM




DA WGQGTTVTVSS



1637
hBFU-3E2.2
CDR-H1

GYTFTESYMY




1638
hBFU-3E2.2
CDR-H2

RIDPEDGSTDYVEKFKN




1639
hBFU-3E2.2
CDR-H3

FGARSYFYPMDA




1640
hBFU-3E2.2 VL

ETVLTQSPATLSLSPGERATLSC RASESVSTLMH WY




QQKPGQQPRLLIY GASNLES GVPARFSGSGSGTDFT




LTISSLEPEDFAVYFC QQSWNDPWT FGGGTKVEIK



1641
hBFU-3E2.2
CDR-L1

RASESVSTLMH




1642
hBFU-3E2.2
CDR-L2

GASNLES




1643
hBFU-3E2.2
CDR-L3

QQSWNDPWT




1644
hBFU-3E2.3 VH

EVQLVQSGAEVKKPGSSVKVSCKAS GYTFTESYMY W




VKQAPGQGLELIG RIDPEDGSTDYVEKFKN KATLTA




DKSTSTAYMELSSLRSEDTAVYFCAR FGARSYFYPM




DA WGQGTTVTVSS



1645
hBFU-3E2.3
CDR-H1

GYTFTESYMY




1646
hBFU-3E2.3
CDR-H2

RIDPEDGSTDYVEKFKN




1647
hBFU-3E2.3
CDR-H3

FGARSYFYPMDA




1648
hBFU-3E2.3 VL

ATQLTQSPSSLSASVGDRVTISC RASESVSTLMH WY




QQKPGKQPRLLIY GASNLES GVPSRFSGSGSGTDFT




LTISSLQPEDFATYFC QQSWNDPWT FGGGTKVEIK



1649
hBFU-3E2.3
CDR-L1

RASESVSTLMH




1650
hBFU-3E2.3
CDR-L2

GASNLES




1651
hBFU-3E2.3
CDR-L3

QQSWNDPWT




1652
hBFU-3E2.4 VH

EVQLVQSGAEVKKPGSSVKVSCKAS GYTFTESYMY W




VRQAPGQGLELIG RIDPEDGSTDYVEKFKN RVTLTA




DKSTSTAYMELSSLRSEDTAVYYCAR FGARSYFYPM




DA WGQGTTVTVSS



1653
hBFU-3E2.4
CDR-H1

GYTFTESYMY




1654
hBFU-3E2.4
CDR-H2

RIDPEDGSTDYVEKFKN




1655
hBFU-3E2.4
CDR-H3

FGARSYFYPMDA




1656
hBFU-3E2.4 VL

ATQLTQSPSSLSASVGDRVTISC RASESVSTLMH WY




QQKPGKQPRLLIY GASNLES GVPSRFSGSGSGTDFT




LTISSLQPEDFATYFC QQSWNDPWT FGGGTKVEIK



1657
hBFU-3E2.4
CDR-L1

RASESVSTLMH




1658
hBFU-3E2.4
CDR-L2

GASNLES




1659
hBFU-3E2.4
CDR-L3

QQSWNDPWT









































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































TABLE 29



VH and VL Amino Acid Sequences of Humanized Versions of

Rat Anti-Human VEGFR II Monoclonal Antibodies (CDRs in bold)






SEQ ID

Protein
V Region

NO:
Clone
Region
12345678901234567890123456



1660
hBCU-6B1.1 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY




WVKQAPGQGLEFMG WINTETGQPTYADDFKG RFVF




SLDTSVSTAYLQISSLKAEDTAVYFCAR LGNNYGI




WFAY WGQGTLVTVSS



1661
hBCU-6B1.1
CDR-H1

GYTFTNYGMY




1662
hBCU-6B1.1
CDR-H2

WINTETGQPTYADDFKG




1663
hBCU-6B1.1
CDR-H3

LGNNYGIWFAY




1664
hBCU-6B1.1 VL

DIQMTQSPSSLSASVGDRVTIEC RASDDLYSTLA W




YQQKPGKSPKLLIF DANRLAA GVPSRFSGSGSGTD




YSLTISSLQPEDVATYFC QQYNKFPWT FGGGTKVE




IK



1665
hBCU-6B1.1
CDR-L1

RASDDLYSTLA




1666
hBCU-6B1.1
CDR-L2

DANRLAA




1667
hBCU-6B1.1
CDR-L3

QQYNKFPWT




1668
hBCU-6B1.2 VH

EVQLVQSGAEVKKPGASVKVSCKAS GYTFTNYGMY




WVKQAPGQGLEFMG WINTETGQPTYADDFKG RFTF




TLDTSTSTAYMELRSLRSDDTAVYFCAR LGNNYGI




WFAY WGQGTLVTVSS



1669
hBCU-6B1.2
CDR-H1

GYTFTNYGMY




1670
hBCU-6B1.2
CDR-H2

WINTETGQPTYADDFKG




1671
hBCU-6B1.2
CDR-H3

LGNNYGIWFAY




1672
hBCU-6B1.2 VL

DIQMTQSPSSLSASVGDRVTIEC RASDDLYSTLA W




YQQKPGKSPKLLIF DANRLAA GVPSRFSGSGSGTD




YSLTISSLQPEDVATYFC QQYNKFPWT FGGGTKVE




IK



1673
hBCU-6B1.2
CDR-L1

RASDDLYSTLA




1674
hBCU-6B1.2
CDR-L2

DANRLAA




1675
hBCU-6B1.2
CDR-L3

QQYNKFPWT




1676
hBCU-6B1.3 VH

EVQLVQSGAEVKKPGASVKVSCKAS GYTFTNYGMY




WVRQAPGQGLEFMG WINTETGQPTYADDFKG RFTF




TLDTSTSTAYMELRSLRSDDTAVYYCAR LGNNYGI




WFAY WGQGTLVTVSS



1677
hBCU-6B1.3
CDR-H1

GYTFTNYGMY




1678
hBCU-6B1.3
CDR-H2

WINTETGQPTYADDFKG




1679
hBCU-6B1.3
CDR-H3

LGNNYGIWFAY




1680
hBCU-6B1.3 VL

DIQMTQSPSSLSASVGDRVTIEC RASDDLYSTLA W




YQQKPGKSPKLLIF DANRLAA GVPSRFSGSGSGTD




YSLTISSLQPEDVATYFC QQYNKFPWT FGGGTKVE




IK



1681
hBCU-6B1.3
CDR-L1

RASDDLYSTLA




1682
hBCU-6B1.3
CDR-L2

DANRLAA




1683
hBCU-6B1.3
CDR-L3

QQYNKFPWT




1684
hBCU-6B1.4 VH

EVQLVQSGAEVKKPGASVKVSCKAS GYTFTNYGMY




WVRQAPGQGLEFMG WINTETGQPTYADDFKG RFTF




TLDTSTSTAYMELRSLRSDDTAVYYCAR LGNNYGI




WFAY WGQGTLVTVSS



1685
hBCU-6B1.4
CDR-H1

GYTFTNYGMY




1686
hBCU-6B1.4
CDR-H2

WINTETGQPTYADDFKG




1687
hBCU-6B1.4
CDR-H3

LGNNYGIWFAY




1688
hBCU-6B1.4 VL

DIQMTQSPSSLSASVGDRVTITC RASDDLYSTLA W




YQQKPGKSPKLLIF DANRLAA GVPSRFSGSGSGTD




YTLTISSLQPEDVATYFC QQYNKFPWT FGGGTKVE




IK



1689
hBCU-6B1.4
CDR-L1

RASDDLYSTLA




1690
hBCU-6B1.4
CDR-L2

DANRLAA




1691
hBCU-6B1.4
CDR-L3

QQYNKFPWT



















































































































TABLE 30



VH and VL Amino Acid Sequences of Humanized Versions of

Rat Anti-Human PDGFR b Monoclonal Antibodies (CDRs in bold)






SEQ ID

Protein
V Region

NO:
Clone
Region
123456789012345678901234567890



1692
hBDE-3C9.1 VH

EVQLVESGGGLVQPGGSLRLSCAAS GFTFSNYGMA




WVRQAPGKGLEWVA SITNSGGNTYYRDSVKG RFTI




SRDNAKNTQYLQMNSLRAEDTAVYFCAR HTPGANY




FDY WGQGTMVTVSS



1693
hBDE-3C9.1
CDR-H1

GFTFSNYGMA




1694
hBDE-3C9.1
CDR-H2

SITNSGGNTYYRDSVKG




1695
hBDE-3C9.1
CDR-H3

HTPGANYFDY




1696
hBDE-3C9.1 VL

DIQMTQSPSSLSASVGDRVTITC QASQSIKNYIA W




YQLKPGKAPRLLMR YTSTLES GTPSRFSGSGSGRD




YTFTISSLQPEDIATYYC VQYANLYT FGGGTKVEI




K



1697
hBDE-3C9.1
CDR-L1

QASQSIKNYIA




1698
hBDE-3C9.1
CDR-L2

YTSTLES




1699
hBDE-3C9.1
CDR-L3

VQYANLYT




1700
hBDE-3C9.2 VH

EVQLVESGGGLVQPGGSLRLSCAAS GFTFSNYGMA




WVRQAPGKGLEWVA SITNSGGNTYYRDSVKG RFTI




SRDNAKNSLYLQMNSLRAEDTAVYYCAR HTPGANY




FDY WGQGTMVTVSS



1701
hBDE-3C9.2
CDR-H1

GFTFSNYGMA




1702
hBDE-3C9.2
CDR-H2

SITNSGGNTYYRDSVKG




1703
hBDE-3C9.2
CDR-H3

HTPGANYFDY




1704
hBDE-3C9.2 VL

DIQMTQSPSSLSASVGDRVTITC QASQSIKNYIA W




YQQKPGKAPRLLIR YTSTLES GVPSRFSGSGSGRD




YTFTISSLQPEDIATYYC VQYANLYT FGGGTKVEI




K



1705
hBDE-3C9.2
CDR-L1

QASQSIKNYIA




1706
hBDE-3C9.2
CDR-L2

YTSTLES




1707
hBDE-3C9.2
CDR-L3

VQYANLYT


































































Generation of Humanized Antibodies
All variants were cloned into pHybE vectors and were transiently transfected into 50 mls of HEK 2936e suspension cell cultures in a ratio of 60% to 40% light to heavy chain construct. 1 mg/ml PEI was used to transfect the cells. Cell supernatants were harvested after six days in shaking flasks, spun down to pellet cells, and filtered through 0.22 μm filters to separate IgG from culture contaminates. All were batch purified by adding 1 supernatant volume of protein A IgG binding buffer (Thermo Scientific 21001) and 1 ml of rProteinA sepharose fast flow beads (GE Healthcare, 17-1279-04). Supernatants, with beads and buffer added, were rocked overnight at 4° C., and the day after beads were collected by gravity over poly prep chromatography columns (Bio Rad, 731-1550). Once supernatants had passed through the columns the beads were washed with 10 column volumes of binding buffer, and IgG was eluted with Immunopure IgG elution buffer (Pierce, 185 1520) and collected in 1 ml aliquots. Fractions containing IgG were pooled and dialyzed in 15 mM Histidine pH 6 overnight at 4° C.
Purified variants were further characterized for their affinities for recombinant human target proteins by binding ELISA, by Biacore, and by cell-based potency assays.





TABLE 31



Summary of Protein Expression and Purification for

Humanized Anti-Human VEGF-A And Humanized

Anti-Human PDGF-BB Monoclonal Antibodies









Octet Titer
~Yield
SEC


Name
(mg/L) 1
(mg/L) 2
(% monomer) 3











hBDB-4G8.1
19.9
19.7
100.0


hBDB-4G8.2
105.3
95.8
100.0


hBDB-4G8.3
34.8
31.9
100.0


hBDB-4G8.4
45.8
34.2
100.0


hBDB-4G8.5
24.7
27.4
100.0


hBDB-4G8.6
28.6
34.2
100.0


hBDB-4G8.7
75.8
63.4
100.0


hBDB-4G8.8
145.9
101.4
100.0


hBDB-4G8.9
38.8
39.0
100.0


hBDB-4G8.10
40.7
32.9
89.1


hBDB-4G8.11
47.9
38.0
87.2


hBDB-4G8.12
37.5
38.3
100.0


hBDB-4G8.13
44.8
35.1
100.0


hBDB-4G8.14
73.0
47.0
100.0


hBDB-4G8.15
161.2
94.9
100.0


hBDI-5H1.1
49.8
38.7
100.0


hBDI-5H1.2
63.4
62.0
100.0


hBDI-5H1.3
94.2
86.5
99.1


hBDI-5H1.4
109.0
123.1
99.2


hBDI-5H1.5
23.0
27.7
100.0


hBDI-5H1.6
41.2
46.0
100.0


hBDI-5H1.7
9.6
9.6
88.1


hBDI-5H1.8
36.0
41.5
100.0


hBDI-5H1.9
56.0
60.2
85.6


hBDI-5H1.10
34.2
31.1
85.2


hBDI-5H1.11
41.0
34.4
96.3


hBDI-5H1.12
37.7
30.2
100.0


hBDI-9E8.1
90.0
72.4
100.0


hBDI-9E8.2
89.9
89.1
99.3


hBDI-9E8.3
28.8
24.4
97.1


hBDI-9E8.4
52.8
54.8
98.2


hBDI-9E8.5
78.0
57.7
100.0


hBDI-9E8.6
60.6
61.4
100.0


hBDI-9E8.7
30.4
27.9
88.1


hBDI-9E8.8
37.1
38.0
98.4


hBDI-9E8.9
50.3
44.9
94.6


hBDI-9E8.10
93.0
56.2
94.7


hBDI-9E8.11
78.4
52.7
99.1


hBDI-9E8.12
92.3
68.5
100.0


hBDI-5H1.13
13.6
10.5
88.1


hBDI-9E8.13
53.5
66.9
100.0


hBDI-1E1.1
133.5
ND
ND


hBDI-1E1.2
115.6
ND
ND


hBDI-1E1.3
83.4
ND
ND


hBDI-1E1.4
137.6
ND
ND


hBDI-1E1.5
97.4
ND
ND


hBDI-1E1.6
70.6
ND
ND


hBDI-1E1.7
91.9
ND
ND


hBDI-1E1.8
71.2
ND
ND


hBDI-1E1.9
94.3
ND
ND


hBDI-1E1.10
72.7
ND
ND


hBDI-1E1.11
57.4
ND
ND


hBDI-1E1.12
151.6
ND
ND


hBEW-9A8.1
0.2
ND
ND


hBEW-9A8.2
0.2
ND
ND


hBEW-9A8.3
0.2
ND
ND


hBEW-9A8.4
0.2
ND
ND


hBEW-9A8.5
0.5
ND
ND


hBEW-9A8.6
0.2
ND
ND


hBEW-9A8.7
0.3
ND
ND


hBEW-9A8.8
3.5
ND
ND


hBEW-9A8.9
15.3
18.6
ND


hBEW-9A8.10
5.2
ND
ND


hBEW-9A8.11
30.6
18.9
ND


hBEW-9A8.12
38.3
28.4
ND


hBEW-9A8.13
0.4
ND
ND


hBEW-9A8.14
0.3
ND
ND


hBEW-9A8.15
0.3
ND
ND


hBEW-9A8.16
3.2
ND
ND


hBEW-6C2.1
5.4
ND
ND


hBEW-6C2.2
1.5
ND
ND


hBEW-6C2.3
14.8
7.8
ND


hBEW-6C2.4
79.6
29.5
ND


hBEW-6C2.5
4.7
ND
ND


hBEW-6C2.6
3.9
ND
ND


hBEW-6C2.7
140.8
39.7
ND


hBEW-6C2.8
75.3
24.8
ND


hBDI-5H1.16
ND
23.9
93.4


hBDI-5H1.17
ND
21.0
92.1


hBFU-3E2.1
ND
40.2
88.1


hBFU-3E2.2
ND
34.6
93.6


hBFU-3E2.3
ND
33.6
84.2


hBFU-3E2.4
ND
38.4
94.7


hBEW-9A8.17
ND
20.0
98.7


hBEW-9A8.20
ND
17.6
86.6


hBEW-9A8.21
ND
13.3
97.5


hBEW-5C3.1
ND
20.8
85.0


hBEW-5C3.2
ND
17.7
74.6


hBEW-5C3.3
ND
6.9
93.7


hBEW-5C3.4
ND
32.0
88.7


hBEW-5C3.5
ND
30.6
85.1


hBEW-5C3.6
ND
19.4
75.4


hBEW-9E10.1
ND
42.7
98.0


hBEW-9E10.2
ND
46.1
98.0


hBEW-9E10.3
ND
45.9
97.6


hBEW-9E10.4
ND
47.1
98.0


hBEW-9E10.5
ND
56.2
97.9


hBEW-9E10.6
ND
52.9
97.6


hBEW-1B10.1
ND
34.1
97.8


hBEW-1B10.2
ND
45.3
98.1


hBEW-1E3.1
ND
29.6
95.5


hBEW-1E3.2
ND
20.9
98.3


hBEW-1E3.3
ND
22.0
98.5


hBEW-1E3.4
ND
48.0
98.1


hBEW-1E3.5
ND
23.8
98.5


hBEW-1E3.6
ND
17.0
98.7





ND = Not Determined


1 Octet titer is the amout of IgG in the unpurified supernatant as determined by protein A binding compared to a standard curve using an Octet instrument.


2 Yield is determined by the total amount of purified protein in mg divided by the total cell culture volume in liters.


3 SEC % monomer is determined using HPLC size exclusion chromatography.






































































































































Humanized anti-VEGF antibodies were tested for their binding to human VEGF-A according to the method described in Example 1.1. The on-rate, off-rate and binding kinetics are summarized in Table 32 below.





TABLE 32



Biacore Binding of Humanized Anti-VEGF Antibodies








Antibody
k on (M−1 s−1)
k off (M−1)
K D (M)











hBDB-4G8.1
1.8E+07
1.0E−04
5.8E−12


hBDB-4G8.2
1.7E+07
6.2E−05
3.6E−12


hBDB-4G8.3
1.0E+07
4.8E−05
4.8E−12


hBDB-4G8.4
2.7E+07
1.5E−04
5.5E−12


hBDB-4G8.5
2.5E+07
4.0E−05
1.6E−12


hBDB-4G8.6
2.6E+07
3.7E−05
1.4E−12


hBDB-4G8.7
3.7E+07
1.3E−03
3.4E−11


hBDB-4G8.8
1.8E+07
8.6E−04
4.7E−11


hBDB-4G8.9
1.4E+07
8.8E−04
6.2E−11


hBDB-4G8.10
2.7E+07
2.2E−04
8.1E−12


hBDB-4G8.11
2.6E+07
3.4E−05
1.3E−12


hBDB-4G8.12
2.6E+07
3.2E−05
1.2E−12


hBDB-4G8.13
2.2E+07
1.7E−04
7.6E−12


hBDB-4G8.14
1.5E+07
5.6E−05
3.7E−12


hBDB-4G8.15
2.0E+07
8.7E−05
4.4E−12


hBEW-9A8.9
1.0E+07
8.2E−03
8.2E−10


hBEW-9A8.11
1.5E+07
1.1E−03
7.4E−11


hBEW-9A8.12
9.6E+06
1.4E−04
1.5E−11


hBEW-9A8.17
7.9E+06
1.4E−05
1.7E−12


hBEW-9A8.20
7.6E+06
1.2E−05
1.6E−12


hBEW-9A8.21
5.8E+06
3.9E−05
6.7E−12


hBEW-5C3.1
1.1E+07
6.9E−05
6.0E−12


hBEW-5C3.4
9.9E+06
8.5E−05
8.6E−12


hBEW-5C3.5
1.2E+07
9.7E−05
8.5E−12


hBEW-9E10.1
1.2E+07
2.5E−05
2.1E−12


hBEW-9E10.2
1.6E+07
1.9E−04
1.2E−11


hBEW-9E10.3
1.3E+07
4.2E−05
3.2E−12


hBEW-9E10.4
1.2E+07
2.5E−05
2.1E−12


hBEW-9E10.5
1.6E+07
2.3E−04
1.5E−11


hBEW-9E10.6
1.5E+07
4.0E−05
2.6E−12


hBEW-1B10.1
7.6E+06
1.4E−04
1.8E−11


hBEW-1B10.2
7.5E+06
1.5E−04
2.0E−11


hBEW-1E3.1
1.1E+07
8.5E−05
7.7E−12


hBEW-1E3.2
1.1E+07
1.0E−04
9.2E−12


hBEW-1E3.4
9.8E+06
9.6E−05
9.7E−12


hBEW-1E3.5
1.0E+07
1.0E−04
1.0E−11




























































Humanized anti-VEGF-A antibodies were tested for potency against hVEGF 165 -induced cell proliferation in one of two cellular assay formats. The HMVEC-d bioassay utilizes cells which natively express VEGFR2 (Example 1.10). The VEGFR2-3T3 cells are stably transfected with VEGFR2 (Example 1.7). The data is summarized in Table 33 below.





TABLE 33



Summary of Characterization of Humanized

Anti-Human VEGF-A Monoclonal Antibodies.






hVEGF 165 IC50 (nM)










VEGFR2-


Humanized Molecules
HMVEC-d
3T3










hBDB-4G8.1
NT
0.847


hBDB-4G8.2
NT
0.603


hBDB-4G8.3
NT
0.665


hBDB-4G8.3 half-body
NT
>10


hBDB-4G8.4
NT
0.918


hBDB-4G8.5
NT
0.620


hBDB-4G8.6
NT
0.488


hBDB-4G8.7
NT
>10


hBDB-4G8.8
NT
>10


hBDB-4G8.9
NT
>10


hBDB-4G8.10
NT
>10


hBDB-4G8.11
NT
0.385


hBDB-4G8.12
NT
0.563


hBDB-4G8.13
NT
0.791


hBDB-4G8.14
NT
0.499


hBDB-4G8.15
NT
0.963


hBEW-1B10.1
0.168
NT


hBEW-1B10.2
0.222
NT


hBEW-1E3.1
0.138
NT


hBEW-1E3.4
0.212
NT


hBEW-1E3.2
0.161
NT


hBEW-1E3.3
0.205
NT


hBEW-1E3.5
0.184
NT


hBEW-1E3.6
0.26
NT


hBEW-5C3.1
0.071
NT


hBEW-5C3.2
0.162
NT


hBEW-5C3.3
>2
NT


hBEW-5C3.4
0.098
NT


hBEW-5C3.5
0.123
NT


hBEW-5C3.6
>2
NT


hBEW-9A8.9
NT
>10


hBEW-9A8.11
NT
>10


hBEW-9A8.12
NT
0.598


hBEW-9A8.17
0.059
NT


hBEW-9A8.20
0.064
NT


hBEW-9A8.21
0.09
NT


hBEW-9E10.1
0.064
NT


hBEW-9E10.2
0.181
NT


hBEW-9E10.3
0.062
NT


hBEW-9E10.4
0.071
NT


hBEW-9E10.5
0.229
NT


hBEW-9E10.6
0.068
NT





NT = Not tested






































































Humanized anti-PDGF-BB antibodies were tested for their binding to human PDGF-BB according to the method described in Example 1.1. The on-rate, off-rate and binding kinetics are summarized in Table 34 below.





TABLE 34



Biacore Binding of Humanized Anti-PDGF Antibodies








Antibody
k on (M−1 s−1)
k off (M−1)
K D (M)











hBDI-9E8.1
≧1.0E+07
5.6E−03
≦5.6E−10


hBDI-9E8.2
≧1.0E+07
5.1E−03
≦5.1E−10


hBDI-9E8.3
≧1.0E+07
6.5E−04
≦6.5E−11


hBDI-9E8.4
>1.0E+07
2.1E−04
≦2.1E−11


hBDI-9E8.5
≧1.0E+07
2.1E−03
≦2.1E−10


hBDI-9E8.6
≧1.0E+07
2.1E−03
≦2.1E−10


hBDI-9E8.7
≧1.0E+07
4.5E−04
≦4.5E−11


hBDI-9E8.8
≧1.0E+07
1.7E−04
≦1.7E−11*


hBDI-9E8.9
≧1.0E+07
1.5E−03
≦1.5E−10


hBDI-9E8.10
≧1.0E+07
1.8E−03
≦1.8E−10


hBDI-9E8.11
≧1.0E+07
7.4E−04
≦7.4E−11


hBDI-9E8.12
≧1.0E+07
2.1E−03
≦2.1E−10


hBDI-9E8.13
≧1.0E+07
1.0E−03*
≦1.0E−10*


hBDI-5H1.1
≧1.0E+07
4.1E−03
≦4.1E−10


hBDI-5H1.2
≧1.0E+07
1.9E−03
≦1.9E−10


hBDI-5H1.3
≧1.0E+07
4.5E−03
≦4.5E−10


hBDI-5H1.4
≧1.0E+07
1.4E−02
≦1.4E−09


hBDI-5H1.5
≧1.0E+07
1.7E−03
≦1.7E−10


hBDI-5H1.6
≧1.0E+07
8.2E−04
≦8.2E−11


hBDI-5H1.7
≧1.0E+07
2.9E−02*
≦2.9E−09*


hBDI-5H1.8
≧1.0E+07
7.2E−01*
≦7.2E−08*


hBDI-5H1.9
≧1.0E+07
3.1E−03
≦3.1E−10


hBDI-5H1.10
≧1.0E+07
2.3E−03
≦2.3E−10


hBDI-5H1.11
≧1.0E+07
3.7E−03
≦3.7E−10


hBDI-5H1.12
≧1.0E+07
2.3E−03
≦2.3E−10


hBDI-5H1.13
≧1.0E+07
4.9E−03*
≦4.9E−10*





*Heterogeneous off-rate
















































Humanized anti-PDGF-BB antibodies were tested for potency against hPDGF-BB in functional assays. The ability to neutralize hPDGF-BB-induced cell proliferation was assessed (Example 1.15) as well as the ability to block binding of hPDGF-BB to hPDGF-Rβ in a competition ELISA format (Example 1.13). The data is summarized in Table 35 below.





TABLE 35



Summary of Characterization of Humanized

Anti-Human PDGF-BB Monoclonal Antibodies









hPDGF-




BB/hPDGFRβ



hPDGF-BB
Competition


Humanized Molecules
IC50 (nM)
IC50 (nM)










hBDI-9E8.1
>5
+


hBDI-9E8.2
>5
+


hBDI-9E8.3
1.583
+


hBDI-9E8.4
0.061
4.301


hBDI-9E8.4 half body
>5
NT


hBDI-9E8.5
>5
+


hBDI-9E8.6
>5
+


hBDI-9E8.7
0.350
+


hBDI-9E8.8
0.105
+


hBDI-9E8.9
0.574
+


hBDI-9E8.10
0.562
+


hBDI-9E8.11
0.309
1.730


hBDI-9E8.12
0.525
+


hBDI-5H1.1
<10
+


hBDI-5H1.2
<10
+


hBDI-5H1.3
<10
−


hBDI-5H1.4
<10
−


hBDI-5H1.9
<10
+


hBDI-5H1.10
<10
−


hBDI-5H1.11
<10
−


hBDI-5H1.12
<10
−


hBDI-5H1.5
<10
+


hBDI-5H1.6
<10
+


hBDI-5H1.7
<10
−


hBDI-5H1.8
<10
−


hBDI-5H1.13
<10
+


hBDI-5H1.16
<10
NT


hBDI-5H1.17
<10
NT


hBFU-3E2.1
0.183
NT


hBFU-3E2.2
0.659
NT


hBFU-3E2.3
0.335
NT


hBFU-3E2.4
0.571
NT





NT—Not tested


























































Humanized anti-VEGFR2 antibodies were tested for potency against hVEGFR2 in functional assay formats. The antibodies were characterized for the ability to block VEGFR2 binding to hVEGF 165 in a competition ELISA format (Example 1.22). The antibodies were also tested for the ability to bind exogeneous hVEGFR2 and allow signaling in response to hVEGF 165 (Example 1.23). The data is summarized in Table 36 below.





TABLE 36



Summary of Characterization of Humanized

Anti-Human VEGFR II Monoclonal Antibodies.






Potency (nM)









hVEGF 165 /
hVEGF 165 /


Humanized
hVEGFR2-Fc
Tyr1054


Molecules
Competition
phospho-assay





hBCU-6B1.1
0.474
NT


hBCU-6B1.2
0.340
NT


hBCU-6B1.3
0.319
NT


hBCU-6B1.4
0.335
NT





NT—Not tested






























Humanized anti-PDGF-Rβ antibodies were characterized for activity in functional assays. Antibodies were assessed for the ability to bind hPDGF-Rβ (Example 1.26) and block binding of hPDGF-Rβ to hPDGF-BB in a competition ELISA format (Example 1.27). They were also tested for the ability to bind exogenoeous hPDGF-Rβ and allow signaling in response to hPDGF-BB (Example 1.28). The data is summarized in Table 37 below.





TABLE 37



Summary of Characterization of Humanized

Anti-Human PDGFR-B Monoclonal Antibodies





Potency (nM)








hPDGF-BB/
hPDGF-BB


hPDGFRβ-Fc
hPDGFRβ-Fc
Tyr751

Humanized Molecules
Binding
Competition
phospho-assay



hBDE-3C9.1
NT
0.217
1.053

hBDE-3C9.2
NT
0.260
0.882



NT—Not tested




























Example 7
Affinity Maturation of Anti-Human VEGF-A Antibody 4G8
Library Designs And Strategy
Two different hBDB-4G8.3 parental sequences were made: One with “DT” and another with “EI” at the beginning of VL. Both parentals were tested as scFv, and the “EI” was chosen as the template for the libraries. Two libraries were made by dope primers: HC and LC. After library selection and diversity reduction, libraries were combined into one recombined library (rHC+LC). Final selected clones from each of 3 libraries were converted to IgG.
HC Library
Doping (X) 11 residues at 76080808: 30, 31, 33, 53, 56, 58, 95, 96, 100, 100a and 100c Co-evolve (1): D61Q/D62G/K64T. Library will contain DDFKG (SEQ ID NO: 1708) or QGFTG (SEQ ID NO: 1709)

A 10 9 library will be able to sample mutants carrying up to 4 doped residues at least 4 times. On average, library members will have 5 doped residues.
LC Library
Doping (X) 10 residues at 76080808: 30, 31, 32, 50, 53, 91-94 and 96 Germline toggle (Z): E27Q, V58I and F87Y Co-evolve (1): M33L/H34A. Library will contain HMHW (SEQ ID NO: 1710) or YLAW (SEQ ID NO: 1711)

A 10 9 library will be able to sample mutants carrying up to 4 doped residues at least 4 times. On average, library members will have 5 doped residues.
Recombined Library
H1+H2 library is recombined with H3 library into a HC library. HC library is combined with LC library for a total recombined library rHC+LC.
Codons Specified for Residues To Be Doped
For instance, if a proline is to be doped, the doping oligo will have C (5-85-5-5) C (5-85-5-5) S codon regardless of the original codon in the antibody sequence. These codons are selected based on the following criteria: Increase non-synonymous mutation; increase coverage of more amino acids when mutated; and uses high frequency codons and avoid SSS and WWW codons
Doping Order is A-C-G-T










A (70-10-10-10)
C (10-70-10-10)
G (10-10-70-10)
T (10-10-10-70)




Alanine (A):


GCN
G (10-10-70-10) C (10-70-10-10) S

Threonine (T):


ACN
A (70-10-10-10) C (10-70-10-10) S

Proline (P):


CCN
C (10-70-10-10) C (10-70-10-10) S

Serine (S):


TCN
T (10-10-10-70) C (10-70-10-10) S

AGY
A (70-10-10-10) G (10-10-70-10) C (10-70-10-10)

Valine (V):


GTN
G (10-10-70-10) T (10-10-10-70) S

Glycine (G):


GGN
G (10-10-70-10) G (10-10-70-10) S

Leucine (L):


CTN
C (10-70-10-10) T (10-10-10-70) S

TTR
T (10-10-10-70) T (10-10-10-70) G (10-10-70-10)

Arginine (R):


CGN
C (10-70-10-10) G (10-10-70-10) S

AGR
A (70-10-10-10) G (10-10-70-10) G (10-10-70-10)

Methionine (M):


ATG
A (70-10-10-10) T (10-10-10-70) G (10-10-70-10)

Tryptophan (W):


TGG
T (10-10-10-70) G (10-10-70-10) G (10-10-70-10)

Pheylalanine (F):


TTY
T (10-10-10-70) T (10-10-10-70) C (10-70-10-10)

Isoleucine (I):


50% ATY
A (70-10-10-10) T (10-10-10-70) C (10-70-10-10)

50% ATA
A (70-10-10-10) T (10-10-10-70) A (70-10-10-10)

Tyrosine (Y):


TAY
T (10-10-10-70) A (70-10-10-10) C

Histidine (H):


CAY
C (10-70-10-10) A (70-10-10-10) C (10-70-10-10)

Glutamine (Q):


CAR
C (10-70-10-10) A (70-10-10-10) G (10-10-70-10)

Asparagine (N):


AAY
A (70-10-10-10) A (70-10-10-10) C (10-70-10-10)

Lysine (K):


AAR
A (70-10-10-10) A (70-10-10-10) G (10-10-70-10)

Aspartic Acid (D):


GAY
G (10-10-70-10) A (70-10-10-10) C (10-70-10-10)

Glutamic acid (E):


GAR
G (10-10-70-10) A (70-10-10-10) G (10-10-70-10)

Cysteine (C):

TGY
NNS





























































List of Amino Acid Sequences of Affinity Matured H4g8.3 VH Variants.
Table 38 provides a list of amino acid sequences of unique, functional VH regions of affinity matured humanized anti-VEGF antibodies derived from hBDB-4G8.3. Amino acid residues of individual CDRs of each VH sequence are indicated in bold.
TABLE 38 List of Amino Acid Sequences of Affinity Matured H4g8.3 VH Variants Clone SEQ ID NO: VH CL-27663 1712 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYRMY WVRQAPGQGL EWMG WINTETGXPAYADDFKR RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TKYYYSSYIFYFDY WGQGTMVTVSS CL-27664 1713 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYSMY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TKYYYRFYLFYFDY WGQGTMVTVSS CL-27665 1714 EVQLVQSGSELKKPGASVKVSCKAS GYTFTYYGMY WVRQAPGQGL EWMG WINTKTGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYGSYIFYFDY WGQGTMVTVSS CL-27666 1715 EVQLVQSGSELKKPGASVKVSCKAS GYTFINYRMY WVRQAPGQGL EWMG WINTETGKPVYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYSSYKFYFDY WGQGTMVTVSS CL-27667 1716 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYAMY WVRQAPGQGL EWMG WINTETGKPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TIYYYXKYIFYFDY WGQGTMVTVSS CL-27668 1717 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR PTYYYWIYIFYFDY WGQGTMVTVSS CL-27669 1718 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYCMY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR RNYYYXCYIFYFDY WGQGTMVTVSS CL-27670 1719 EVQLVQSGSELKKPGASVKVSCKAS GYTFTTYDMY WVRQAPGQGL EWMG WINTVTGSPAYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TTYYYCSYTFYFDY WGQGTMVTVSS CL-27671 1720 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTGTGXPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR XNYYYXSYXFYFDY WGQGTMVTVSS CL-27672 1721 EVQLVQSGSELKKPGASVKVSCKAS GYTFSKYGMY WVRQAPGQGL EWMG WINTYTGKPLYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYMGYRFYFDY WGQGTMVTVSS CL-27673 1722 EVQLVQSGSELKKPGASVKVSCKAS GYTFTPYGMY WVRQAPGQGL EWMG WINTETGVPSYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SNYYYRSYRFYFDY WGQGTMVTVSS CL-27674 1723 EVQLVQSGSELKKPGASVKVSCKAS GYTFINYVMY WVRQAPGQGL EWMG WINTATGXPSYAQGFTG RFVFSFDTSVSTTYLQISSLKAED TAVYYCAR TTYYYRRYIFYFDY WGQGTMVTVSS CL-27675 1724 EVQLVQSGSELKKPGASVKVSCKAS GYTFTKYDMY WVRQAPGQGL EWMG WINTATGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TLYYYRRYIFYFDY WGQGTMVTVSS CL-27676 1725 EVQLVQSGSELKKPGASVKVSCKAS GYTFIKYGMY WVRQAPGQGL EWMG WINTETGRPAYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR IRYYYGSYIFYFDY WGQGTMVTVSS CL-27677 1726 EVQLVQSGSELKKPGASVKVSCKAS GYTFKNYEMY WVRQAPGQGL EWMG WINTETGKPRYADDFKG RFVFSLDTSVNTAYLQISSLKAED TAVYYCAR TNYYYRSYVFYFDY WGQGTMVTVSS CL-27678 1727 EVQLVQSGSELKKPGASVKVSCKAS GYTFPLYSMY WVRQAPGQGL EWMG WINTHTGNPSYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYTFYFDY WGQGTMVTVSS CL-27679 1728 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTATGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR MNYYYRSYIFYFDY WGQGTMVTVSS CL-27680 1729 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYCMY WVRQAPGQGL EWMG WINTETGKPLYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR RNYYYGGYIFYFDY WGQGTMVTVSS CL-27681 1730 EVQLVQSGSELKKPGASVKVSCKAS GYTFTXYGMY WVRQAPGQGL EWMG WINTQTGPPPYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TYYYYRWYIFYFDY WGQGTMVTVSS CL-27682 1731 EVQLVQSGSELKKPGASVKVSCKAS GYTFTIYEMY WVRQAPGQGL EWMG WINTETGTPPYAXDFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR XXYYYXSYIFYFDY WGQGTMVTVSS CL-27683 1732 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYVMY WVRQAPGQGL EWMG WINTDTGNPAYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TTYYYRVYMFYFDY WGQGTMVTVSS CL-27685 1733 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYCMY WVRQAPGQGL EWMG WINTATGNPSYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYASYIFYFDY WGQGTMVTVSS CL-27686 1734 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYAMY WVRQAPGQGL EWMG WINTPTGMPNYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TSYYYSSYLFYFDY WGQGTMVTVSS CL-27687 1735 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTDTGTPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TEYYYRSYIFYFDY WGQGTMVTVSS CL-27688 1736 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYEMY WVRQAPGQGL EWMG WINTATGKPSYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TIYYYVRYIFYFDY WGQGTMVTVSS CL-27689 1737 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGTPSYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TVYYYRSYLFYFDY WGQGTMVTVSS CL-27690 1738 EVQLVQSGSELKKPGASVKVSCKAS GYTFATYGMY WVGQAPGQGL EWMG WINTETGMPAYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR IRYYYGRYLFYFDY WGQGTMVTVSS CL-27691 1739 EVQLVQSGSELKKPGASVKVSCKAS GYTFSIYYMY WVRQAPGQGL EWMG WINTGTGTPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TSYYYRSYLFYFDY WGQGTMVTVSS CL-27692 1740 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYAMY WVRQAPGQGL EWMG WINTQTGKPRYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR PQYYYTSYIFYFDY WGQGTMVTVSS CL-27694 1741 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTXTGXPTYAXDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR XXYYYRSYXFYFDY WGQGTMVTVSS CL-27695 1742 EVQLVQSGSELKKPGASVKVSCKAS GYTFTYYNMY WVRQAPGQGL EWMG WINTATGSPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR STYYYRSYIFYFDY WGQGTMVTVSS CL-27696 1743 EVQLVQSGSELKKPGASVKVSCKAS GYTFTKYGMY WVRQAPGQGL EWMG WINTQTGKPRYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYWSYIFYFDY WGQGTMVTVSS CL-27697 1744 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYPMY WVRQAPGQGL EWMG WINTETGXPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR XXYYYXRYIFYFDY WGQGTMVTVSS CL-27699 1745 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYDMY WVRQAPGQGL EWMG WINTATGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYRSYLFYFDY WGQGTMVTVSS CL-27700 1746 EVQLVQSGSELKKPGASVKVSCKAS GYTFAHYGMY WVRQAPGQGL EWMG WINTETGNPDYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRCYIFYFDY WGQGTMVTVSS CL-27701 1747 EVQLVQSGSELKKPGASVKVSCKAS GYTFTIYGMY WVRQAPGQGL EWMG WINTETGKPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRCYMFYFDY WGQGTMVTVSS CL-27702 1748 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTVTGAPIYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYWGYRFYFDY WGQGTMVTVSS CL-27703 1749 EVQLVQSGSELKKPGASVKVSCKAS GYTFRSYVMY WVRQAPGQGL EWMG WINTDTGTPSYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR PYYYYRRYIFYFDY WGQGTMVTVSS CL-27704 1750 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYCMY WVRQAPGQGL EWMG WINTKTGNPAYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR XIYYYRRYVLYFDY WGQGTMVTVSS CL-27705 1751 EVQLVQSGSELKKPGASVKVSCKAS GYTFANYSMY WVRQAPGQGL EWMG WINTETGKPKYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRRYSFYFDY WGQGTMVTVSS CL-27706 1752 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYCMY WVRQAPGQGL EWMG WINTTTGKPNYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SNYYYRRYLFYFDY WGQGTMVTVSS CL-27708 1753 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTMTGKPNYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TDYYYRSYDFYFDY WGQGTMVTVSS CL-27709 1754 EVQLVQSGSELKKPGASVKVSCKAS GYTFPKYAMY WVRQAPGQGL EWMG WINTETGXPRYAHDFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRGYIFYFDY WGQGTMVTVSS CL-27710 1755 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYVMY WVRQAPGQGL EWMG WINTETGTPMYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR RDYYYRRYVFYFDY WGQGTMVTVSS CL-27711 1756 EVQLVQSGSELKKPGASVKVSCKAS GYTFTKYDMY WVRQVPGQGL EWMG WVNTDTGKPPYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SKYYYWTYVFYFDY WGQGTMVTVSS CL-27712 1757 EVQLVQSGSELKKPGASVKVSCKAS GYTFTYYDMY WVRQAPGQGL EWMG WINTXTGKPIYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TIYYYGRYSFYFDY WGQGTMVTVSS CL-27713 1758 EVQLVQSGSELKKPGASVKVSCKAS GYTFPFYVMY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRRYIFYFDY WGQGTMVTVSS CL-27714 1759 EVQLVQSGSELKKPGASVKVSCKAS GYTFTTYSMY WVRQAPGQGL EWMG WINTKTGKPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TIYYYMCYVFYFDY WGQGTMVTVSS CL-27715 1760 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGNPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR KHYYYGSYLFYFDY WGQGTMVTVSS CL-27716 1761 EVQLVQSGSELKKPGASVKVSCKAS GYTFPDYDMY WVRQAPGQGL EWMG WINTETGMPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRGYIFYFDY WGQGTMVTVSS CL-27717 1762 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTDTGKPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TYYYYKKYIFYFDY WGQGTMVTVSS CL-27718 1763 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTGTGRPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TQYYYRRYIFYFDY WGQGTMVTVSS CL-27719 1764 EVQLVQSGSELKKPGASVKVSCKAS GYTFPNYGMY WVRQAPGQGL EWMG WINTKTGKPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR KNYYYKSYVFYFDY WGQGTMVTVSS CL-27721 1765 EVQLVQSVSELKKPGASVKVSCKAS GYTFTKYTMY WVRQAPGQGL EWMG WINTETGNPMYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRIYIFYFDY WGQGTMVTVSS CL-27722 1766 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTATGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SSYYYRNYIFYFDY WGQGTMVTVSS CL-27723 1767 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTVTGKPDYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR QKYYYRSYFFYFDY WGQGTMVTVSS CL-27725 1768 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYDMY WVRQAPGQGL EWMG WINTDTGKPAYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR PSYYYVXYIFYFDY WGQGTMVTVSS CL-27726 1769 EVQLVQSGSELKKPGASVKVSCKAS GYTFTLYXMY WVRQAPGQGL EWMG WINTATGKPTYAHDFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TXYYYRSYIFYFDY WGQGTMVTVSS CL-27727 1770 EVQLVQSGSELKKPGASVKVSCKAS GYTFTKYGMY WVRQAPGQGL EWMG WINTHTGNPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRCYIFYFDY WGQGTMVTVSS CL-27728 1771 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGKPEYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR PNYYYRSYFFYFDY WGQGTMVTVSS CL-27729 1772 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTETGRPGYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR LWYYYWMYIFYFDY WGQGTMVTVSS CL-27730 1773 EVQLVQSGSELKKPGASVKVSCKAS GYTFTYYGMY WVRQAPGQGL EWMG WINTETGTPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR VYYYYGSYSFYFDY WGQGTMVTVSS CL-27731 1774 EVQLVQSGSELKKPGASVKVSCKAS GYTFVNYAMY WVRQAPGQGL EWMG WINTXTGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR KTYYYRGYIFYFDY WGQGTMVTVSS CL-27733 1775 EVQLVQSGSELKKPGASVKVSCKAS GYTFTHYYMY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SKYYYRSYTFYFDY WGQGTMVTVSS CL-27734 1776 EVQLVQSGSELKKPGASVKVSCKAS GYTFLHYGMY WVRQAPGQGL EWMG WINTETGWPRYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TSYYYVSYIFYFDY WGQGTMVTVSS CL-27735 1777 EVQLVQSGSELKKPGASVKVSCKAS GYTFTIYGMY WVRQAPGQGL EWMG WINTATGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TXYYYRSYVFYFDY WGQGTMVTVSS CL-27736 1778 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGNPIYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR AHYYYRTYXFYFDY WGQGTMVTVSS CL-27737 1779 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGNPIYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR AHYYYRTYNFYFDY WGQGTMVTVSS CL-27738 1780 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYWMY WVRQAPGQGL EWMG WINTETGRPRYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR VYYYYRCYSFYFDY WGQGTMVTVSS CL-27739 1781 EVQLVQSGSELKKPGASVKVSCKAS GYTFTHYWMY WVRQAPGQGL EWMG WINTETGTPSYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TTYYYRSYIFYFDY WGQGTMVTVSS CL-27741 1782 EVQLVQSGSELKKPGASVKVSCKAS GYTFTKYGMY WVRQAPGQGL EWMG WINTNTGKPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR AYYYYWSYIFYFDY WGQGTMVTVSS CL-27742 1783 EVQLVQSGSELKKPGASVKVSCKAS GYTFTSYVMY WVRQAPGQGL EWMG WINTKTGMPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TTYYYMSYIFYFDY WGQGTMVTVSS CL-27744 1784 EVQLVQSGSELKKPGASVKVSCKAS GYTFTQYGMY WVRQAPGQGL EWMG WINTETGKPKYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYWSYKFYFDY WGQGTMVTVSS CL-27747 1785 EVQLVQSGSELKKPGASVKVSCKAS GYTFSTYMMY WVRQAPGQGL EWMG WINTETGXPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SNYYYRSYIFYFDY WGQGTMVTVSS CL-27750 1786 EVQLVQSGSELKKPGASVKVSCKAS GYTFMNYVMY WVRQAPGQGL EWMG WINTKTGMPRYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYMRYIFYFDY WGQGTMVTVSS CL-27751 1787 EVQLVQSGSELKKPGASVKVSCKAS GYTFTTYGMY WVRQAPGQGL EWMG WINTQTGEPPYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TGYYYWNYLFYFDY WGQGTMVTVSS CL-27752 1788 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYRMY WVRQAPGQGL EWMG WINTETGKPPYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYMSYIFYFDY WGQGTMVTVSS CL-27753 1789 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGSPRYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYVSYIFYFDY WGQGTMVTVSS CL-27755 1790 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGXPTYAHDFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR XNYYYXXYIFYFDY WGQGTMVTVSS CL-27756 1791 EVQLVQSGSELKKPGASVKVSCKAS GYTFTIYGMY WVRQAPGQGL EWMG WINTDTGRPIYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR IIYYYCSYIFYFDY WGQGTMVTVSS CL-27757 1792 EVQLVQSGSELKKPGASVKVSCKAS GYTFNNYGMY WVRQAPGQGL EWMG WINTETGKPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYIFYFDY WGQGTMVTVSS CL-27758 1793 EVQLVQSGSELKKPGASVKVSCKAS GYTFSLYAMY WVRQAPGQGL EWMG WINTETGKPTYADDFKG QFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYNFYFDY WGQGTMVTVSS CL-27760 1794 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYIFYFDY WGQGTMVTVSS CL-27824 1795 EVQLVQSGSELNXPGASLKVSCKAS GYTFXNYGXY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYIFYFDY WGQGTMVTVSS CL-27833 1796 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGIY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYIFYFDY WGQGTMVTVSS CL-29884 1797 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRLYMFYFDY WGQGTMVTVSS CL-29885 1798 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYQSYMFYFDY WGQGTMVTVSS CL-29887 1799 EVQLVQSGSELKKPGASVKVSCKAS GYTFPNYGMY WVRQAPGQGL EWMG WINTETGEPSYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-29888 1800 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYRTYMFYFDY WGQGTMVTVSS CL-29889 1801 EVQLVQSGSELKKPGASVKVSCKAS GYTFADYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SNYYYRTYMFYFDY WGQGTMVTVSS CL-29890 1802 EVQLVQSGSELKKPGASVKVSCKAS GYTFTTYGMY WVRQAPGQGL EWMG WINTETGXPTYAXDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR RXYYYXSYXFYFDY WGQGTMVTVSS CL-29891 1803 EVQLVQSGSELKKPGASVKVSCKAS GYTFPNYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-29892 1804 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WINTETGQPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-29893 1805 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR VNYYYRNYMFYFDY WGQGTMVTVSS CL-29895 1806 EVQLVQSGSELKKPGASVKVSCKAS GYTFSDYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR VNYYYMSYMFYFDY WGQGTMVTVSS CL-29896 1807 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRMYMFYFDY WGQGTMVTVSS CL-29897 1808 EVQLVQSGSELKKPGASVKVSCKAS GYTFLNYGMY WVRQAPGQGL EWMG WINTETGKPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TKYYYWRYIFYFDY WGQGTMVTVSS CL-29898 1809 EVQLVQSGSELKKPGASVKVSCKAS GYTFNDYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-29899 1810 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR INYYYRSYMFYFDY WGQGTMVTVSS CL-29901 1811 EVQLVQSGSELKKPGASVKVSCKAS GYTFMNYGMY WVRQAPGQGL EWMG WIDTETGXXXYAHDFTG RFVFSLDTSVSTAYLEISSLKAED TAVYYCAR XNYYYXXYMFYFDY WGQGTMVTVSS CL-29902 1812 EVQLVQSGSELKKPGASVKVSCKAS GYTFTSYGMY WVRQAPGQGL EWMG WINTETGQPMYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR RIYYYRCYLFYFDY WGQGTMVTVSS CL-29904 1813 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTDTGMPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYRSYMFYFDY WGQGTMVTVSS CL-29906 1814 EVQLVQSGSELKKPGASVKVSCKAS GYTFNNYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRNYMFYFDY WGQGTMVTVSS CL-29907 1815 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTETGEPSYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SNYYYRSYMFYFDY WGQGTMVTVSS CL-29908 1816 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYKSYMFYFDY WGQGTMVTVSS CL-29909 1817 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYRSYMFYFDY WGQGTMVTVSS CL-29910 1818 EVQLVQSGSELKKPGASVKVSCKAS GYTFNYYGMY WVRQAPGQRL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYESYMFYFDY WGQGTMVTVSS CL-29912 1819 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTDTGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-29913 1820 EVQLVQSGSELKKPGASVKVSCKAS GYTFTKYRMY WVRQAPGQGL EWMG WINTVTGKPKYADDFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR FKYYYGSYFFYFDY WGQGTMVTVSS CL-29914 1821 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGQPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-29915 1822 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRNYMFYFDY WGQGTMVTVSS CL-29916 1823 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTETGDPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-29917 1824 EVQLVQSGSELKKPGASVKVSCKAS GYTFNNYGMY WVRQAPGQGL EWMG WIDTETGQPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPRYMFYFDY WGQGTMVTVSS CL-29918 1825 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WINTDTGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYASYMFYFDY WGQGTMVTVSS CL-29919 1826 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYQSYMFYFDY WGQGTMVTVSS CL-29921 1827 EVQLVQSGSELKKPGASVKVSCKAS GYTFSHYGMY WVRQAPGQGL EWMG WINTETGSPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-29922 1828 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTDTGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-29924 1829 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTETGNPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-29925 1830 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WINTETGEPTYAXGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-29926 1831 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SNYYYTSYMFYFDY WGQGTMVTVSS CL-29927 1832 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTETGQPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRMYMFYFDY WGQGTMVTVSS CL-29928 1833 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGEPYYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPKYMFYFDY WGQGTMVTVSS CL-29929 1834 EVQLVQSGSELKKPGASVKVSCKAS GYTFTHYWMY WVRQAPGQGL EWMG WINTETGKPAYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYIYYLFYFDY WGQGTMVTVSS CL-29931 1835 EVQLVQSGSELKKPGASVKVSCKAS GYTFPNYGMY WVRQAPGQGL EWMG WINTGTGKPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRNYMFYFDY WGQGTMVTVSS CL-29932 1836 EVQLVQSGSELKKPGASVKVSCKAS GYTFTPYGMY WVRQAPGQGL EWMG WINTDTGXPPYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYTCYIFYFDY WGQGTMVTVSS CL-29934 1837 EVQLVQSGSELKKPGASVKVSCKAS GYTFTHYGMY WVRQAPGQGL EWMG WINTETGXPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPRYMFYFDY WGQGTMVTVSS CL-29935 1838 EVQLVQSGSELKKPGASVKVSCKAS GYTFPDYGMY WVRQAPGQGL EWMG WIDTETGMPXYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRNYMFYFDY WGQGTMVTVSS CL-29936 1839 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-29937 1840 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGDPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR XNYYYRXYMFYFDY WGQGTMVTVSS CL-29938 1841 EVQLVQSGSELKKPGASVKVSCKAS GYTFNKYDMY WVRQAPGQGL EWMG WINTKTGKPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TAYYYRNYKSTLIT GGQGTMVTVSS CL-29939 1842 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYKGYMFYFDY WGQGTMVTVSS CL-29940 1843 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGTPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TYYYYRTYIFYFDY WGQGTMVTVSS CL-29941 1844 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRGYMFYFDY WGQGTMVTVSS CL-29942 1845 EVQLVQSGSELKKPGASVKVSCKAS GYNFTKYEMY WVRQAPGQGL EWMG WINTETGNPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TKYYYRSYVFYFDY WGQGTMVTVSS CL-29943 1846 EVQLVQSGSELKKPGASVKVSCKAS GYTFPNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYLSYMFYFDY WGQGTMVTVSS CL-29946 1847 EVQLVQSGSELKKPGASVKVSCKAS GYTFTHYGMY WVRQAPGQGL EWMG WINTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-29947 1848 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTDTGDPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYRTYMFYFDY WGQGTMVTVSS CL-29948 1849 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGTPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-29949 1850 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGDPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR VNYYYRSYMFYFDY WGQGTMVTVSS CL-29950 1851 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTQTGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SNYYYRLYMFYFDY WGQGTMVTVSS CL-29951 1852 EVQLVQSGSELKKPGASVKVSCKAS GYTFPDYGMY WVRQAPGQGL EWMG WIDTETGQPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ADYYYPTYMFYFDY WGQGTMVTVSS CL-29952 1853 EVQLVQSGSELKKPGASVKVSCKAS GYTFTHYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPTYMFYFDY WGQGTMVTVSS CL-29955 1854 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SNYYYRSYMFYFDY WGQGTMVTVSS CL-29957 1855 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTVTGQPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR THYYYRTYLFYFDY WGQGTMVTVSS CL-29958 1856 EVQLVQSGSELKKPGASVKVSCKAS GYTFPNYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-29959 1857 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRGYMFYFDY WGQGTMVTVSS CL-29960 1858 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYSMY WVRQAPGQGL EWMG WINTXTGKPIYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TKYYYRTYRFYFDY WGQGTMVTVSS CL-29961 1859 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WIDTETGTPVYADDFKG RFVFSLDTSVNTAYLQISSLKAED TAVYYCAR TNYYYKSYMFYFDY WGQGTMVTVSS CL-29962 1860 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SNYYYSSYMFYFDY WGQGTMVTVSS CL-29963 1861 EVQLVQSGSELKKPGASVKVSCKAS GYTFSEYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-29966 1862 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR VNYYYRWYMFYFDY WGQGTMVTVSS CL-29967 1863 EVQLVQSGSELKKPGASVKVSCKAS GYTFPNYGMY WVRQAPGQGL EWMG WINTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-29968 1864 EVQLVQSGSELKKPGASVKVSCKAY GYTFTDYGMY WVRQAPGQGL EWMG WINTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYEKYMFYFDY WGQGTMVTVSS CL-29969 1865 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SNYYYRGYMFYFDY WGQGTMVTVSS CL-29970 1866 EVQLVQSGSELKKPGASVKVSCKAS GYTFMTYVMY WVRQAPGQGL EWMG WINTETGKPSYAHDFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR MXYYYXIYMFYFDY WGQGTMVTVSS CL-29971 1867 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-29972 1868 EVQLVQSGSELKKPGASVKVSCNAS GXTFTNYGMY WVRQAPGQGL EWMG WINTETGKPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR INYYYRSYIFYFDY WGQGTMVTVSS CL-29973 1869 EVQLVQSGSELKKPGASVKVSCKAS GYTFNDYGMY WVRQAPGQGL EWMG WINTETGEPTYAXXFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYEGYMFYFDY WGQGTMVTVSS CL-29974 1870 EVQLVQSGSELKKPGASVKVSCKAS GYTFSDYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-29975 1871 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYKSYMFYFDY WGQGTMVTVSS CL-29976 1872 EVQLVQSGSELRKPGASVKVSCKAS GYTFNNYGMY WVRQAPGQGL EWMG WIDTETGRPWYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYQGYMFYFDY WGQGTMVTVSS CL-29980 1873 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMH WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYIFYFDY WGQGTMVTVSS CL-30036 1874 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSHIFYFDY WGQGTMVTVSS CL-30060 1875 EVQLVQSGSELKKPGASVRVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYIFYFDY WGQGTMVTVSS CL-30075 1876 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTXTGKPTYAXGFTG RFVFSLDTSVSTAYLQIXXLXAXD TAVYYCAR XKYYYXSYIFYFDY WGQGTMVTVSS CL-30076 1877 EVQLVQSGSELKKPGASVKVSCKAS GYTFYNYCMY WVRQAPGQGL EWMG WINTETGIPKYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR INYYYKRYIFYFDY WGQGTMVTVSS CL-30077 1878 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYYMY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TXYYYXRYXFYFDY WGQGTMVTVSS CL-30078 1879 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYIFYFDY WGQGTMVTVFS CL-30079 1880 EVQLVQSGSELKKPGASVKVSCKAS GYTFIHYGMY WVRQAPGQGL EWMG WINTETGRPTYADDFKG RFVFSLDTSVSTAYLQISSLKXED TAVYYCAR TVYYYPRYTFYFDY WGQGTMVTVSS CL-30082 1881 EVQLVQSGSELKKPGASVKVSCKAS GYTFMNYGMY WVRQAPGQGL EWMG WINTETGKPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPGYIFYFDY WGQGTMVTVSS CL-30083 1882 EVQLVQSGSELKKPGASVKVSCKAS GYTFTLYGMY WVRQAPGQGL EWMG WINTDTGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYXSYIFYFDY WGQGTMVTVSS CL-30084 1883 EVQLVQSGSELKKPGASVKVSCKAS GYTFNKYGMY WVRQAPGQGL EWMG WINTETGKPSYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR AKYYYRSYIFYFDY WGQGTMVTVSS CL-30086 1884 EVQLVQSGSELKKPGASVKVSCKAS GYTFLNYGMY WVRQAPGQGL EWMG WINTETGRPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRIYRFYFDY WGQGTMVTVSS CL-30087 1885 EVQLVQSGSELKKPGASVKVSCKAS GYTFYNYGMY WVRQAPGQGL EWMG WINTATGKPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR XKYYYXSXXFYFDY WGQGTMVTVSS CL-30091 1886 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYDMY WVRQAPGQGL EWMG WINTVTGLPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TIYYYKSYIFYFDY WGQGTMVTVSS CL-30092 1887 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WINTGTGIPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TSYYYRNYLFYFDY WGQGTMVTVSS CL-30093 1888 EVQLVQSGSELKKPGASVKVSCKAS GYTFTKYGMY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TTYYYRRYIFYFDY WGQGTMVTVSS CL-30096 1889 EVQLVQSGSELKKPGASVKVSCKAS GYTFTTYAMY WVRQAPGQGL EWMG WINTETGKPRYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYRSYIFYFDY WGQGTMVTVSS CL-30097 1890 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQIXXLKTED TAVYYCAR SNYYYRGYIFYFDY WGQGTMVTVSS CL-30103 1891 EVQLVQSGSELKKPGASVKVSCKAS GYTFAIYRMY WVRQAPGQGL EWMG WINTDTGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SKYYYGFYMFYFDY WGQGTMVTVSS CL-30107 1892 EVQLVQSGSELKKPGASVKVSCKAS GYTFMNYGMY WVRQAPGQGL EWMG WINTETGRPVYAQGFTG RFVFSLDTSVSTAYLQISSLKAXD TAVYYCAR TNYYYLRYVFYFDY WGQGTMVTVSS CL-30108 1893 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTGTGMPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR NKYYYRSYMFYFDY WGQGTMVTVSS CL-30110 1894 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYDMY WVRQAPGQGL EWMG WINTETGKPPYADGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYIFYFDY WGQGTMVTVSS CL-30113 1895 EVQLVQSGSELKKPGASVKVSCKAS GYTFTSYGMY WVRQAPGQGL EWMG WINTETGIPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR WDYYYTSYKFYFDY WGQGTMVTVSS CL-30114 1896 EVQLVQSGSELKKPGASVKVSCKAS GYTFTIYGMY WVRQAPGQGL EWMG WINTVTGNPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TEYYYMNYIFYFDY WGQGTMVTVSS CL-30116 1897 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYDMY WVRQAPGQGL EWMG WINTGTGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYSRYDFYFDY WGQGTMVTVSS CL-30119 1898 EVQLVQSGSELKKPGASVKVSCKAS GYTFTKYGMY WVRQAPGQGL EWMG WINTQTGKPAYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR AIYYYRIYIFYFDY WGQGTMVTVSS CL-30124 1899 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYAMY WVRQAPGQGL EWMG WINTQTGEPSYAQGFTG XFVFSLDTSASTEYLXISILXDXD TAVYYCAR XTYYYXNYIFYFDY WGXGTMVTVSS CL-30127 1900 EVQLVQSGSELKKPGASVKVSCKAS GYTFTTYGMY WVRQAPGQGL EWMG WINTETGRPTYADDFNG WFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRIYIFYFDY WGQGTMVTVSS CL-30128 1901 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYIFYFDY WGQGTMVTVSS CL-30129 1902 EVQLVQSGSELKKPGASVKVSCKAS GYTFNNYGMY WVRQAPGQGL EWMG WINTGTGKPTYAQGFTG RFVFSLDTSVSTAYLQIXSLKAED TAVYYCAR PIYYYIRYIFYFDY WGQGTMVTVSS CL-30130 1903 EVQLVQSGSELKKPGASVKVSCKAS GYTFADYPMY WVRQAPGQGL EWMG WINTXTGQPLYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TSYYYRSYIFYFDY WGQGTMVTVSS CL-30135 1904 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAXD TAVYYCAR TNYYYRSYIFYFDY WGQGTMVTVSS CL-30136 1905 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYSMY WVRQAPGQGL EWMG WINTETGKPRYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TSYYYRSYIFYFDY WGQGTMVTVSS CL-30138 1906 EVQLVQSGSELKKPGASVKVSCKAS GYTFTTYWMY WVRQAPGQGL EWMG WINTETGEPRYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TEYYYKSYNFYFDY WGQGTMVTVSS CL-30140 1907 EVQLVQSGSELKKPGASVKVSCKAS GYTFTAYGMY WVRQAPGQGL EWMG WINTETGMPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TKYYYRSYMFYFDY WGQGTMVTVSS CL-30141 1908 EVQLVQSGSELKKPGASVKVSCKAS GYTFHNYGMY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TSYYYRSYFFYFDY WGQGTMVTVSS CL-30142 1909 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYVMY WVRQAPGQGL EWMG WINTETGNPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR LIYYYXTYIFYFDY WGQGTMVTVSS CL-30145 1910 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYAMY WVRQAPGQGL EWMG WINTETGKPPYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TLYYYRTYIFYFDY WGQGTMVTVSS CL-30147 1911 EVQLVQSGSELKKPGASVKVSCKAS GYTFTHYGMY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRRYIFYFDY WGQGTMVTVXS CL-30148 1912 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WINTETGQPSYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRCYIFYFDY WGQGTMVTVSS CL-30151 1913 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGKPNYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR PNYYYRSYIFYFDY WGQGTMVTVSS CL-30154 1914 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYAMY WVRQAPGQGL EWMG WINTETGNPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYGIYLFYFDY WGQGTMVTVSS CL-30156 1915 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYDMY WVRQAPGQGL EWMG WINTVTGRPAYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ITYYYRMYRFYFDY WGQGTMVTVSS CL-30159 1916 EVQLVQSGSELKKPGASVKVSCKAS GYTFIDYLMY WVRQAPGQGL EWMG WINTVTGKPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR THYYYRSYAFYFDY WGQGTMVTVSS CL-30161 1917 EVQLVQSGSELKKPGASVKVSCKAS GYTFAKYEMY WVRQAPGQGL EWMG WINTETGNPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRDYTFYFDY WGQGTMVTVSS CL-30162 1918 EVQLVQSGSELKKPGASVKVSCKAS GYTFTTYRMY WVRQAPGQGL EWMG WINTVTGRPSYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR NIYYYRSYIFYFDY WGQGTMVTVSS CL-30164 1919 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYIFYFDY WGQGTMVTVSS CL-30165 1920 EVQLVQSGSELKKPGASVKVSCKAS GYTFRNYVMY WVRQAPGQGL EWMG WINTQTGEPSYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYGIYIFYFDY WGQGTMVTVSS CL-30166 1921 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLQAED TAVYYCAR TNYYYRSYIFYFDY WGQGTMVTVSS CL-30168 1922 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTETGMPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SNYYYRGYIFYFDY WGQGTMVTVSS CL-30169 1923 EVQLVQSGSELKKPGASVKVSCKAS GYTFLGYSMY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR KFYYYESYIFYFDY WGQGTMVTVSS CL-30170 1924 EVQLVQSGSELKKPGASVKVSCKAS GYTFTYYCMY WVRQAPGQGL EWMG WINTHTGKPMYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR KKYYYRSYIFYFDY WGQGTMVTVSS CL-30593 1925 EVQLVQSGSELKKPGASVKVSCKAS GYTFSDYGMY WVRQAPGQGL EWMG WIDTETGDPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYMSYMFYFDY WGQGTMVTVSS CL-30594 1926 EVQLVQSGSELKKPGASVKVSCKAS GYTFMNYGMY WVRQAPGQGL EWMG WINTETGKPMYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TIYYYPRYIFYFDY WGQGTMVTVSS CL-30595 1927 EVQLVQSGSELKKPGASVKVSCKAS GYTFAMYKMY WVRQAPGQGL EWMG WINTQTGGPSYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TKYYYWRYVFYFDY WGQGTMVTVSS CL-30597 1928 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WINTETGQPMYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-30599 1929 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGNPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SNYYYSSYMFYFDY WGQGTMVTVSS CL-30600 1930 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTATGQPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYMYYLFYFDY WGQGTMVTVSS CL-30602 1931 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYRLYMFYFDY WGQGTMVTVSS CL-30604 1932 EVQLVQSGSELKKPGASVKVSCKAS GYTFPNYGMY WVRQAPGQGL EWMG WINTWTGKPTYAXDFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-30605 1933 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYRTYMFYFDY WGQGTMVTVSS CL-30606 1934 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYRMY WVRQAPGQGL EWMG WINTETGKPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYSSYMFYFDY WGQGTMVTVSS CL-30608 1935 EVQLVQSGSELKKPGASVKVSCKAS GYTFTTYDMY WVRQAPGQGL EWMG WINTVTGXPTYAXXFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SXYYYRSYIFYFDY WGQGTMVTVSS CL-30609 1936 EVQLVQSGSELKKPGASVKVSCKAS GYTFNNYGMY WVRQAPGQGL EWMG WINTETGKPRYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TDYYYRRYTFYFDY WGQGTMVTVSS CL-30611 1937 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WINTYTGIPSYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR VNYYYSTYIFYFDY WGQGTMVTVSS CL-30613 1938 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGIY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SNYYYRGYMFYFDY WGQGTMVTVSS CL-30614 1939 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SNYYYRSYMFYFDY WGQGTMVTVSS CL-30615 1940 EVQLVQSGSELKKPGASVKVSCKAS GYTFNNYGMY WVRQAPGQGL EWMG WINTDTGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR VNYYYRSYMFYFDY WGQGTMVTVSS CL-30616 1941 EVQLVQSGSELKKPGASVKVSCKAS GYTFTTYGMY WVRQAPGQGL EWMG WINTLTGAPMYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYSSYIFYFDY WGQGTMVTVSS CL-30617 1942 EVQLVQSGSELKKPGASVKVSCKAS GYTFKNYSMY WVRQAPGQGL EWMG WINTDTGMPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRFYIFYFDY WGQGTMVTVSS CL-30618 1943 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR VNYYYRSYMFYFDY WGQGTMVTVSS CL-30619 1944 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYRSYMFYFDY WGQGTMVTVSS CL-30620 1945 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRGYMFYFDY WGQGTMVTVSS CL-30623 1946 EVQLVQSGSELKKPGASVKVSCKAS GYTFANYGMY WVRQAPGQGL EWMG WINTETGQPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYQSYMFYFDY WGQGTMVTVSS CL-30624 1947 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTDTGTPAYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYTRYNFYFDY WGQGTMVTVSS CL-30626 1948 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-30628 1949 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WINTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYRSYMFYFDY WGQGTMVTVSS CL-30629 1950 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYDMY WVRQAPGQGL EWMG WINTETGNPTYAXXFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR XNYYYSSYIFYFDY WGQGTMVTVSS CL-30630 1951 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR SNYYYRTYMFYFDY WGQGTMVTVSS CL-30631 1952 EVQLVQSGSELKKPGASVKVSCKAS GYTFNNYGMY WVRQAPGQGL EWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-30632 1953 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-30634 1954 EVQLVQSGSELKKPGASVKVSCKAS GYTFTYYGMY WVRQAPGQGL EWMG WINTETGKPSYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TIYYYTTYIFYFDY WGQGTMVTVSS CL-30635 1955 EVQLVQSGSELKKPGASVKVSCKAS GYTFPNYGMY WVRQAPGQGL EWMG WIDTETGEPIYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR INYYYPNYMFYFDY WGQGTMVTVSS CL-30636 1956 EVQLVQSGSELKKPGASVKVSCKTS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRGYMFYFDY WGQGTMVTVSS CL-30637 1957 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-30638 1958 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WIDTETGNPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYRSYMFYFDY WGQGTMVTVSS CL-30639 1959 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGTPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-30640 1960 EVQLVQSGSELKKPGASVKVSCKAS GYTFSSYGMY WVRQAPGQGL EWMG WIDTETGEPKYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-30642 1961 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR YNYYYRIYLFYFDY WGQGTMVTVSS CL-30643 1962 EVQLVQSGSELKKPGASVKVSCKAS GYTFPYYSMY WVRQAPGQGL EWMG WINTDTGTPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TTYYYWSYIFYFDY WGQGTMVTVSS CL-30644 1963 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGDPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-30645 1964 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTXTGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TSYYYRCYIFYFDY WGQGTMVTVSS CL-30647 1965 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTETGQPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-30649 1966 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WIDTDTGKPTYAXDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYTGYMFYFDY WGQGTMVTVSS CL-30651 1967 EVQLVQSGSELEKPGASVKVSCKAS GYTFPNYGMY WVRQAPGQGL EWMG WIDTDTGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYRSYMFYFDY WGQGTMVTVSS CL-30653 1968 EVQLVQSGSELKKPGASVKVSCKAS GYTFNNYGMY WVRQAPGQGL EWMG WIDTETGDPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYLSYMFYFDY WGQGTMVTVSS CL-30654 1969 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYIFYFDY WGQGTMVTVSS CL-30655 1970 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGEPSYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-30657 1971 EVQLVQSGSELKKPGASVKVSCKAS GYTFANYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYKSYMFYFDY WGQGTMVTVSS CL-30658 1972 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WINTDTGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-30659 1973 EVQLVQSGSELKKPGASVKVSCKAS GYTFPYYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYRMYMFYFDY WGQGTMVTVSS CL-30660 1974 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGDPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRGYMFYFDY WGQGTMVTVSS CL-30662 1975 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGSPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR IIYYYLSYLFYFDY WGQGTMVTVSS CL-30663 1976 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WINTETGDPTYAQGFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-30664 1977 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYSGYMFYFDY WGQGTMVTVSS CL-30665 1978 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRYYMFYFDY WGQGTMVTVSS CL-30666 1979 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-30669 1980 EVQLVQSGSELKKPGASVKVSCKAS GYTFTKYAMY WVRQAPGQGL EWMG WINTYTGVPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR GHYYYMMYIFYFDY WGQGTMVTVSS CL-30670 1981 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WIDTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR YKYYYRSYKFYFDY WGQGTMVTVSS CL-30671 1982 EVQLVQSGSELKKPGASVKVSCKAS GYTFPDYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRGYMFYFDY WGQGTMVTVSS CL-30674 1983 EVQLVQSGSELKKPGASVKVSCKAS GYTFSHYGMY WVRQAPGQGL EWMG WINTETGDPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-30675 1984 EVQLVQSGSELKKPGASVKVSCKAS GYTFPNYGMY WVRQAPGQGL EWMG WINTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-30676 1985 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGYPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYRTYMFYFDY WGQGTMVTVSS CL-30677 1986 EVQLVQSGSELKKPGASVKVSCKAS GYTFNNYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRTYMFYFDY WGQGTMVTVSS CL-30678 1987 EVQLVQSGSELKKPGASVKVSCKAS GYTFSHYGMY WVRQAPGQGL EWMG WINTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYRSYMFYFDY WGQGTMVTVSS CL-30679 1988 EVQLVQSGSELKKPGASVKVSCKAS GYTFTSYRMY WVRQAPGQGL EWMR WINTETGWPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TSYYYRNYMFYFDY WGQGTMVTVSS CL-30682 1989 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTETGNPMYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-30684 1990 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRNYMFYFDY WGQGTMVTVSS CL-30685 1991 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCVR TNYYYRTYMFYFDY WGQGTMVTVSS CL-32447 1992 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WXRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-32466 1993 EVQLVQSGSELKKPGASVKVSCKAS GYTFHDYGMY WVRQAPGQGL EWMG WIDTETGTPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYSSYMFYFDY WGQGTMVTVSS CL-32470 1994 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGXPTYAXXFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-32507 1995 EVQLVQSGSELKKPGASVKVSCKAS GYTFNDYGMY WVRQAPGQGL EWMG WIDTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYSSYMFYFDY WGQGTMVTVSS CL-34445 1996 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WINTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-34457 1997 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPTYAHDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR XNYYYRSYMFYFDY WGQGTMVTVSS CL-34458 1998 EVQLVQSGSELKKPGAPVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-34465 1999 EVQLVQSGSELKKPGASVKVSCKAS GYTFPDYGMY WVRQAPGQGL EWMG WIDTETGQPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRTYMFYFDY WGQGTMVTVSS CL-34466 2000 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPIYAQGFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYNSYMFYFDY WGQGTMVTVSS CL-34468 2001 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPRYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-34478 2002 EVQLVQSGSELKKPGASVKVSCKAS GYTFPHYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYSSYMFYFDY WGQGTMVTVSS CL-34480 2003 EVQLVQSGSELKKPGASVKVSCKAS GYTFEDYGMY WVRQAPGQGL EWMG WINTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRNYMFYFDY WGQGTMVTVSS CL-34482 2004 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRTYMFYFDY WGQGTMVTVSS CL-34488 2005 EVQLVQSGSELKKPGASVKVSCKAS GYTFDDYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-34490 2006 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGTPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-34493 2007 EVQLVQSGSELKKPGASVKVSCKAS GYTFGDYGMY WVRQAPGQGL EWMG WIDTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR VNYYYRNYMFYFDY WGQGTMVTVSS CL-34495 2008 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGQPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYKSYMFYFDY WGQGTMVTVSS CL-34496 2009 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRGYMFYFDY WGQGTMVTVSS CL-34499 2010 EVQLVQSGSELKKPGASVKVSCKAS GYTFSDYGMY WVRQAPGQGL EWMG WIDTETGDPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-34502 2011 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-34503 2012 EVQLVQSGSELKKPGASVKVSCKAS GYTFSDYGMY WVRQAPGQGL EWMG WIDTETGTPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYKSYMFYFDY WGQGTMVTVSS CL-34505 2013 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGQPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-34510 2014 EVQLVQSGSELKKPGASVKVSCKAS GYTFSHYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYMSYMFYFDY WGQGTMVTVSS CL-34512 2015 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTDTGTPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPKYMFYFDY WGQGTMVTVSS CL-34527 2016 EVQLVQSGSELKKPGASVKVSCKAS GYTFANYGMY WVRQAPGQGL EWMG WIDTETGTPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-34528 2017 EVHLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WIDTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-34529 2018 EVQLVQSGSELNKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPSYADDFKG RFVFSLDTXVSTAYXQISSLKAED XAVYXCAR TNYYYSSYMFYFDY WGQGTXVTVSS CL-34534 2019 EVQLVQSGSELKKPGASVKVSCKAS GYTFNDYGMY WVRQAPGQGL EWMG WIDTETGNPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYRSYMFYFDY WGQGTMVTVSS CL-34539 2020 EVQLVPSGSHFNNPGASXKVSCSAS GYTFSDYGMY WVRQAPGQGL EWMG WIDTETGDPTYADDFKG XFVFSLDTSVXXAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-34548 2021 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGDPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-34562 2022 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGKPTYADDFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRTYMFYFDY WGQGTMVTVSS CL-34568 2023 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGQPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-34577 2024 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGTPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYESYMFYFDY WGQGTMVTVSS CL-34582 2025 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-34586 2026 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPTYAXXFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-34590 2027 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGKPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-34592 2028 EVQLVQSGSELKKPGASVKVSCKAS GYTFNDYGMY WVRQAPGQGL EWMG WIDTETGTPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYSSYMFYFDY WGQGTMVTVSS CL-34595 2029 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRTYMFYFDY WGQGTMVTVSS CL-34596 2030 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRNYMFYFDY WGQGTMVTVSS CL-34597 2031 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-34599 2032 EVQLVQSGSELKKPGASVKVSCKAS GYTFSDYGMY WVRQAPGQGL EWMG WIDTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-34600 2033 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISNLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-34617 2034 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPRYMFYFDY WGQGTMVTVSS CL-40631 2035 EVQLVQSGSELKKPGASVKVSCXAS GYTFSDYGMY WVRQAPGQGL EWMG WIDTETGDPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYRSYMFYFDY WGQGTMVTVSS CL-40642 2036 RVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-40646 2037 EVQLVQSGSELKKPGASVKVSCEAS GYTFSDYGMY WVRQAPGQGL EWMG WIDTETGDPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYRSYMFYFDY WGQGTMVTVSS CL-40665 2038 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTSLQ CL-40668 2039 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKVED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-40671 2040 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGTPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYSSYMFYFDY WGQGTMVTVSS CL-40687 2041 ASAAVQSGSELKKPGASVKVSCKAS GYTFENYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYSSYMFYFDY WGQGTMVTVSS CL-40688 2042 EVQLVQSGSELKKPGASVKVSCKAS GYTFENYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYSSYMFYFDY WGQGTMVTVSS CL-40694 2043 EVQLVQSGSELKKPGASVKVSCKAS GYTFENYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLGTSVSTAYLQISSLKAED TAVYYCAR TNYYYSSYMFYFDY WGQGTMVTVSS CL-40708 2044 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYSSYMFYFDY WGQGTMVTVSS CL-40716 2045 EVQLVQSGSELKKPGASVKVSCKAS GYTFSDYGMY WVRQAPGQGL EWMG WIDTETGDPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR ANYYYRSYMFYFDY WGQGTMVTVSS CL-40717 2046 EVQLVQSGSELKKPGASVKVSCKAS GYTFDDYGMY WVRQAPGQGL EWMG WIDTETGTPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYSSYMFYFDY WGQGTMVTVSS CL-40721 2047 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-40722 2048 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-40723 2049 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-40736 2050 EVQLVQSGSELKKPGASVKVSCKAS GYTFTHYGMY XVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-40740 2051 EVQLVQSGSELKKPGASVKVSCKAS GYTFSDYGMY WVRQAPGQGL EWMG WIDTETGDPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-40741 2052 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGP EWMG WIDTETGNPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-40742 2053 EVQLVQSGSELKKPGASVKVSCKAS GYTFTHYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAEN TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-40745 2054 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-40746 2055 EVQLVQSGSXLKXPGXSXKVSCXVS GYTFQNYGMY CVRPAPGQWL XWMG WIDXXTGEPTYAYDFKG WFLFSLHTSVSMSSLQNXSLKXDD TAVYYCAK TNYYYNSYMFYFDY WGQGTXXTVSS CL-40747 2056 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGQPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRNYMFYFDY WGQGTMVTVSS CL-40753 2057 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGDPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRNYMFYFDY WGQGTMVTVSS CL-40758 2058 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPTYAQGFTG RFVFSLDTSVSTAYLQISSLKAED TAVHYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-40760 2059 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYSSYMFYFDY WGQGTMVTVSS CL-40763 2060 EVQLVQSGSELKKPGASVKVSCKAS GYTFTHYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-40764 2061 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGNPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-40765 2062 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGQPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-40766 2063 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAEG TAVYYCAR TNYYYSSYMFCFDY WGQGTMVTVSS CL-40768 2064 EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYSSYMFYFDY WGQGAMVTVSS CL-40770 2065 EVQLVQSGSELKKPGASVKVSCKAS GYTFTHYGMY WVRRAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-40774 2066 EVQLVQSGSELKKPGASVKVSCKAS GYTFSDYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKVED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-40779 2067 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-40780 2068 EVQLVQSGSELEKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRGYMFYFDY WGQGTMVTSLQ CL-40788 2069 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDAETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRGYMFYFDY WGQGTMVTVSS CL-40790 2070 EGHLGQSGSELKNPGASVKVSCXAS GYTFXNYGMY WVRQAPGQGL EWMG WIDTETGEPTYAXDFKG RFVFSLGTSVSTAYLQIXSLRAED TAVYYCEX TNYYYSRYMFYFXY WGQGTMVTVSS CL-40791 2071 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG XIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYKSYMFYFDY WGQGTMVTVSS CL-40793 2072 EVQLVQSGSELKKPGASVKVSCKAS GYTFSDYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVFS CL-40795 2073 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRGYMLYFDY WGQGTMVTVSS CL-40796 2074 EVQLVQSGSELKKPGASVKVSCKAS GYTFPNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYKSYMFYFDY WGQGTMVTVSS CL-40800 2075 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRRAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRGYMFYFDY WGQGTMVTVSS CL-40801 2076 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RLVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYKSYMFYFDY WGQGTMVTVSS CL-40805 2077 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYSSYMFYFDY WGQGTMVTVSS CL-40806 2078 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRGYMFYFDY WGQGTMVTVSS CL-40811 2079 EVQLVQSGSELKKPGASVKVSCKAS GYTFPNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS CL-40812 2080 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYXSYMFYFDY WGQGTMVTVSS CL-40815 2081 EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYKSYMFYFDY WGQGTMVTVSS CL-40816 2082 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG QFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSYMFYFDY WGQGTMVTVSS CL-40817 2083 EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYPSHMFYFDY WGQGTMVTVSS CL-40819 2084 EVQLVQSGSELKKPGASVKVSCKAS GYTFSDYGMY WVRQAPGQGL EWMG WIDTETGEPTYADDFKG RFVFSLDTSVSTAYLQISSLKAED TAVYYCAR TNYYYRSYMFYFDY WGQGTMVTVSS
List of Amino Acid Sequences of Affinity Matured h4G8.3 VL Variants

Table 39 provides a list of amino acid sequences of unique, functional VL regions of affinity matured humanized VEGF antibodies derived from hBDB-4G8.3. Amino acid residues of individual CDRs of each VL sequence are indicated in bold.





TABLE 39



List of Amino Acid Sequences of Affinity Matured

H4g8.3 VL Variants





Clone
SEQ ID NO:
VL



CL-27686
2085
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGXA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPFT FGQGTKLEIK



CL-27698
2086
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSRSGTDFTLTISSLEPEDFAVY



FC QQSWNDPFT FGQGTKLEIK



CL-27717
2087
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPFT FGQGAKLEIK



CL-27741
2088
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPFT FGLGTKLEIK



CL-27758
2089
EIVLTQFPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPFT FGQGTKLEIK



CL-27762
2090
EIVLTQSPATLSLSPGERATLSC RASQSVTPHMH WYQQKPGQA



PRLLIY GASTLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSCNDPFT FGQGTKLEIK



CL-27763
2091
EIVLTQSPATLSLSPGERATLSG RASESVDKYMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSRNDPLT FGQGTKLEIK



CL-27764
2092
EIVLTQSPATLSLSPGERATLSC RASQSVKTDMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSRNEPFT FGQGTKLEIK



CL-27765
2093
EIVLTQSPATLSLSPGERATLSC RASQSVSTHLA WYQQKPGQA



PRLLIY RASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQNWNDPLT FGQGTKLEIK



CL-27766
2094
EIVLTQSPATLSLSPGERATLSC RASQSVRTHMH WYQQKPGQA



PRLLIY GASALES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQGCNXPFT FGQGTKLEIK



CL-27767
2095
EIVLTQSPATLSLSPGERATLSC RASQSVRTHMH WYQQKPGQA



PRLLIY EASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSCNDPFT FGQGTKLEIK



CL-27768
2096
EIVLTQSPATLSLSPGERATLSC RASQSVSTDMH WYQQKPGQA



PRLLIY GASKLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPFT FGQGTKLEIK



CL-27770
2097
EIVLTQSPATLSLSPGERATLSC RASQSVSPHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTSNEPFT FGQGTKLEIK



CL-27771
2098
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASDLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSXIDPVT FGQGTKLEIK



CL-27772
2099
EIVLTQSPATPSLSPGERATLSC RASESVNAHMH WYQQKPGQA



PRLLIY DASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWSDPFT FGQGTKLEIK



CL-27773
2100
EIVLTQSPATLSLSPGERATLSC RASESVRTQLA WYQQKPGQA



PRLLIY SASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSRTEPFT FGQGTKLEIK



CL-27774
2101
EIVLTQSPATLSLSPGERATLSC RASQSVSTPMH WYQQKPGQA



PRLLIY SASNLES GIPARFSDSGSGTDFTLTISSLEPEDFAVY



YC QQFWDDPYT FGQGTKLEIK



CL-27775
2102
EIVLTQSPATLSLSPGERATLSC RASESVITHLA WYQQKPGQA



PRLLIY SASILES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQCCIDPFT FGQGTKLEIK



CL-27776
2103
EIVLTQSPATLSLSPGERATLSC RASQSVRSQLA WYQQKPGQA



PRLLIY VASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSXNDPFT FGQGTKLEIK



CL-27779
2104
EIVLTQSPATLSLSPGERATLSC RASESVRTHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWIDPFT FGQGTKLEIK



CL-27780
2105
EIVLTQSPATLSLSPGERATLSC RASESVSIHLA WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPFT FGQGTKLEIK



CL-27781
2106
EIVLTQSPATLSLSPGERATLSC RASQSVSTPMH WYQQKPGQA



PRLLIY GASYLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNEPYT FGQGTKLEIK



CL-27782
2107
EIVLTQSPATLSLSPGERATLSC RASESVSAHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWIYPFT FGQGTKLEIK



CL-27783
2108
EIVLTQSPATLSLSPGERATLSC RASQSVRTHMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGIDFTLTISSLEPEDFAVY



YC QQSXRYPFT FGQGTKLEIK



CL-27784
2109
EIVLTQSPATLSLSPGERATLSC RASQSVRTHMH WYQQKPGQA



PRLLIY RASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQRSNEPFT FGQGTKLEIK



CL-27785
2110
EIVLTQSPATLSLSPGERATLSC RASQSVRSHMH WYQQKPGQA



PRLLIY GASGLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQRWNEPST FGQGTKLEIK



CL-27786
2111
EIVLTQSPATLSLSPGERATLSC RASQSVRFHMH WYQQKPGQA



PRLLIY GASPLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSRRHPFT FGQGTKLEIK



CL-27787
2112
EIVLTQSPATLSLSPGERATLSC RASQSVSIQMH WYQQKPGQA



PRLLIY GASKLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQQWNVPFT FGQGTKLEIK



CL-27788
2113
EIVLTQSPATLSLSPGERATLSC RASQSVSTPMH WYQQKPGQA



PRLLIY RASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQGGNDPYT FGQGTKLEIK



CL-27790
2114
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY WASDLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQCWNGPLT FGQGTKLEIK



CL-27791
2115
EIVLTQSPATLSLSPGERATFSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGCGTDFTLTISSLEPEDFAVY



XC QQSGNDPFT FGQGTKLEIK



CL-27792
2116
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY RASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQGGNVPCT FGQGTKLEIK



CL-27794
2117
EIVLTQSPATLSLSPGERATLSC RASESVSWHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQIRADPFT FGQGTKLEIK



CL-27795
2118
EIVLTQSPATLSLSPGERATLSC RASESVCAHMH WYQQKPGQA



PRLLIY WASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSGLDPVT FGQGTKLEIK



CL-27796
2119
EIVLTQSPATLSLSPGERATLSC RASESVSTQMH WYQQKPGQA



PRLLIY GASILES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSGNNPFT FGQGTKLEIK



CL-27797
2120
EIVLTQSPATLSLSPGERATLSC RASQSVSTLMH WYQQKPGQA



PRLLIY RASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQGWNKPFT FGQGTKLEIK



CL-27798
2121
EIVLTQSPATLSLSPGERATLSC RASQSVTTHLA WYQQKPGQA



PRLLIY WASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSSKNPFT FGQGTKLEIK



CL-27799
2122
EIVLTQSPATLSLSPGERATLSC RASESVSXHMH WYQQKPGQA



PRLLIY WASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPPT FGQGTKLEIK



CL-27800
2123
EIVLTQSPATLSLSPGERATLSC RASQSVSSHLA WYQQKPGQA



PRLLIY GASKLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSSRDPFT FGQGTKLEIK



CL-27801
2124
EIVLTQSPATLSLSPGERATLSC RASQSVTTNMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQRWNDPFT FGQGTKLEIK



CL-27802
2125
EIVLTQSPATLSLSPGERATLSC RASQSVSTHLA WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQKSNXPFT FGQGTKLEIK



CL-27803
2126
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY RASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWKDPYT FGQGTKLEIK



CL-27805
2127
EIVLTQSPATLSLSPGERATLSC RASQSVSAHLA WYQQKPGQA



PRLLIY EASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNVPFT FGQGTKLEIK



CL-27806
2128
EIVLTQSPATLSLSPGERATLSC RASESVLILMH WYQQKPGQA



PRLLIY EASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSSNDPFT FGQGTKLEIK



CL-27807
2129
EIVLTQSPATLSLSPGERATLSC RASQSVSSLMH WYQQKPGQA



PRLLIY GASCLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQYXNDPYT FGQGTKLEIK



CL-27809
2130
EIVLTQSPATLSLSPGERATLSC RASQSVITHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQRWKFPFT FGQGTKLEIK



CL-27810
2131
EIVLTQSPATLSLSPGERATLSC RASESVSTQLA WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQNWNNPLT FGQGTKLEIK



CL-27811
2132
EIVLTQSPATLSLSPGERATLSC RASQSVSRDMH WYQQKPGQA



PRLLIY GASYLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQRWKEPFT FGQGTKLEIK



CL-27812
2133
EIVLTQSPATLSLSPGERATLSC RASQSVTTLMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQGCNDPLT FGQGTKLEIK



CL-27813
2134
EIVLTQSPATLSLSPGERATLSC RASESVVTHMH WYQQKPGQA



PRLLIY RASGLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWQHPFT FGQGTKLEIK



CL-27814
2135
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSGNDPCT FGQGTKLEIK



CL-27815
2136
EIVLTQSPATLSLSPGERATLSC RASQSVNSYLA WYQQKPGQA



PRLLIY WASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQAWNDPST FGQGTKLEIK



CL-27816
2137
EIVLTQSPATLSLSPGERATLSC RASQSVSNPMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPFT FGQGTKLEIK



CL-27818
2138
EIVLTQSPATLSLSPGERATLSC RASQSVSTLMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQGLTDPFT FGQGTKLEIK



CL-27819
2139
EIVLTQSPATLSLSPGERATLSC RASESVSPPLA WYQQKPGQA



PRLLIY GASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSENDPLT FGQGTKLEIK



CL-27820
2140
EIVLTQSPATLSLSPGERATLSC RASESVNTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWNHPFT FGQGTKLEIK



CL-27821
2141
EIVLTQSPATLSLSPGERATLSC RASESVSYPMH WYQQKPGQA



PRLLIY GASRLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQRWSDPFT FGQGTKLEIK



CL-27822
2142
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY IASFLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSXFEPST FGQGTKLEIK



CL-27823
2143
EIVLTQSPATLSLSPGERATLSC RASESVSTQMH WYQQKPGQA



PRLLIY GASYLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWKDPFT FGQGTKLEIK



CL-27824
2144
EIVLTQSPATLSLSPGERATLSC RASQSVSTKMH WYQQKPGQA



PRLLIY RASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWIDPFT FGQGTKLEIK



CL-27826
2145
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY RASYLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWKDPFT FGQGTKLEIK



CL-27827
2146
EIVLTQSPATLSLSPGERATLSC RASQSVMTHLA WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNEPFT FGQGTKLEIK



CL-27828
2147
EIVLTQSPATLSLSPGERATLSC RASQSVXTHLA WYQQKPGQA



PRLLIY GASKLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWQDPIT FGQGTKLEIK



CL-27833
2148
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY AASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



XX QQSWNDPFT FGQGTKLEIK



CL-27838
2149
EIVLTQSPATLSLSPGERATLSC RASQSVSSLMH WYQQKPGQA



PRLLIY VASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNYPFT FGQGTKLEIK



CL-27840
2150
EIVLTQSPATLSLSPGERATLSC RASQSVITPLA WYQQKPGQA



PRLLIY GASRLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQIWNDPFT FGQGTKLEIK



CL-27841
2151
EIVLTQSPATLSLSPGERATLSC RASQSVSPLLA WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQRWNEPFT FGQGTKLEIK



CL-27842
2152
EIVLTQSPATLSLSPGERATLSC RASQSVNPHLA WYQQKPGQA



PRLLIY WASSLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQNWNDPFT FGQGTKLEIK



CL-27843
2153
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASRLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQGWNYPFT FGQGTKLEIK



CL-27844
2154
EIVLTQSPATLSLSPGERATLSC RASQSVSTRMH WYQQKPGQA



PRLLIY GASYLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTRYDPFT FGQGTKLEIK



CL-27845
2155
EIVLTQSPATLSLSPGERATLSC RASESVSSHMH WYQQKPGQA



PRLLIY GASRLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPFT FGQGTKLEIK



CL-27846
2156
EIVLTQSPATLSLSPGERATLSC RASQSVTTHMH WYQQKPGQA



PRLLIY AASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNHPFT FGQGTKLEIK



CL-27847
2157
EIVLTQSPATLSLSPGERATLSC RASQSVKTQLA WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQRCNGPFT FGQGTKLEIK



CL-27848
2158
EIVLTQSPATLSLSPGERATLSC RASQSVSTQLA WYQQKPGQA



PRLLIY GASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTGNDPFT FGQGTKLEIK



CL-27849
2159
EIVLTQSPATLSLSPGERATLSC RASESVSPLMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWKDPFT FGQGTKLEIK



CL-27850
2160
EIVLTQSPATLSLSPGERATLSC RASESVSAHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQWWNNPFT FGQGTKLEIK



CL-27851
2161
EIVLTQSPATLSLSPGERATLSC RASQSVNTHMH WYQQKPGQA



PRLLIY RASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNEPLT FGQGTKLEIK



CL-29979
2162
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWQDPLT FGQGTKLEIK



CL-29980
2163
EIVLTQSPATLSLSPGERATLSC RASQSVNTNMH WYQQKPGQA



PRLLIY GASILES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWNVPFT FGQGTKLEIK



CL-29981
2164
EIVLTQSPATLSLSPGERATLSC RASESVSTAMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWNVPIT FGQGTKLEIK



CL-29982
2165
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASMLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-29983
2166
EIVLTQSPATLSLSPGERATLSC RASESVNDHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNNPIT FGQGTKLEIK



CL-29984
2167
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASYLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPLT FGQGTKLEIK



CL-29985
2168
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWDDPIT FGQGTKLEIK



CL-29986
2169
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSFLDPIT FGQGTKLEIK



CL-29987
2170
EIVLTQSPATLSLSPGERATLSC RASESVSTNMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQGWSDPLT FGQGTKLEIK



CL-29988
2171
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWIDPLT FGQGTKLEIK



CL-29989
2172
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWIDPIT FGQGTKLEIK



CL-29990
2173
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGCGTDFTLTISSLEPEDFAVY



FC QQSWHDPLT FGQGTKLEIK



CL-29991
2174
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWDDPIT FGQGTKLEIK



CL-29992
2175
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASELES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWNDPIT FGQGTKLEIK



CL-29993
2176
EIVLTQSPATLSLSPGERATLSC RASESVNTLMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWNEPIT FGQGTKLEIK



CL-29994
2177
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWSDPLT FGQGTKLEIK



CL-29995
2178
EIVLTQSPATLSLSPGERATLSC RASQSVSKHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNNPIT FGQGTKLEIK



CL-29996
2179
EIVLTQSPATLSLSPGERATLSC RASQSVDTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWHDPIT FGQGTKLEIK



CL-29997
2180
EIVLTQSPATLSLSPGERATLSC RASESVSNHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWTDPLT FGQGTKLEIK



CL-29998
2181
EIVLTQSPATLSLSPGERATLSC RASQSVSSHMH WYQQKPGQA



PRLLIY GASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPLT FGQGTKLEIK



CL-29999
2182
EIVLTQSPATLSLSPGERATLSC RASESVSTNMH WYQQKPGQA



PRLLIY AASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNEPFT FGQGTKLEIK



CL-30000
2183
EIVLTQSPATLSLSPGERATLSC RASQSVDTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWGDPLT FGQGTKLEIK



CL-30001
2184
EIVLTQSPATLSLSPGERATLSC RASESVSNNLA WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWNDPIT FGQGTKLEIK



CL-30002
2185
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPIT FGQGTKLEIK



CL-30003
2186
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNEPWT FGQGTKLEIK



CL-30004
2187
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASKLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWIDPLT FGQGTKLEIK



CL-30005
2188
EIVLTQSPATLSLSPGERATLSC RASQSVGNNMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30006
2189
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFGGSGSGTDFTLTISSLEPEDFAVY



YC QQSWTDPLT FGQGTKLEIK



CL-30007
2190
EIVLTQSPATLSLSPGERATLSC RASESVYTXLA WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQILNDPFT FGQGTKLEIK



CL-30009
2191
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30010
2192
EIVLTQSPATLSLSPGERATLSC RASQSVGTNMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPIT FGQGTKLEIK



CL-30011
2193
EIVLTQSPATLSLSPGERATLSC RASESVATHMH WYQQKPGQA



PRLLIY GASYLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30012
2194
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30013
2195
EIVLTQSPATLSLSPGERATLSC RASESVMNHLA WYQQKPGQA



PRLLIY GASYLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWSDPLT FGQGTKLEIK



CL-30014
2196
EIVLTQSPATLSLSPGERATLSC RASQSVGTSMH WYQQKPGQA



PRLLIY AASELES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPFT FGQGTKLEIK



CL-30015
2197
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPLT FGQGTKLEIK



CL-30017
2198
EIVLTQSPATLSLSPGERATLSC RASESVSNNMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWSDPFT FGQGTKLEIK



CL-30018
2199
EIVLTQSPATLSLSPGERATLSC RASQSVSSHMH WYQQKPGQA



PRLLIY GASKLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSFSDPIT FGQGTKLEIK



CL-30019
2200
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWSDPLT FGQGTKLEIK



CL-30020
2201
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30021
2202
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNPPIT FGQGTKLEIK



CL-30022
2203
EIVLTQSPATLSLSPGERATLSC RASESVSNHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNEPFT FGQGTKLEIK



CL-30023
2204
EIVLTQSPATLSLSPGERATLSC RASQSVGTNMH WYQQKPGQA



PRLLIY GASILES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWNEPIT FGQGTKLEIK



CL-30024
2205
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPVT FGQGTKLEIK



CL-30025
2206
EIVLTQSPATLSLSPGERATLSC RASESVGTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWNDPLT FGQGTKLEIK



CL-30026
2207
EIVLTQSPATLSLSPGERATLSC RASQSVSSHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-30027
2208
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-30028
2209
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWSDPLT FGQGTKLEIK



CL-30029
2210
EIVLTQSPATLSLSPGERATLSC RASESVSTHMN WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNVPYT FGQGTKLEIK



CL-30030
2211
EIVLTQSPATLSLSPGERATLSC RASESVTSNMH WYQQKPGQA



PRLLIY AASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWQNPIT FGQGTKLEIK



CL-30031
2212
EIVLTQSPATLSLSPGERATLSC RASESVSDHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWTDPLT FGQGTKLEIK



CL-30032
2213
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30033
2214
EIVLTQSPATLSLSPGERATLSC RASESVSNYMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWTDPLT FGQGTKLEIK



CL-30034
2215
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASILES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWNDPIT FGQGTKLEIK



CL-30035
2216
EIVLTQSPATLSLSPGERATLSC RASQSVGTAMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWDAPFT FGQGTKLEIK



CL-30036
2217
EIVLTQSPATLSLSPGERATLSC RASQSVRSHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWTPPIT FGQGTKLEIK



CL-30037
2218
EIVLTQSPATLSLSPGERATLSC RASESVSTSMN WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWKDPIT FGQGTKLEIK



CL-30038
2219
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNVPWT FGQGTKLEIK



CL-30039
2220
EIVLTQSPATLSLSPGERATLSC RASESVSNSMH WYQQKPGQA



PRLLIY GASTLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWTDPLT FGQGTKLEIK



CL-30040
2221
EIVLTQSPATLSLSPGERATLSC RASESVGTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWNDPST FGQGTKLEIK



CL-30041
2222
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30042
2223
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASTLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWSDPLT FGQGTKLEIK



CL-30043
2224
EIVLTQSPATLSLSPGERATLSC RASESVDSNMH WYQQKPGQA



PRLLIY RASILES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWGDPIT FGQGTKLEIK



CL-30044
2225
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASYLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30045
2226
EIVLTQSPATLSLSPGERATLSC RASESVSNHMH WYQQKPGQA



PRLLIY GASYLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30046
2227
EIVLTQSPATLSLSPGERATLSC RASESVSDHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWTDPLT FGQGTKLEIK



CL-30047
2228
EIVLTQSPATLSLSPGERATLSC RASESVGTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30048
2229
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWSDPLT FGQGTKLEIK



CL-30049
2230
EIVLTQSPATLSLSPGERATLSC RASESVNTHLA WYQQKPGQA



PRLLIY GASMLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWSLPYT FGQGTKLEIK



CL-30050
2231
EIVLTQSPATLSLSPGERATLSC RASQSVSSHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30053
2232
EIVLTQSPATLSLSPGERATLSC RASESVSTHMN WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPFT FGQGTKLEIK



CL-30054
2233
EIVLTQSPATLSLSPGERATLSC RASESVGTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNEPYT FGQGTKLEIK



CL-30055
2234
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWGDPIT FGQGTKLEIK



CL-30056
2235
EIVLTQSPATLSLSPGERATLSC RASQSVSTNMH WYQQKPGQA



PRLLIY AASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWNEPIT FGQGTKLEIK



CL-30057
2236
EIVLTQSPATLSLSPGERATLSC RASESVGKHMH WYQQKPGQA



PRLLIY GASKLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWNDPIT FGQGTKLEIK



CL-30058
2237
EIVLTQSPATLSLSPGERATLSC RASESVSNHMH WYQQKPGQA



PRLLIY GASFLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWTNPIT FGQGTKLEIK



CL-30059
2238
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWDDPLT FGQGTKLEIK



CL-30060
2239
EIVLTQSPATLSLSPGERATLSC RASESVGTHMH WYQQKPGQA



PRLLIY GASYLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWTDPIT FGQGTKLEIK



CL-30061
2240
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWIDPIT FGQGTKLEIK



CL-30062
2241
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASKLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPIT FGQGTKLEIK



CL-30063
2242
EIVLTQSPATLSLSPGERATLSC RASESVCTRMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPYT FGQGTKLEIK



CL-30064
2243
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTFDDPLT FGQGTKLEIK



CL-30066
2244
EIVLTQSPATLSLSPGERATLSC RASQSVGDSLA WYQQKPGQA



PRLLIY AASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWNVPIT FGQGTKLEIK



CL-30067
2245
EIVLTQSPATLSLSPGERATLSC RASESVANHLA WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPIT FGQGTKLEIK



CL-30068
2246
EIVLTQSPATLSLSPGERATLSC RASESVSTHMN WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQGWYDPLT FGQGTKLEIK



CL-30069
2247
EIVLTQSPATLSLSPGERATLSC RASESVSSHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPIT FGQGTKLEIK



CL-30070
2248
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNVPFT FGQGTKLEIK



CL-30071
2249
EIVLTQSPATLSLSPGERATLSC RASESVNKHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWIDPFT FGQGTKLEIK



CL-30072
2250
EIVLTQSPATLSLSPGERATLSC RASQSVGNHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNMPIT FGQGTKLEIK



CL-30073
2251
EIVLTQSPATLSLSPGERATLSC RASESVGEHMH WYQQKPGQA



PRLLIY AASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-30074
2252
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWDVPLT FGQGTKLEIK



CL-30078
2253
ENVLTQSPATLSLSPGERATLSC RASESVITHMN WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPFT FGQGTKLEIK



CL-30090
2254
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-30095
2255
EIVLTQSPATLSLSPGERATLSC RASESVSNHMH WYQQKPGQA



PRLLIY GASELES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWSDPLT FGQGTKLEIK



CL-30098
2256
EIVLTQSPATLSLSPGERATLSC RASQSVDTHMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWIDPIT FGQGTKLEIK



CL-30099
2257
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWIDPLT FGQGTKLEIK



CL-30103
2258
EIVLTQSPATPSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPFT FGQGTKLEIK



CL-30104
2259
EIVLTQSPATLSLSPGERATLSC RASESVSSHMH WYQQKPGQA



PRLLIY GASILES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWNDPIT FGQGTKLEIK



CL-30106
2260
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30109
2261
EIVLTQSPATLSLSPGERATLSC RASQSVITHMN WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWNDPIT FGQGTKLEIK



CL-30115
2262
EIVLTQSPATLSLSPGERATLSC RASESVQTHMN WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPFT FGQGTKLEIK



CL-30120
2263
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY AASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-30121
2264
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPLT FGQGTKLEIK



CL-30123
2265
EIVLTQSPATLSLSPGERATLSC RASESVITHMN WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWDNPIT FGQGTKLEIK



CL-30126
2266
EIVLTQSPATLSLSPGERATLSC RASQSVHKHMN WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQGWDDPLT FGQGTKLEIK



CL-30128
2267
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30131
2268
EIVLTQSPATLSLSPGERATLSC RASESVLTHMN WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWYEPWT FGQGTKLEIK



CL-30132
2269
EIVLTQSPATLSLSPGERATLSC RASESVDTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPIT FGQGTKLEIK



CL-30133
2270
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWSDPIT FGQGTKLEIK



CL-30134
2271
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMN WYQQKPGQA



PRLLIY GASFLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWSDPIT FGQGTKLEIK



CL-30135
2272
EIVLTQSPATLSLSPGERATLSC RASQSVGTPMH WYQQKPGQA



PRLLIY GASTLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-30137
2273
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASYLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPIT FGQGTKLEIK



CL-30143
2274
EIVLTQSPATLSLSPGERATLSC RASESVDTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPIT FGQGTKLEIK



CL-30144
2275
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASMLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWTDPIT FGQGTKLEIK



CL-30147
2276
EIVLTQSPATLSLXPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLEY GVPARFSGSGCGTDFTLTISSIEHEDFAVY



FC QQSWNDPFT FGQGTKLEIK



CL-30150
2277
EIVLTQSPATLSLSPGERATLSC RASQSVANHLA WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWTDPIT FGQGTKLEIK



CL-30152
2278
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASMLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNNPIT FGQGTKLEIK



CL-30155
2279
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY AASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWDDPLT FGQGTKLEIK



CL-30158
2280
EIVLTQSPATLSLSPGERVTLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPIT FGQGTKLEIK



CL-30160
2281
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY AASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30163
2282
EIVLTQSPATLSLSPGERATLSC RASQSVSSHMH WYQQKPGQA



PRLLIY AASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-30164
2283
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWMDPIT FGQGTKLEIK



CL-30166
2284
EIVLTQSPATLSLSPGERATLSC RASESVSTNMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWSEPWT FGQGTKLEIK



CL-30167
2285
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWSDPLT FGQGTKLEIK



CL-30593
2286
EIVLTQSPATLSLSPGERATLSC RASQSVDTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-30594
2287
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNEPFT FGQGTKLEIK



CL-30595
2288
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPIT FGQGTKLEIK



CL-30597
2289
EIVLTQSPATLSLSPGERATLSC RASESVSNHMH WYQQKPGQA



PRLLIY GASTLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30598
2290
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASVLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWDDPLT FGQGTKLEIK



CL-30600
2291
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWLDPIT FGQGTKLEIK



CL-30601
2292
EIVLTQSPATLSLSPGERATLSC RASQSVNTHLA WYQQKPGQA



PRLLIY AASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWTDPLT FGQGTKLEIK



CL-30602
2293
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWSDPLT FGQGTKLEIK



CL-30604
2294
EIVLTQSPATLSLSPGERATLSC RASQSVSNPMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNXPFT FGQGTKLEIK



CL-30606
2295
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWDDPFT FGQGTKLEIK



CL-30608
2296
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWSDPLT FGQGTKLEIK



CL-30609
2297
EIVLTQSPATLSLSPGERATLSC RASESVNSNMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-30610
2298
EIVLTQSPATLSLSPGERATLSC RASQSVRNHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWDDPLT FGQGTKLEIK



CL-30611
2299
EIVLTQSPATLSLSPGERATLSC RASESVSNHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWDDPLT FGQGTKLEIK



CL-30613
2300
EIVLTQSPATLSLSPGERATLSC RASQSVNTAMH WYQQKPGQA



PRLLIY GASSLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30614
2301
EIVLTQSPATLSLSPGERATLSC RASESVGSHMH WYQQKPGQA



PRLLIY GASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNLPLT FGQGTKLEIK



CL-30615
2302
EIVLTQSPATLSLSPGERATLSC RASESVSNHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPIT FGQGTKLEIK



CL-30616
2303
EIVLTQSPATLSLSPGERATLSC RASQSVITHMN WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWGDPWT FGQGTKLEIK



CL-30617
2304
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWIDPLT FGQGTKLEIK



CL-30618
2305
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASMLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWDDPLT FGQGTKLEIK



CL-30619
2306
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY AASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPIT FGQGTKLEIK



CL-30620
2307
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPIT FGQGTKLEIK



CL-30624
2308
EIVLTQSPATPSLSPGERATLSC RASESVGSCMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWYDPLT FGQGTKLEIK



CL-30626
2309
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPLT FGQGTKLEIK



CL-30627
2310
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30628
2311
EIVLTQSPATLSLSPGERATLSC RASESVSRHMH WYQQKPGQA



PRLLIY GASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNNPLT FGQGTKLEIK



CL-30629
2312
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPAT FGQGTKLEIK



CL-30630
2313
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30631
2314
EIVLTQSPATLSLSPGERATLSC RASQSVGRHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWTDPLT FGQGTKLEIK



CL-30632
2315
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWSDPIT FGQGTKLEIK



CL-30634
2316
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30635
2317
EIVLTQSPATLSLSPGERATLSC RASESVSSNMN WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSFYDPIT FGQGTKLEIK



CL-30636
2318
EIVLTQSPATLSLSPGERATLSC RASESVSSHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWSDPLT FGQGTKLEIK



CL-30637
2319
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWHDPLT FGQGTKLEIK



CL-30638
2320
EIVLTQSPATLSLSPGERATLSC RASESVSNHMH WYQQKPGQA



PRLLIY AASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWIDPIT FGQGTKLEIK



CL-30639
2321
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWTDPLT FGQGTKLEIK



CL-30640
2322
EIVLTQSPATLSLSPGERATLSC RASESVRSHLA WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSIEPEDFAVY



FC QQSWNAPFT FGQGTKLEIK



CL-30641
2323
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWSDPLT FGQGTKLEIK



CL-30642
2324
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASILES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWDDPIT FGQGTKLEIK



CL-30643
2325
EIVLTQSPATLSLSPGERATLSC RASESVSNHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNEPLT FGQGTKLEIK



CL-30644
2326
EIVLTQSPATLSLSPGERATLSC RASESVSTHMP WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30645
2327
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWSDPLT FGQGTKLEIK



CL-30647
2328
EIVLTQSPATLSLSPGERATLSC RASQSVSTAMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWFDPLT FGQGTKLEIK



CL-30648
2329
EIVLTQSPATLSLSPGERATLSC RASESVSNHMH WYQQKPGQA



PRLLIY GASILES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWSDPIT FGQGTKLEIK



CL-30649
2330
EIVLTQSPATLSLSPGERATLSC RASESVNSDMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-30650
2331
EIVLTQSPATLSLSPGERATLSC RASESVSNHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNVPIT FGQGTKLEIK



CL-30651
2332
EIVLTQSPATLSLSPGERATLSC RASESVSTNLA WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWNDPIT FGQGTKLEIK



CL-30653
2333
EIVLTQSPATLSLSPGERATLSC RASESVSNHMH WYQQKPGQA



PRLLIY AASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWTDPIT FGQGTKLEIK



CL-30654
2334
EIVLTQSPATLSLSPGERATLSC RASESVSTHMN WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWTDPIT FGQGTKLEIK



CL-30655
2335
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWDVPFT FGQGTKLEIK



CL-30657
2336
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWSDPIT FGQGTKLEIK



CL-30658
2337
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQCRNDPFT FGQGTKLEIK



CL-30659
2338
EIVLTQSPATLSLSPGERATLSC RASESVSKHMN WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWTDPLT FGQGTKLEIK



CL-30660
2339
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASRLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30662
2340
EIVLTQSPATLSLSPGERATLSC RASESVGTHMH WYQQKPGQA



PRLLIY GASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWDDPLT FGQGTKLEIK



CL-30663
2341
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNEPYT FGQGTKLEIK



CL-30664
2342
EIVLTQSPATLSLSPGERATLSC RASESVGMHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30665
2343
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMN WYQQKPGQA



PRLLIY AASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSFNNPLT FGQGTKLEIK



CL-30666
2344
EIVLTQSPATLSLSPGERATLSC RASQSVNTHLH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWFDPLT FGQGTKLEIK



CL-30667
2345
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPLT FGQGTKLEIK



CL-30669
2346
EIVLTQSPATLSLSPGERATLSC RASESVSNHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-30670
2347
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWLDPLT FGQGTKLEIK



CL-30671
2348
EIVLTQSPATLSLSPGERATLSC RASESVSNHMH WYQQKPGQA



PRLLIY GASILES GVLARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30672
2349
EIVLTQSPATLSLSPGERATLSC RASESVSSHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWNYPIT FGQGTKLEIK



CL-30673
2350
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPIT FGQGTKLEIK



CL-30674
2351
EIVLTQSPATLSLSPGERATLSC RASESVGNHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWIDPLT FGQGTKLEIK



CL-30675
2352
EIVLTQSPATLSLSPGERATLSC RASESVSNHMH WYQQKPGQA



PRLLIY AASKLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWVEPFT FGQGTKLEIK



CL-30676
2353
EIVLTQSPATLSLSPGERATLSC RASQSVETHMH WYQQKPGQA



PRLLIY GASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWRDPLT FGQGTKLEIK



CL-30677
2354
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMN WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWDDPLT FGQGTKLEIK



CL-30678
2355
EIVLTQSPATLSLSPGERATLSC RASQSVGSSMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPLT FGQGTKLEIK



CL-30679
2356
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30681
2357
EIVLTQSPATLSLSPGERATLSC RASQSVTNHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWHDPLT FGQGTKLEIK



CL-30682
2358
EIVLTQSPATLSLSPGERATLSC RASESVSSHLA WYQQKPGQA



PRLLIY GASTLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWGDPFT FGQGTKLEIK



CL-30683
2359
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWSDPLT FGQGTKLEIK



CL-30684
2360
EIVLTQSPATLSLSPGERATLSC RASESVHDHMH WYQQKPGQA



PRLLIY AASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPLT FGQGTKLEIK



CL-30685
2361
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWADPLT FGQGTKLEIK



CL-34444
2362
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASILES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34445
2363
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPFT FGQGTKLEIK



CL-34446
2364
EIVLTQSPATLSLSPGERATLSC RASESVSNHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSFYDPLT FGQGTKLEIK



CL-34447
2365
EIVLTQSPATLSLSPGERATLSC RASESVGTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34448
2366
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASMLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWMDPIT FGQGTKLEIK



CL-34450
2367
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWMDPLT FGQGTKLEIK



CL-34451
2368
EIVLTQSPATLSLSPGERATLSC RASESVSNHMH WYQQKPGQA



PRLLIY GASILES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34452
2369
EIVLTQSPATLSLSPGERATLSC RASESVGTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWHDPLT FGQGTKLEIK



CL-34453
2370
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSFTNPLT FGQGTKLEIK



CL-34454
2371
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34457
2372
EIVLTQSPATLSLSPGERATLSC RASXSVNTHMH WYQQKPGQA



PRLLIY GASXLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQXWYDPIT FGQGTKLEIK



CL-34458
2373
EIVLTQSPATLSLSPGERATLSC RASESVRTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34459
2374
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-34460
2375
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34461
2376
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34462
2377
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASVLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34464
2378
EIVLTQSPATLSLSPGERATLSC RASQSVSRHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPIT FGQGTKLEIK



CL-34465
2379
EIVLTQSPATLSLSPGERATLSC RASQSVSSHMH WYQQKPGQA



PRLLIY GASILES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWDDPIT FGQGTKLEIK



CL-34467
2380
EIVLTQSPATLSLSPGERATLSC RASESVSTSMH WYQQKPGQA



PRLLIY GASQLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNVPFT FGQGTKLEIK



CL-34468
2381
EIVLTQSPATLSLSPGERATLSC RASESVGTHMH WYQQKPGQA



PRLLIY GASRLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWTVPLT FGQGTKLEIK



CL-34472
2382
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-34473
2383
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASVLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-34474
2384
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASTLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-34478
2385
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASYLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWYDPLT FGQGTKLEIK



CL-34479
2386
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASTLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-34480
2387
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34481
2388
EIVLTQSPATLSLSPGERATLSC RASQSVNNHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34482
2389
EIVLTQSPATLSLSPGERATLSC RASQSVGEHMH WYQQKPGQA



PRLLIY GASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPIT FGQGTKLEIK



CL-34485
2390
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-34487
2391
EIVLTQSPATLSLSPGERATLSC RASQSVSTNMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWYDPIT FGQGTKLEIK



CL-34488
2392
EIVLTQSPATLSLSPGERATLSC RASESVGTHMH WYQQKPGQA



PRLLIY GASTLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34490
2393
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-34494
2394
EIVLTQSPATLSLSPGERATLSC RASQSVGSHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPIT FGQGTKLEIK



CL-34496
2395
EIVLTQSPATLSLSPGERATLSC RASQSVGNHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-34498
2396
EIVLTQSPATLSLSPGERATLSC RASESVGTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-34499
2397
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPIT FGQGTKLEIK



CL-34500
2398
EIVLTQSPATLSLSPGERATLSC RASESVGTHMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPIT FGQGTKLEIK



CL-34502
2399
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34504
2400
EIVLTQSPATLSLSPGERATLSC RASESVSRHMN WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWYDPIT FGQGTNLEIK



CL-34505
2401
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASYLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPIT FGQGTKLEIK



CL-34506
2402
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPIT FGQGTKLEIK



CL-34508
2403
EIVLTQSPATLSLSPGERATLSC RASESVDTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34509
2404
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPIT FGQGTKLEIK



CL-34511
2405
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34512
2406
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34514
2407
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASILES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34515
2408
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWYDPIT FGQGTKLEIK



CL-34517
2409
EIVLTQSPATLSLSPGERATLSC RASESVGTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34520
2410
EIVLTQSPATLSLSPGERATLSC RASESVGTHMH WYQQKPGQA



PRLLIY GASILES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-34521
2411
EIVLTQSPATLSLSPGERATLSC RASESVDRHMH WYQQKPGQA



PRLLIY GASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-34523
2412
EIVLTQSPATLSLSPGERATLSC RASQSVTNHMH WYQQKPGQA



PRLLIY GASVLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34524
2413
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPIT FGQGTKLEIK



CL-34525
2414
EIVLTQSPATLSLSPGERATLSC RASESVSNHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPIT FGQGTKLEIK



CL-34526
2415
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-34529
2416
EIVLTQSPATLYLXPGERATLSC RASQSVSTHMH WYQQKPGQA



ARLVMY GASNLEF GVPARFSGSGSGTEFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34533
2417
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPIT FGQGTKLEIK



CL-34534
2418
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34536
2419
EIVLTQSPATLSLSPGERATLSC RASQSVGAHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-34539
2420
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWSDPLT FGQGTKLEIK



CL-34541
2421
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASILES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPIT FGQGTKLEIK



CL-34548
2422
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34556
2423
EIVLTQSPATLSLSPGERATLSC RASESVSXHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34558
2424
EIVLTQSPATLSLSPGERATLSC RASESVSTAMH WYQQKPGQA



PRLLIY AASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34561
2425
EIVLTQSPATLSLSPGERATLSC RASESVGTHMH WYQQKPGQA



PRLLIY GASYLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPIT FGQGTKLEIK



CL-34562
2426
EIVLTQSPATLSLSPGERATLSC RASQSVGSHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-34563
2427
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-34566
2428
EIVLTQSPATLSLSPGERATLSC RASQSVGTNMH WYQQKPGQA



PRLLIY GASVLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWYDPIT FGQGTKLEIK



CL-34568
2429
EIVLTQSPATLSLSPGERATLSC RASESVGKHMH WYQQKPGQA



PRLLIY GASHLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWMDPLT FGQGTKLEIK



CL-34573
2430
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASFLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34574
2431
EIVLTQSPATLSLSPGERATLSC RASESVGTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWGDPLT FGQGTKLEIK



CL-34577
2432
EIVLTQSPATLSLSPGERATLSC RASESVSKHMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34580
2433
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASMLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWDDPLT FGQGTKLEIK



CL-34582
2434
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34585
2435
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-34586
2436
EIVLTQSPATLSLSPGERATLSC RASQSVXXHMH WYQQKPGQA



PRLLIY GASTLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWTDPXT FGQGTKLEIK



CL-34587
2437
EIVLTQSPATLSLSPGERATLSC RASESVSTHLH WYQQKPGQA



PRLLIY GASILES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34590
2438
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34591
2439
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPIT FGQGTKLEIK



CL-34592
2440
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPIT FGQGTKLEIK



CL-34593
2441
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASMLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34594
2442
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPIT FGQGTKLEIK



CL-34598
2443
EIVLTQSPATLSLSPGERATLSC RASQSVSNHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWIEPYT FGQGTKLEIK



CL-34599
2444
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPIT FGQGTKLEIK



CL-34600
2445
EIVLTQSPATLSLSPGERATLSC RASESVNTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWNDPFT FGQGTKLEIK



CL-34601
2446
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASILES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-34602
2447
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPGT FGQGTKLEIK



CL-34604
2448
EIVLTQSPATLSLSPGERATLSC RASQSVNNHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-34610
2449
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-34612
2450
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMQ WYQQKPGQA



PRLLIY GASILES GIPARFSGSGSGTDFTLTISSLEHEDFAVY



XC QQSWYDPLT FGQGTKLEIK



CL-34613
2451
EIVLTQSPATLSLSPGERATLSC RASESVGRHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWYDPIT FGQGTKLEIK



CL-34614
2452
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASYLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-34617
2453
EIVLTQSPATLSLSPGERATLSC RASESVDSSMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-34618
2454
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPIT FGQGTKLEIK



CL-40245
2455
EIVLTQSPATLSLSPGERAALSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-40250
2456
EIVLTQSPATLSLSPGERATLSYRASQSVGTHMHWYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-40251
2457
EIVLTQSPGTLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-40253
2458
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGADFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-40255
2459
EIVLTQSPGTLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-40258
2460
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASHPES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-40266
2461
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPMT FGQGTKLEIK



CL-40271
2462
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLGSN



CL-40272
2463
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLRSN



CL-40283
2464
EIVLTQSPGTLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPMT FGQGTKLEIK



CL-40284
2465
EIVLTQSPATLSLSPGERAILSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLA FGQGTKLEIK



CL-40286
2466
EIVLPQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLEP GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPFT FGQGTKLEIK



CL-40287
2467
EIVLTQSPGTLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPFT FGQGTKLEIK



CL-40288
2468
EIVLTQSPGTLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-40299
2469
RNCVTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-40302
2470
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWCDPLT FGQGTKLEIK



CL-40303
2471
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLPIYGASNLESGVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-40317
2472
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLGPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-40324
2473
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-40327
2474
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPMT FGQGTKLEIK



CL-40328
2475
EIVLTQSPGTLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-40331
2476
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQRTKLEIK



CL-40332
2477
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPMA FGQGTKLEIK



CL-40335
2478
RNCVDKSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASHLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-40336
2479
EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-40337
2480
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QRSWYDPLT FGQGTKLEIK



CL-40338
2481
EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWNDPFT FGQGTKLEIK



CL-40339
2482
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-40341
2483
EIVLTQSPATLSLSPGERATLFC RASQSVSNHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFVVY



YC QQSWYDPIT FGQGTKLEIK



CL-40342
2484
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTCYDPLT FGQGTKLEIK



CL-40350
2485
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGADFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-40356
2486
EIVLTQSPATLSLSPGERATLSC RASESVGKHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWYDPIT FGQGTKLEIK



CL-40357
2487
EIVLTQSPATLSLSPGERATLFC RASQSVSNHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-40364
2488
EIVLTQSPGTLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSFYDPLT FGQGTKLEIK



CL-40367
2489
EIVLTQSPGTLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWYDPLT FGQGTKLEIK



CL-40370
2490
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFILTISSLEPEDFAVY



YC QQSFYDPLT FGQGTKLEIK



CL-40373
2491
EIVLTQSPGTLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-40381
2492
EIVLTQSPGTLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAIY



FC QQTWYDPLT FGQGTKLEIK



CL-40382
2493
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGIDFTLTISSLEPEDFAVY



FC QQTWYDPLT FGQGTKLEIK



CL-40390
2494
EIVLTQSPATLSLSPGERATLSC RASGSVGKHMH WYQQKPGQA



PRLLIY AASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-40394
2495
EIVLTQSPGTLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEEFAVY



FC QQTWYDPLT FGQGTKLEIK



CL-40399
2496
EIVLTQSPATLSLSPGERATLSC RASQSVSKHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDSTLTISSLEPEDFAVY



FC QQTWYDPIT FGQGTKLEIK



CL-40408
2497
EIVLTQSPATLSLPPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSFYDPLT FGQGTKLEIK



CL-40414
2498
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFGGSGSGTDFTLTISSLEPEDFAVY



YC QQSFYDPLT FGQGTKLEIK



CL-40426
2499
EIVSTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTIGSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-40440
2500
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTNLEIK



CL-40441
2501
EIVLTQSPATLSLSPGERATFSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-40443
2502
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAAY



FC QQTWYDPLT FGQGTKLEIK



CL-40445
2503
EIVLTQSPSTLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWYDPLT FGQGTKLEIK



CL-40447
2504
EIVLTQSPATLSLSPGERATLSC RASQSVNNHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIX



CL-40453
2505
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMHWCQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWYDPLT FGQGTKLEIK



CL-40463
2506
EIVLTQSPGTLSLSPGERATLSC RASQSVNNHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-40466
2507
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-40470
2508
EIVLTQSPGTLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-40472
2509
EIVLTQSPATLSLSPGERATLSC RASQSVNNHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-40476
2510
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLRSN



CL-40479
2511
EIVLTQSPATLSLSPGERATLSC RASQSVATHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLRSN



CL-40480
2512
EIVLTQSPGTLSLSPGERATLSC RASQSVSTHMH WYQQEPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-40484
2513
EIVLTQSPGTLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-40485
2514
RNLLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWYDPLT FGQGTKLEIK



CL-40489
2515
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWYDPLT FGQGTKLVIK



CL-40494
2516
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGADFTLTISSLEPEDFAVY



FC QQTWYDPLT FGQGTKLEIK



CL-40498
2517
EIVLTQSPATLSLSPGERATLSC RASQSVNNHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSRYDPLT FGQGTKLEIK



CL-40503
2518
EIVLTQSPGTLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWYDPLT FGQGTKLEIK



CL-40505
2519
EIVLTQSPGTLSLSPGERATLSC RASQSVATHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-40511
2520
AIVLTQSPATLSLSPGERATLSC RASQSVATHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-40526
2521
EIVLTQSPAALSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWYDPLT FGQGTKLEIK



CL-40531
2522
EIVLTQSPATLSLSPGERATLSC RASQSVNNHMH WYQQKPGQA



PRLLIY GASIPES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-41836
2523
AIVLTQSPGTLSLSPGERATLSC RASQSVATHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-41845
2524
EIVLTQSPATLSLSPGERATLSC RASQSVNNHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-41849
2525
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASKLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-41850
2526
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK



CL-41852
2527
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-41854
2528
EIVLTQSPATLSLSPGERATLSC RASQSVATHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-41855
2529
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWYDPLT FGQGTKLEIK



CL-41885
2530
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTITSLEPEDFAVY



FC XQTWYDPLT FGQGTKLEIK



CL-41886
2531
EIVLTQSPATLSLSPGERATLFC RASQSVSNHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPIT FGQGTKLRSN



CL-41888
2532
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-41920
2533
EIVLTQSPGTLSLSPGERASLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSFYDPLT FGRGTKLEIK



CL-41923
2534
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIN



CL-41928
2535
EIVLTQSPATLSLSPGERATLSC RTSESVGKHMH WYQQKPGQA



PRLLIY AASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-41938
2536
EIVLTQSPATLSLSPGERATLSC RASESVGKHMH WYQQKPGQA



PRLLIY AASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPLT FGQGTKLEIK



CL-41940
2537
EIVLTQSPATLSLSPGERATLFC RASQSVSNHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSWYDPIT FGQGTKLEIK



CL-41941
2538
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASILES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWYDPLT FGQGTKLEIK



CL-41947
2539
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSFYDPLT FGQGTKLEIQ



CL-41949
2540
EIVLTQSPATLSLSPGERATLSC RASQSVSKHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQTWYDPIT FGQGTKLEIK



CL-41950
2541
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQTWYDPLT FGQGTKLEIK



CL-41951
2542
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



YC QQSFYDPLT FGQGTKLEIK



CL-41952
2543
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQA



PRLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVY



FC QQSWYDPLT FGQGTKLEIK





































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































TABLE 40



Amino Acid Residues Found In Each Position of the Heavy

Chain Variable Region During The Affinity Maturation Of

Humanized Anti-Human VEGF Antibody Hbdb-4G8.3

hBDB-4G8|Heavy Chain Variable Region




SEQ ID NO:
Sequence



2544
1 2 3 4 5 6


123456789012345678901234567890123456789012345678901234567890


EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPGQGLEWMG WINTETGKPTY


R S S S Y N I


N QK D L D M


DY K V T K


ET C W P A


NM V A W N


AG E Q Y P


GA L H V L


HI W G S V


KL P K M W


ME Y N A D


LP M M I Y


RQ N T G G


IF T P R E


Y L


V


7 8 9 10 11 12


123456789012345678901234567890123456789012345678901234567890


ADDFKG RFVFSLDTSVSTAYLQISSLKAEDTAVYYCAR TNYYYRSYIFYFDY WGQGTMVT


Y N T D H N L


H T YI ST N


GT NK T


ID EM V


S MY A


KF LC R


NL TI F


PE WF D


LV QL


WY GD S


MA IW


FG AX


RW CV


QQ V


R


123


VSS


SFQ


L




































































TABLE 41



Amino Acid Residues Found In Each Position of the Light

Chain Variable Region During The Affinity Maturation Of

Humanized Anti-Human VEGF Antibody Hbdb-4G8.3

hBDB-4G8|Light Chain Variable Region




SEQ ID NO:
Sequence



2545
1 2 3 4 5 6


123456789012345678901234567890123456789012345678901234567890


EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQAPRLLIY GASNLES GVPA


A NSA A W H Y


DRD P V Y


C I M


TAP E T


RER S F


HDY D V


EM R


IPL Q


LYQ A


QIK S


CW E


MF G


Y C


K D


V P


7 8 9 10


12345678901234567890123456789012345678901234567


RFSGSGSGTDFTLTISSLEPEDFAVYFC QQSWNDPFT FGQGTKLEIK


CCIN M G


GLTY G


IGDA Y


W GL


REM A


NSSM W


A HP S


Y AG V


K RH C


Q VF P


F LK


F


K


Q































































TABLE 42



Variable Region Sequences of hBDB-4G8.3 Affinity

Matured Clones Converted To IgG






SEQ ID

Protein
V Region

NO:
Clone
Region
123456789012345678901234567890



2546
CL-32416 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY W




VRQAPGQGLEWMG WIDTETGEPTYADDFKG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR TNYYYRSYMF




YFDY WGQGTMVTVSS



2547
CL-32416
CDR-H1

GYTFTDYGMY




2548
CL-32416
CDR-H2

WIDTETGEPTYADDFKG




2549
CL-32416
CDR-H3

TNYYYRSYMFYFDY




2550
CL-32416 VL

EIVLTQSPATLSLSPGERATLSC RASESVSTHMH WY




QQKPGQAPRLLIY GASNLES GVPARFSGSGSGTDFT




LTISSLEPEDFAVYFC QQSWNDPFT FGQGTKLEIK



2551
CL-32416
CDR-L1

RASESVSTHMH




2552
CL-32416
CDR-L2

GASNLES




2553
CL-32416
CDR-L3

QQSWNDPFT




2554
CL-34449 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY W




VRQAPGQGLEWMG WIDTETGEPTYADDFKG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR TNYYYRSYMF




YFDY WGQGTMVTVSS



2555
CL-34449
CDR-H1

GYTFTDYGMY




2556
CL-34449
CDR-H2

WIDTETGEPTYADDFKG




2557
CL-34449
CDR-H3

TNYYYRSYMFYFDY




2558
CL-34449 VL

EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WY




QQKPGQAPRLLIY GASHLES GIPARFSGSGSGTDFT




LTISSLEPEDFAVYYC QQTWYDPLT FGQGTKLEIK



2559
CL-34449
CDR-L1

RASQSVGTHMH




2560
CL-34449
CDR-L2

GASHLES




2561
CL-34449
CDR-L3

QQTWYDPLT




2562
CL-34455 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY W




VRQAPGQGLEWMG WIDTETGEPTYAQGFTG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR TNYYYPSYMF




YFDY WGQGTMVTVSS



2563
CL-34455
CDR-H1

GYTFTNYGMY




2564
CL-34455
CDR-H2

WIDTETGEPTYAQGFTG




2565
CL-34455
CDR-H3

TNYYYPSYMFYFDY




2566
CL-34455 VL

EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WY




QQKPGQAPRLLIY GASKLES GVPARFSGSGSGTDFT




LTISSLEPEDFAVYYC QQSWYDPLT FGQGTKLEIK



2567
CL-34455
CDR-L1

RASQSVGTHMH




2568
CL-34455
CDR-L2

GASKLES




2569
CL-34455
CDR-L3

QQSWYDPLT




2570
CL-34463 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY W




VRQAPGQGLEWMG WIDTETGNPTYADDFKG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR TNYYYPSYMF




YFDY WGQGTMVTVSS



2571
CL-34463
CDR-H1

GYTFTDYGMY




2572
CL-34463
CDR-H2

WIDTETGNPTYADDFKG




2573
CL-34463
CDR-H3

TNYYYPSYMFYFDY




2574
CL-34463 VL

EIVLTQSPATLSLSPGERATLSC RASQSVSKHMH WY




QQKPGQAPRLLIY GASNLES GIPARFSGSGSGTDFT




LTISSLEPEDFAVYFC QQTWYDPIT FGQGTKLEIK



2575
CL-34463
CDR-L1

RASQSVSKHMH




2576
CL-34463
CDR-L2

GASNLES




2577
CL-34463
CDR-L3

QQTWYDPIT




2578
CL-34469 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY W




VRQAPGQGLEWMG WIDTETGEPTYADDFKG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR TNYYYRSYMF




YFDY WGQGTMVTVSS



2579
CL-34469
CDR-H1

GYTFTNYGMY




2580
CL-34469
CDR-H2

WIDTETGEPTYADDFKG




2581
CL-34469
CDR-H3

TNYYYRSYMFYFDY




2582
CL-34469 VL

EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WY




QQKPGQAPRLLIY GASNLES GVPARFSGSGSGTDFT




LTISSLEPEDFAVYYC QQSWYDPLT FGQGTKLEIK



2583
CL-34469
CDR-L1

RASQSVSTHMH




2584
CL-34469
CDR-L2

GASNLES




2585
CL-34469
CDR-L3

QQSWYDPLT




2586
CL-34475 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY W




VRQAPGQGLEWMG WIDTETGEPTYADDFKG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR TNYYYSSYMF




YFDY WGQGTMVTVSS



2587
CL-34475
CDR-H1

GYTFTDYGMY




2588
CL-34475
CDR-H2

WIDTETGEPTYADDFKG




2589
CL-34475
CDR-H3

TNYYYSSYMFYFDY




2590
CL-34475 VL

EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WY




QQKPGQAPRLLIY GASNLES GIPARFSGSGSGTDFT




LTISSLEPEDFAVYYC QQSWYDPLT FGQGTKLEIK



2591
CL-34475
CDR-L1

RASQSVSTHMH




2592
CL-34475
CDR-L2

GASNLES




2593
CL-34475
CDR-L3

QQSWYDPLT




2594
CL-34483 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFPNYGMY W




VRQAPGQGLEWMG WIDTETGEPTYADDFKG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR TNYYYRSYMF




YFDY WGQGTMVTVSS



2595
CL-34483
CDR-H1

GYTFPNYGMY




2596
CL-34483
CDR-H2

WIDTETGEPTYADDFKG




2597
CL-34483
CDR-H3

TNYYYRSYMFYFDY




2598
CL-34483 VL

EIVLTQSPATLSLSPGERATLSC RASQSVATHMH WY




QQKPGQAPRLLIY GASNLES GVPARFSGSGSGTDFT




LTISSLEPEDFAVYYC QQSWYDPLT FGQGTKLEIK



2599
CL-34483
CDR-L1

RASQSVATHMH




2600
CL-34483
CDR-L2

GASNLES




2601
CL-34483
CDR-L3

QQSWYDPLT




2602
CL-34489 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFSNYGMY W




VRQAPGQGLEWMG WIDTETGEPTYADDFKG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR TNYYYSSYMF




YFDY WGQGTMVTVSS



2603
CL-34489
CDR-H1

GYTFSNYGMY




2604
CL-34489
CDR-H2

WIDTETGEPTYADDFKG




2605
CL-34489
CDR-H3

TNYYYSSYMFYFDY




2606
CL-34489 VL

EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WY




QQKPGQAPRLLIY GASNLES GIPARFSGSGSGTDFT




LTISSLEPEDFAVYFC QQSWYDPLT FGQGTKLEIK



2607
CL-34489
CDR-L1

RASQSVSTHMH




2608
CL-34489
CDR-L2

GASNLES




2609
CL-34489
CDR-L3

QQSWYDPLT




2610
CL-34501 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFSDYGMY W




VRQAPGQGLEWMG WIDTETGDPTYADDFKG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR TNYYYPSYMF




YFDY WGQGTMVTVSS



2611
CL-34501
CDR-H1

GYTFSDYGMY




2612
CL-34501
CDR-H2

WIDTETGDPTYADDFKG




2613
CL-34501
CDR-H3

TNYYYPSYMFYFDY




2614
CL-34501 VL

EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WY




QQKPGQAPRLLIY GASILES GVPARFSGSGSGTDFT




LTISSLEPEDFAVYFC QQTWYDPLT FGQGTKLEIK



2615
CL-34501
CDR-L1

RASQSVSTHMH




2616
CL-34501
CDR-L2

GASILES




2617
CL-34501
CDR-L3

QQTWYDPLT




2618
CL-34513 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY W




VRQAPGQGLEWMG WIDTETGEPTYADDFKG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR TNYYYRGYMF




YFDY WGQGTMVTVSS



2619
CL-34513
CDR-H1

GYTFTDYGMY




2620
CL-34513
CDR-H2

WIDTETGEPTYADDFKG




2621
CL-34513
CDR-H3

TNYYYRGYMFYFDY




2622
CL-34513 VL

EIVLTQSPATLSLSPGERATLSC RASQSVNNHMH WY




QQKPGQAPRLLIY GASILES GVPARFSGSGSGTDFT




LTISSLEPEDFAVYFC QQSWYDPLT FGQGTKLEIK



2623
CL-34513
CDR-L1

RASQSVNNHMH




2624
CL-34513
CDR-L2

GASILES




2625
CL-34513
CDR-L3

QQSWYDPLT




2626
CL-34518 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY W




VRQAPGQGLEWMG WIDTETGEPTYADDFKG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR TNYYYKSYMF




YFDY WGQGTMVTVSS



2627
CL-34518
CDR-H1

GYTFTNYGMY




2628
CL-34518
CDR-H2

WIDTETGEPTYADDFKG




2629
CL-34518
CDR-H3

TNYYYKSYMFYFDY




2630
CL-34518 VL

EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WY




QQKPGQAPRLLIY GASKLES GVPARFSGSGSGTDFT




LTISSLEPEDFAVYYC QQSWYDPLT FGQGTKLEIK



2631
CL-34518
CDR-L1

RASQSVSTHMH




2632
CL-34518
CDR-L2

GASKLES




2633
CL-34518
CDR-L3

QQSWYDPLT




2634
CL-34522 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFENYGMY W




VRQAPGQGLEWMG WIDTETGEPTYADDFKG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR TNYYYSSYMF




YFDY WGQGTMVTVSS



2635
CL-34522
CDR-H1

GYTFENYGMY




2636
CL-34522
CDR-H2

WIDTETGEPTYADDFKG




2637
CL-34522
CDR-H3

TNYYYSSYMFYFDY




2638
CL-34522 VL

EIVLTQSPATLSLSPGERATLSC RASQSVGTHMH WY




QQKPGQAPRLLIY GASKLES GVPARFSGSGSGTDFT




LTISSLEPEDFAVYYC QQSWYDPLT FGQGTKLEIK



2639
CL-34522
CDR-L1

RASQSVGTHMH




2640
CL-34522
CDR-L2

GASKLES




2641
CL-34522
CDR-L3

QQSWYDPLT




2642
CL-34537 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFSDYGMY W




VRQAPGQGLEWMG WIDTETGDPTYADDFKG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR ANYYYRSYMF




YFDY WGQGTMVTVSS



2643
CL-34537
CDR-H1

GYTFSDYGMY




2644
CL-34537
CDR-H2

WIDTETGDPTYADDFKG




2645
CL-34537
CDR-H3

ANYYYRSYMFYFDY




2646
CL-34537 VL

EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WY




QQKPGQAPRLLIY GASNLES GIPARFSGSGSGTDFT




LTISSLEPEDFAVYFC QQSWYDPMT FGQGTKLEIK



2647
CL-34537
CDR-L1

RASQSVSTHMH




2648
CL-34537
CDR-L2

GASNLES




2649
CL-34537
CDR-L3

QQSWYDPMT




2650
CL-34538 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY W




VRQAPGQGLEWMG WIDTETGEPTYADDFKG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR TNYYYPSYMF




YFDY WGQGTMVTVSS



2651
CL-34538
CDR-H1

GYTFTDYGMY




2652
CL-34538
CDR-H2

WIDTETGEPTYADDFKG




2653
CL-34538
CDR-H3

TNYYYPSYMFYFDY




2654
CL-34538 VL

EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WY




QQKPGQAPRLLIY GASNLES GVPARFSGSGSGTDFT




LTISSLEPEDFAVYFC QQTWYDPLT FGQGTKLEIK



2655
CL-34538
CDR-L1

RASQSVSTHMH




2656
CL-34538
CDR-L2

GASNLES




2657
CL-34538
CDR-L3

QQTWYDPLT




2658
CL-34540 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY W




VRQAPGQGLEWMG WIDTETGQPTYADDFKG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR TNYYYRSYMF




YFDY WGQGTMVTVSS



2659
CL-34540
CDR-H1

GYTFTDYGMY




2660
CL-34540
CDR-H2

WIDTETGQPTYADDFKG




2661
CL-34540
CDR-H3

TNYYYRSYMFYFDY




2662
CL-34540 VL

EIVLTQSPATLSLSPGERATLSC RASESVGKHMH WY




QQKPGQAPRLLIY AASNLES GVPARFSGSGSGTDFT




LTISSLEPEDFAVYYC QQSWYDPLT FGQGTKLEIK



2663
CL-34540
CDR-L1

RASESVGKHMH




2664
CL-34540
CDR-L2

AASNLES




2665
CL-34540
CDR-L3

QQSWYDPLT




2666
CL-34565 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY W




VRQAPGQGLEWMG WIDTETGDPTYADDFKG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR TNYYYRNYMF




YFDY WGQGTMVTVSS



2667
CL-34565
CDR-H1

GYTFTDYGMY




2668
CL-34565
CDR-H2

WIDTETGDPTYADDFKG




2669
CL-34565
CDR-H3

TNYYYRNYMFYFDY




2670
CL-34565 VL

EIVLTQSPATLSLSPGERATLFC RASQSVSNHMH WY




QQKPGQAPRLLIY GASILES GVPARFSGSGSGTDFT




LTISSLEPEDFAVYYC QQSWYDPIT FGQGTKLEIK



2671
CL-34565
CDR-L1

RASQSVSNHMH




2672
CL-34565
CDR-L2

GASILES




2673
CL-34565
CDR-L3

QQSWYDPIT




2674
CL-34570 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFDDYGMY W




VRQAPGQGLEWMG WIDTETGTPTYADDFKG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR TNYYYSSYMF




YFDY WGQGTMVTVSS



2675
CL-34570
CDR-H1

GYTFDDYGMY




2676
CL-34570
CDR-H2

WIDTETGTPTYADDFKG




2677
CL-34570
CDR-H3

TNYYYSSYMFYFDY




2678
CL-34570 VL

EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WY




QQKPGQAPRLLIY GASNLES GIPARFSGSGSGTDFT




LTISSLEPEDFAVYYC QQSWYDPLT FGQGTKLEIK



2679
CL-34570
CDR-L1

RASQSVSTHMH




2680
CL-34570
CDR-L2

GASNLES




2681
CL-34570
CDR-L3

QQSWYDPLT




2682
CL-34603 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFTDYGMY W




VRQAPGQGLEWMG WIDTETGEPTYAQGFTG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR TNYYYRSYMF




YFDY WGQGTMVTVSS



2683
CL-34603
CDR-H1

GYTFTDYGMY




2684
CL-34603
CDR-H2

WIDTETGEPTYAQGFTG




2685
CL-34603
CDR-H3

TNYYYRSYMFYFDY




2686
CL-34603 VL

EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WY




QQKPGQAPRLLIY GASNLES GVPARFSGSGSGTDFT




LTISSLEPEDFAVYYC QQTWYDPLT FGQGTKLEIK



2687
CL-34603
CDR-L1

RASQSVSTHMH




2688
CL-34603
CDR-L2

GASNLES




2689
CL-34603
CDR-L3

QQTWYDPLT




2690
CL-34605 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFTHYGMY W




VRQAPGQGLEWMG WIDTETGEPTYADDFKG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR TNYYYRSYMF




YFDY WGQGTMVTVSS



2691
CL-34605
CDR-H1

GYTFTHYGMY




2692
CL-34605
CDR-H2

WIDTETGEPTYADDFKG




2693
CL-34605
CDR-H3

TNYYYRSYMFYFDY




2694
CL-34605 VL

EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WY




QQKPGQAPRLLIY GASNLES GIPARFSGSGSGTDFT




LTISSLEPEDFAVYYC QQSFYDPLT FGQGTKLEIK



2695
CL-34605
CDR-L1

RASQSVSTHMH




2696
CL-34605
CDR-L2

GASNLES




2697
CL-34605
CDR-L3

QQSFYDPLT




2698
CL-34633 VH

EVQLVQSGSELKKPGASVKVSCKAS GYTFSDYGMY W




VRQAPGQGLEWMG WIDTETGEPTYADDFKG RFVFSL




DTSVSTAYLQISSLKAEDTAVYYCAR TNYYYRSYMF




YFDY WGQGTMVTVSS



2699
CL-34633
CDR-H1

GYTFSDYGMY




2700
CL-34633
CDR-H2

WIDTETGEPTYADDFKG




2701
CL-34633
CDR-H3

TNYYYRSYMFYFDY




2702
CL-34633 VL

EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WY




QQKPGQAPRLLIY GASNLES GVPARFSGSGSGTDFT




LTISSLEPEDFAVYFC QQSWYDPLT FGQGTKLEIK



2703
CL-34633
CDR-L1

RASQSVSTHMH




2704
CL-34633
CDR-L2

GASNLES




2705
CL-34633
CDR-L3

QQSWYDPLT































































































































































































































































































































































































































































TABLE 43



Summary of Protein Expression and Purification Affinity

Matured Humanized Anti-Human VEGF-A Antibodies








Yield
SEC (%


Name
(mg/L) 1
monomer) 2










CL-32416-IgG
28.5
100.0


CL-34449-IgG
16.1
100.0


CL-34455-IgG
34.1
100.0


CL-34469-IgG
21.3
100.0


CL-34475-IgG
33.6
100.0


CL-34522-IgG
18.4
100.0


CL-34538-IgG
40.8
100.0


CL-34540-IgG
80.0
100.0


CL-34565-IgG
133.6
100.0


CL-34570-IgG
28.3
100.0


CL-34633-IgG
49.9
100.0





1 Yield is determined by the total amount of purified protein in mg divided by the total cell culture volume in liters.


2 SEC % monomer is determined using HPLC size exclusion chromatography.









































TABLE 44



Biacore Binding of Affinity Matured Humanized

Anti-VEGF Antibodies








Antibody
k on (M−1 s−1)
k off (M−1)
K D (M)





CL-28815-IgG
9.2E+06
1.1E−04
1.2E−11


(El version of


parent mAb)


CL-32416-IgG
2.0E+07
1.1E−05
5.4E−13


CL-34449-IgG
1.1E+07
9.1E−06
8.5E−13


CL-34455-IgG
2.2E+07
1.0E−05
4.6E−13


CL-34469-IgG
1.5E+07
9.5E−06
6.2E−13


CL-34475-IgG
2.7E+07
1.4E−05
5.2E−13


CL-34522-IgG
2.0E+07
1.0E−05
5.3E−13


CL-34538-IgG
3.3E+07
8.1E−06
2.4E−13


CL-34540-IgG
8.4E+06
7.1E−06
8.5E−13


CL-34565-IgG
2.0E+07
7.8E−06
4.0E−13


CL-34570-IgG
1.9E+07
5.5E−06
2.9E−13


CL-34633-IgG
1.7E+07
4.1E−06
2.4E−13




































Affinity matured humanized anti-VEGF antibodies were characterized for hVEGF 165 binding and potency. Binding affinity of these molecules to hVEGF 165 was determined by Biacore analysis (Example 1.1). Potency was evaluated in both cell-based and ELISA formats. The ability to block binding of hVEGF 165 to hVEGFR2 was evaluated in a competition ELISA (Example 1.4) Inhibition of hVEGF 165 -induced cell proliferation was assessed using HMVEC-d cells (Example 1.10). The data is summarized in Table 45 below.





TABLE 45



Summary of Characterization of Affinity Matured Humanized

Anti-Human VEGF-A Antibodies





hVEGF 165 IC50 (nM)






Affinity Matured
VEGFR2
Potency
Potency

Humanized IgG
Competition
HMVEC-d
VEGFR2-3T3








CL-32416-IgG
<0.1
0.117
NT

CL-34449-IgG
<0.1
0.077
NT

CL-34455-IgG
<0.1
0.105
NT

CL-34469-IgG
<0.1
0.094
NT

CL-34475-IgG
<0.1
0.106
NT

CL-34522-IgG
<0.1
0.116
NT

CL-34540-IgG
<0.1
0.139
NT

CL-34633-IgG
<0.1
0.138
NT

CL-34538-IgG
<0.1
0.127
NT

CL-34570-IgG
<0.1
0.11
NT

CL-34565-IgG
<0.1
0.126
NT








































Example 8
Affinity Maturation of Anti-Human PDGF-BB Antibody hBDI-9E8
The PDGF-β antibody hBDI-9E8.4 was obtained from rat hybridomas generated at Aldevron and was humanized at AbbVie Bioresearch Center (100 Research Drive, Worcester, Mass. 01605). The human germlines for this clone are VH2-70 and IGKV3-20. To improve the affinity of hBDI-9E8.4, hypermutated CDR residues were identified from other human antibody sequences in the IgBLAST database that also shared high identity to germlines VHVH2-70 and IGKV3-20. The corresponding h9E8.4 CDR residues were then subjected to limited mutagenesis by PCR with primers having low degeneracy at these positions to create three antibody libraries in the scFv format suitable for surface display. To improve the affinity of hBDI-9E8.4 to PDGFβ we generated three antibody libraries in scFv format suitable for surface display. In the first library, residues 30, 32, 34, 35, and 35b in the VH CDR1 and residues 50, 52, 54, 56, 57, 58, 60, 61 and 65 (Kabat numbering) in the VH CDR2 were subjected to limited mutagenesis by primers. In the second library residues 95-100a, 100c and 102 (Kabat numbering) in the VH CDR3 were subjected to limited mutagenesis by primers. In the third library residues 24, 25, 27b, and 29-32 in the VL CDR1, residues 47, 50, 51, 53, 55, and 56 in the VL CDR2 and residues 90, 93-95a, 96 and 97 (Kabat numbering) in the VL CDR3 were subjected to limited mutagenesis by primers.
These hBDI-9E8.4 libraries were displayed to be selected against a low concentration of biotinylated PDGFβ by magnetic then fluorescence activated cell sorting. Selections for improved on-rate, off-rate, or both were carried out and antibody protein sequences of affinity-modulated hBDI-9E8.4 clones.
Table 46 provides a list of amino acid sequences of VH regions of affinity matured humanized PDGF antibodies derived from hBDI-9E8.4. Amino acid residues of individual CDRs of each VH sequence are indicated in bold.





TABLE 46



List of amino Acid Sequences Of Affinity Matured

hBDI-9E8.4 VH Variants





Clone
SEQ ID NO:
VH



CL-22556
2706
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGVGVG WIRQPPGK



ALEWLA NIWWVDEIFYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22557
2707
EVTLRESGPALVKPTQTLTLTCTFS GFSLWTSGMGVV WIRQPPGK



ALEWLA LIDWADVKSYNPSLKN RLTISEDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22558
2708
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGVSVG WIRQPPGK



ALEWLA LIDWYDDMYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22559
2709
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVRVV WIRQPPGK



ALEWLA NIWWDDYLDYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22560
2710
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMSVG WIRQPPGK



ALEWLA LIDWADDTYYNPSLNN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22561
2711
EVTLRESGPALVKPTQTLTLTCTFS GFSLATYGMSVA WIRQPPGK



ALEWLA LIDWYDDEYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22562
2712
EVTLRESGPALVKPTQTLTLTCTFS GFSLXTYGVGVG WIRQPPGK



ALEWLA NIWWVDDKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22563
2713
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVGVG WIRQPPGK



ALEWLA LIDWADDKYYNPSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22564
2714
EVTLRESGPALVKPTQTLTLTCTFS GFSLCTSGVRVR WIRQPPGK



ALEWLA LIDWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22565
2715
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVGVG WIRQPPGK



ALEWLA NIWWDDNXYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22567
2716
EVTLRESGPALVKPTQTLTLTCTFS GFSLATSGVSVG WIRQPPGK



ALEWLA LIDWEDDKGYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22569
2717
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMRVG WIRQPPGK



ALEWLA LIDWDDHKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22570
2718
EVTLRESGPALVKPTQTLTLTCTFS GFSLCTSGVGVG WIRQPPGK



ALEWLA LIDWDDDNYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22571
2719
EVTLRESGPALVKPTQTLTLTCTFS GFSLFTYGMGVG WIRQPPGK



ALEWLA LIDWVDDKFYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22572
2720
EVTLRESGPALVKPTQTLTLTCTFS GFSLCTSGVGVG WIRQPPGK



ALEWLA NIWWDDDRYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22573
2721
EVTLRESGPALVKPTQTLTLTCTFS GFSLCTSGMSVG WIRQPPGK



ALEWLA LICWDDDRYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22575
2722
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGMRVG WIRQPPGK



ALEWLA LIDWGDDMSYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22576
2723
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGMGVG WIRQPPGK



ALEWLA LIDWEDDKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22578
2724
EVTLRESGPALVKPTQTLTLTCTFS GFSLLTYGVGVC WIRQPPGK



ALEGWLN IWWADGKCYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22581
2725
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVRVS WIRQPPGK



ALEWLA LIDWDDEECYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22582
2726
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGMSVS WIRQPPGK



ALEWLA LIDWVDDMGYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22583
2727
EVTLRESGPALVKPTQTLTLTCTFS GFSLXTYGMGVG WIRQPPGK



ALEWLA LIDWADYRSYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22584
2728
EVTLRESGPALVKPTQTLTLTCTFS GFSLATYGVGVG WIRQPPGK



ALEWLA LIDWEDAVNYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22585
2729
EVTLRESGPALVKPTQTLTLTCTFS GFSLCTYGMGVC WIRQPPGK



ALEWLA LIGWDDENYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22586
2730
EVTLRESGPALVKPTQTLTLTCTFS GFSLTTYGVRVG WIRQPPGK



ALEWLA LIDWDDDKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22587
2731
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMSVC WIRQPPGK



ALEWLA NIWWDDGCCYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22588
2732
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGMRVG WIRQPPGK



ALEWLA LIDWCDDKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22589
2733
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGMGVS WIRQPPGK



ALEWLA LIDWDDHXHYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22591
2734
EVTLRESGPALVKPTQTLTLTCTFS GFSLWTSGVGVG WIRQPPGK



ALEWLA LIDWEDNKDYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22593
2735
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVRVG WIRQPPGK



ALEWLA LIDWVDDMYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22595
2736
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVE WIRQPPGK



ALEWLA LIDWDDDKDYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22596
2737
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGMGVG WIRQPPGK



ALEWLA LIDWCDNRYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22597
2738
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGMRVG WIRQPPGK



ALEWLA LIDWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22598
2739
EVTLRESGPALVKPTQTLTLTCTFS GFSLRTYGVSVG WIRQPPGK



ALEWLA LIDWYDGKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22599
2740
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVD WIRQPPGK



ALEWLA LIDWEDDKSYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22600
2741
EVTLRESGPALVKPTQTLTLTCTFS GFSLWTYGVSVR WIRQPPGK



ALEWLA LIDWDDVKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22601
2742
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVGVG WIRQPPGK



ALEWLA LIDWDDDKFYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22602
2743
EVTLRESGPALVKPTQTLTLTCTFS GFSLPTYGVRVG WIRQPPGK



ALEWLA NIWWVDNKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22603
2744
EVTLRESGPALVKPTQTLTLTCTFS GFSLXTSGVRVG WIRQPPGK



ALEWLA LIDWDDYQYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22604
2745
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGVSVG WIRQPPGK



ALEWLA NIWWYDLKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22605
2746
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGVGVG WIRQPPGK



ALEWLA LIDWDDDKCYNPSLKNRLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22606
2747
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVSVG WIRQPPGK



ALEWLA NIWWDDEKAYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22607
2748
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVGVS WIRQPPGK



ALEWLA LIDWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22608
2749
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA LIDWDDDKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22609
2750
EVTLRESGPALVKPTQTLTLTCTFS GFSLPTSGVSVG WIRQPPGK



ALEWLA NIWWADSKFYSTSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22610
2751
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGVSVD WIRQPPGK



ALEWLA LIDWGDQTNYNPSLKN RLTISKDTSKNQVVXTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22611
2752
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGVGVE WIRQPPGK



ALEWLA LIDWYDDKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22612
2753
EVTLRESGPALVKPTQTLTLTCTFS GFSLPTSGVGVG WIRQPPGK



ALEWLA LIDWEDHMDYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22614
2754
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMRVG WIRQPPGK



ALEWLA LIDWXDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22615
2755
EVTLRESGPALVKPTQTLTLTCTFS GFSLTTSGVGVG WIRQPPGK



ALEWLA LIDWYDERFYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22617
2756
EVTLRESGPALVKPTQTLTLTXTFS GFSLSTYGMRVG WIRQPPGK



ALEWLA NIWWADNXSYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22618
2757
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMSVG WIRQPPGK



ALEWLA LIDWADDNYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22619
2758
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVSVG WIRQPPGK



ALEWLA LIDWEDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22620
2759
EVTLRESGPALVKPTQTLTLTCTFS GFSLWTSGMGVG WIRQPPGK



ALEWLA LIDWDDEKAYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22621
2760
EVTLRESGPALVKPTQTLTLTCTFS GFSLWTSGMRVG WIRQPPGK



ALEWLA NIWWDDDKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22622
2761
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGVSVG WIRQPPGK



ALEWLA LIDWHDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22624
2762
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMSVG WIRQPPGK



ALEWLA LIDWNDNKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22625
2763
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVGVG WIRQPPGK



ALEWLA LIDWDDDKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22626
2764
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVRVC WIRQPPGK



ALEWLA LIDWDDDKSYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22627
2765
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGVSVT WIRQPPGK



ALEWLA LIDWNDDNHYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22628
2766
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVSVV WIRQPPGK



ALEWLA NIWWDDEKCYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22629
2767
EVTLRESGPALVKPTQTLTLTCTFT GFSLYTSGMGVG WIRQPPGK



ALEWLA LIDWDDDKNYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22630
2768
EVTLRESGPALVKPTQTLTLTCTFS GFSLFTYGVGVD WIRQPPGK



ALEWLA NIWWPDDNYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22631
2769
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVGVG WIRQPPGK



ALEWLA LIDWDDDXCYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22633
2770
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGVSVG WIRQPPGK



ALEWLA LIDWDDEKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22634
2771
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVGVG WIRQPPGK



ALEWLA LIDWIDDEDYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22635
2772
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVSVR WIRQPPGK



ALEWLA NIWWDDNKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22636
2773
EVTLRESGPALVKPTQTLTLTCTFS GFSLCTSGMGVG WIRQPPGK



ALEWLA NIWWDDDNYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22637
2774
EVTLRESGPALVKPTQTLTLTCTFS GFSLLTYGMGVG WIRQPPGK



ALEWLA NIWWHDDKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22638
2775
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVSVA WIRQPPGK



ALEWLA NIWWDDDKYYSTSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22639
2776
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVRVG WIRQPPGK



ALEWLA LIDWEDYLCYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22640
2777
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVGVG WIRQPPGK



ALEWLA LIDWDDDYYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22641
2778
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22642
2779
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGMGVG WIRQPPGK



ALEWLA NIWWVDDNYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22643
2780
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVY WIRQPPGK



ALEWLA LIDWDDDNYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22644
2781
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVSVG WIRQPPGK



ALEWLA LIDWDDGKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22645
2782
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVRVV WIRQPPGK



ALEWLA LIDWNDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22646
2783
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGVSVV WIRQPPGK



ALEWLA NIWWHDDKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22648
2784
EVTLRESGPALVKPTQTLTLTCTFS GFSLMTSGMSVC WIRQPPGK



ALEWLA NIWWYDHKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22649
2785
EVTLRESGPALVKPTQTLTLTCTFS GFSLRTYGVSVG WIRQPPGK



ALEWLA NIWWDDAKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22650
2786
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGVRVA WIRQPPGK



ALEWLA NIWWDDVKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22651
2787
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIAASYSFDY WGQGTMVTVSS



CL-22652
2788
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR FEYLGAMYXFDY WGQGTMVTVSS



CL-22653
2789
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR XDSFRKPYSFDY WGQGTMVTVSS



CL-22654
2790
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IXSIGSTYWFDY WGQGTMVTVSS



CL-22655
2791
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR LVSIVTKYSFDY WGQGTMVTVSS



CL-22656
2792
XVTLXESGPALXKPTXTLTLTCTFS GFXLSTXGMGVG WIRQPPRK



ALXWLA NXWWDDDKYYNPSLXN RLXISKDTSKNQVVLTMTNMDPV



DTAXYYCAR XXXXXMXYSFDY WGQGTMVTXSX



CL-22658
2793
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR LEPIPMTYSFDY WGQGTMVTVSS



CL-22659
2794
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IEWSAITYSFDY WGQGTMVTVSS



CL-22660
2795
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IECTXNRYXFDY WGQGTMVTVSS



CL-22661
2796
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IECNSTTYSFDY WGQGTMVTVSS



CL-22664
2797
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR LASLCATYYFDY WGQGTMVTVSS



CL-22665
2798
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IGWRLRMYSFDY WGQGTMVTVSS



CL-22666
2799
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IVSIGGTYSFDY WGQGTMVTVSS



CL-22668
2800
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR VESIGTTYYFDY WGQGTMVTVSS



CL-22669
2801
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR YAPIGTTYWFDY WGQGTMVTVSS



CL-22670
2802
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESTRTTYLFDY WGQGTMVTVSS



CL-22671
2803
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESTGTAYSFDY WGQGTMVTVSS



CL-22672
2804
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IASVGTSYSFDY WGQGTMVTVSS



CL-22673
2805
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAREESTCPTYYFDYWGQGTMVTVSS



CL-22675
2806
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR TESIDRAYSFDY WGQGTMVTVSS



CL-22677
2807
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IGSTGISYSFDY WGQGTMVTVSS



CL-22678
2808
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR RESIGTTYSFDY WGQGTMVTVSS



CL-22679
2809
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR KVTIETAYYFDY WGQGTMVTVSS



CL-22680
2810
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATXYCAR FASIGTTYSFDY WGQGTMVTVSS



CL-22681
2811
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR MKSIATTYSFDY WGQGTMVTVSS



CL-22682
2812
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESRRATYSFDY WGQGTMVTVSS



CL-22683
2813
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IGXIGSAYTFDY WGQGTMVTVSS



CL-22685
2814
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR TGSGVTTYSFDY WGQGTMVTVSS



CL-22688
2815
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IGSIESAYSFDY WGQGTMVTVSS



CL-22689
2816
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR VYSKGTTYSFDY WGQGTMVTVSS



CL-22691
2817
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR FEALGLSYSFDY WGQGTMVTVSS



CL-22692
2818
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATXYCAR RGTIRTTYSFDY WGQGTMVTVSS



CL-22694
2819
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IYWIGPTYCFDY WGQGTMVTVSS



CL-22695
2820
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESMRTTYSFDY WGQGTMVTVSS



CL-22696
2821
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IRSIVTTYSFDY WGQGTMVTVSS



CL-22698
2822
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR TQSSAMTYSFDY WGQGTMVTVSS



CL-22702
2823
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR NESMGTSYSFDY WGQGTMVTVSS



CL-22703
2824
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IEFVRAIYSFDY WGQGTMVTVSS



CL-22704
2825
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR FESLGETYSFDY WGQGTMVTVSS



CL-22705
2826
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IEAIGNQYSFDY WGQGTMVTVSS



CL-22706
2827
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR KDSMVTTYLFDY WGQGTMVTVSS



CL-22707
2828
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR VEWQGSTYSFDY WGQGTMVTVSS



CL-22708
2829
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYMFDY WGQGTMVTVSS



CL-22709
2830
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR CASVSTTYCFDY WGQGTMVTVSS



CL-22710
2831
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR ILSIGNTYSFDY WGQGTMVTVSS



CL-22711
2832
EVTLRESGPALVKPTQTLTLTCTFF GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWCDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESNGNTYSFDY WGQGTMVTVSS



CL-22712
2833
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR RDSTGTPYSFDY WGQGTMVTVSS



CL-22713
2834
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR VESIVTTYYFDY WGQGTMVTVSS



CL-22714
2835
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR LEKFGRTYPFDY WGQGTMVTVSS



CL-22715
2836
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR FKSNRPSYSFDY WGQGTMVTVSS



CL-22716
2837
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSXKN RLXISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLDTTYXFDX XGQGXMXTVSS



CL-22717
2838
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IXATGMLYSFDY WGQGTMVTVSS



CL-22718
2839
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIETTYXFDY WGQGTMVTVSS



CL-22719
2840
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IEXMAPMYSFDY WGQGTMVTVSS



CL-22720
2841
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR VRPLVTIYSFDY WGQGTMVTVSS



CL-22721
2842
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IDSVWTTYSFDY WGQGTMVTVSS



CL-22722
2843
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR VEEIGNTYNFDY WGQGTMVTVSS



CL-22723
2844
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR RGLFRIRYSFDY WGQGTMVTVSS



CL-22724
2845
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RXTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22725
2846
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IEVIGTAYSFDY WGQGTMVTVSS



CL-22726
2847
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR LDVIGMLYAFDY WGQGTMVTVSS



CL-22728
2848
EVTLRESGPALVKPTKTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IMSIGSSYXFDY WGQGTMVTVSS



CL-22729
2849
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IDWIGTTYSFDY WGQGTMVTVSS



CL-22730
2850
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR NSSIGSTYSFDY WGQGTMVTVSS



CL-22731
2851
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESPGTWYSFDY WGQGTMVTVSS



CL-22732
2852
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IEWIGITYCFDY WGQGTMVTVSS



CL-22733
2853
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IEXLGTTYSFDY WGQGTMVTVSS



CL-22734
2854
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR KELTCSTYSFDY WGQGTMVTVSS



CL-22736
2855
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IEXIRMRYSFDY WGQGTMVTVSS



CL-22737
2856
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR KAAIATLYLFDY WGQGTMVTVSS



CL-22738
2857
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR RRPIVTTYSFDY WGQGTMVTVSS



CL-22740
2858
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTVYSFDY WGQGTMVTVSS



CL-22741
2859
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IASIGSMYSFDY WGQGTMVTVSS



CL-22742
2860
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESRATTYSFDY WGQGTMVTVSS



CL-22743
2861
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR NVWLGTTYSFDY WGQGTMVTVSS



CL-22744
2862
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IMSIGTAYSFDY WGQGTMVTVSS



CL-22745
2863
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IKWIWTTYSFDY WGQGTMVTVSS



CL-22746
2864
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IEXRGSTYIFDY WGQGTMVTVSS



CL-22759
2865
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCXR IESIGTTYSFDY WGQGTMVTVSS



CL-22763
2866
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNXDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-22806
2867
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYXFXY WGQGTMVTVSS



CL-22812
2868
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATXYCAR IESIGTTYSFDY XGQGTMVTVSS



CL-22819
2869
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAX IESIGTTYSFDY WGQGTMVTVSS



CL-22833
2870
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYXCAR IESIGTTYSXDY WGQGTXVTVSS



CL-25629
2871
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRKPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25633
2872
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNVDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25645
2873
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ELEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25649
2874
EVTLRESGPALVKPTQTLTLTCTFS GFSLATSGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25656
2875
EVTLRESGPALVKPTQTLTLTCTFS GFRLSTYGMGVG WIRKPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25657
2876
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTANYYCAR IASIPTMYAFDY WGQGTMVTVSS



CL-25676
2877
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWMA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25679
2878
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDHDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25684
2879
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25696
2880
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGVGVG WIRQPPGK



ALEWLA NIWWDDDKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25697
2881
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRKPPGK



ALEWLA NIWWDDDKYYNPSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25699
2882
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGMGVG WIRQPPGK



ALEWLA NIWWDDDRYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25700
2883
EVTLRESGPALVKPTQTLTLTCTFS GFSLMTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25702
2884
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNTSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25710
2885
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLE NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25738
2886
EVTLKKSGPALVKPXQTLTLTCTFS GFSLSTYGMGVG WIRXPPGK



GLEWLA NIWWDDDKYYNPSLKN RLTIXKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25739
2887
EVTLKESGPALVKPTXTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25745
2888
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSX



CL-25749
2889
EVTLRESGPALVKPTXTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25755
2890
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR MKSIGSTYSFDY WGQGTMVTVSS



CL-25763
2891
EVTLKESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25765
2892
EVTLRESGPALVKPTXTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGXMVTVSS



CL-25769
2893
EVTLKESGPALVKPTXTLTLTCTFS GFSLSTYGMGVG WIRHPPGK



ALEWLA NIWWNNDNYYNPSLKN RLTINKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25773
2894
EVTLKESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEGLA NIWWDDDKYYNPSLKN RLTINKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25789
2895
EVTLRESGPALVKPTHTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25791
2896
EVTLKESGPALVKPTQTLTLTCTFS GFRLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25797
2897
EVTLXESGPALVKPTXTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-25815
2898
EVTLKESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTINKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-28144
2899
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESGWTTYSFDY WGQGTMVTVSS



CL-28145
2900
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIWTSYSFDY WGQGTMVTVSS



CL-28146
2901
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IVSSWTIYSFDY WGQGTMVTVSS



CL-28147
2902
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IYSSGTVYSFDY WGQGTMVTVSS



CL-28148
2903
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLGISYSFDY WGQGTMVTVSS



CL-28149
2904
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESTGTSYSFDY WGQGTMVTVSS



CL-28151
2905
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLGPSYSFDY WGQGTMVTVSS



CL-28152
2906
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGSSYSFDY WGQGTMVTVSS



CL-28155
2907
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IVSIGWSYSFDY WGQGTMVTVSS



CL-28156
2908
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IYSDWTIYSFDYW GQGTMVTVSS



CL-28157
2909
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWITYSFDY WGQGTMVTVSS



CL-28160
2910
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESEWTTYNFDY WGQGTMVTVSS



CL-28161
2911
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSPTTYSFDY WGQGTMVTVSS



CL-28162
2912
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGISYSFDY WGQGTMVTVSS



CL-28163
2913
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSATIYSFDY WGQGTMVTVSS



CL-28164
2914
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESTGTTYSFDY WGQGTMVTVSS



CL-28167
2915
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTSYSFDY WGQGTMVTVSS



CL-28169
2916
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCARIVSTWTTYSFDYWGQGTMVTVSS



CL-28170
2917
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLGTSYNFDY WGQGTMVTVSS



CL-28173
2918
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESTWWTYSFDY WGQGTMVTVSS



CL-28175
2919
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSGWSYAFDY WGQGTMVTVSS



CL-28177
2920
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGYSYSFDY WGQGTMVTVSS



CL-28180
2921
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWMA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCARIETLGISYSFDYWGQGTMVTVSS



CL-28181
2922
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESMWSSYSFDY WGQGTMVTVSS



CL-28182
2923
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IETIGTSYSFDY WGQGTMVTVSS



CL-28186
2924
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IVSDVTTYSFDY WGQGTMVTVSS



CL-28187
2925
EVTLRESGPALVKPTKTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESFGTSYSFDY WGQGTMVTVSS



CL-28189
2926
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IKSIGWTYSFDY WGQGTMVTVSS



CL-28190
2927
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESNFWSYSFDY WGQGTMVTVSS



CL-28195
2928
EVTLRESGPALVKPTHTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IMSLETRYDFYY WGQGTMVTVSS



CL-28196
2929
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESVETSYNFDY WGQGTMVTVSS



CL-28198
2930
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESFWTTYSFDY WGQGTMVTVSS



CL-28204
2931
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESMGTSYSFDY WGQGTMVTVSS



CL-28205
2932
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIWSSYSFDY WGQGTMVTVSS



CL-28208
2933
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGFSYSFDY WGQGTMVTVSS



CL-28212
2934
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESVGPSYSFDY WGQGTMVTVSS



CL-28213
2935
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLGWTYSFDY WGQGTMVTVSS



CL-28215
2936
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESDWTTYSFDY WGQGTMVTVSS



CL-28219
2937
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGPSYSFDY WGQGTMVTVSS



CL-28233
2938
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLVTSYDFDY WGQGTMVTVSS



CL-28235
2939
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESVGTSYNFDY WGQGTMVTVSS



CL-29595
2940
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESTEASYSFDY WGQGTMVTVSS



CL-29596
2941
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESNGASYSFDY WGQGTMVTVSS



CL-29597
2942
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSVTTYSFDY WGQGTMVTVSS



CL-29598
2943
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDNYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR XESXWTSYSFDY WGQGTMVTVSS



CL-29600
2944
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGASYSFDY WGQGTMVTVSS



CL-29601
2945
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESTGRSYGFDY WGQGTMVTVSS



CL-29607
2946
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IETLGTSYSFDY WGQGTMVTVSS



CL-29608
2947
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLGTTYSFDY WGQGTMVTVSS



CL-29611
2948
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIPTAYSFDY WGQGTMVTVSS



CL-29612
2949
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLGTTYSFDY WGQGTMVTVSS



CL-29613
2950
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCARLESIATTYSFDYWGQGTMVTVSS



CL-29614
2951
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGPSYSFDY WGHGTMVTVSS



CL-29617
2952
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSYTSYSFDY WGQGTMVTVSS



CL-29618
2953
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESTWTSYSFDY WGQGTMVTVSS



CL-29620
2954
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSVTNYQFDY WGQGTMVTVSS



CL-29621
2955
EVTLRESGPALVKPTQTLTLICTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTSYSFDY WGQGTMVTVSS



CL-29625
2956
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLGPAYSFDY WGQGTMVTVSS



CL-29627
2957
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSNNQVVLTMTNMDPV



DTATYYCAR IESFGSSYSFDY WGQGTMVTVSS



CL-29629
2958
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSETTYTFDY WGQGTMVTVSS



CL-29630
2959
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIWTTYSFDY WGQGTMVTVSS



CL-29631
2960
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN LLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESFGTSYSFDY WGQGTMVTVSS



CL-29632
2961
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IASXGTSYSFDY WGQGTMVTVSS



CL-29634
2962
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDEKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTSYSFDY WGQGTMVTVSS



CL-29635
2963
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSPTSYSFDY WGQGTMVTVSS



CL-29636
2964
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGWSYAFDY WGQGTMVTVSS



CL-29637
2965
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGWTYSFDY WGQGTMVTVSS



CL-29638
2966
EVTLRESGPALVKPTQTLTLTCTFS GFSLATSGVSVL WIRQPPGK



ALEWLA NIWWDDGXYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESFGTSYSFDY WGQGTMVTVSS



CL-29639
2967
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLWTTYSFDY WGQGTMVTVSS



CL-29643
2968
EVTLRESGPALVKPTQTLTLTCTFS GFSLDTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSGYTYSFDY WGQGTMVTVSS



CL-29644
2969
EVTLRESGPALVKPTQTLTLTCTFS GFSLTTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSGSSYSFDY WGQGTMVTVSS



CL-29645
2970
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR VASSWVEYSFDY WGQGTMVTVSS



CL-29647
2971
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESFGTSYSFDY WGQGTMVTVSS



CL-29648
2972
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSGTTYSFDY WGQGTMVTVSS



CL-29649
2973
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRKPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESMGISYSFDY WGQGTMVTVSS



CL-29651
2974
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGIAYSFDY WGQGTMVTVSS



CL-29654
2975
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIXWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIVTTYSFDY WGQGTMVTVSS



CL-29658
2976
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESGWTIYSFDY WGQGTMVTVSS



CL-29662
2977
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLGPTYSFDY WGQGTMVTVSS



CL-29663
2978
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESVGTSYSFDY WGQGTMVTVSS



CL-29665
2979
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGMGVG WIRQPPGK



ALEWLA NIWWDDDQYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWTTYSFDY WGQGTMVTVSS



CL-29667
2980
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESFGPSYSFDY WGQGTMVTVSS



CL-29668
2981
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSGTSYSFDY WGQGTMVTVSS



CL-29673
2982
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCARXXSIVTTYSFDYWGQGTMVTVSS



CL-29674
2983
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYSTSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTSYSFDY WGQGTMVTVSS



CL-29676
2984
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVGLIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESVGTSYSFDY WGQGTMVTVSS



CL-29678
2985
EVTLKESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCARIGSSGTTYSFDYWGQGTMVTVSS



CL-29679
2986
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNTSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IDSFGAIYSFDY WGQGTMVTVSS



CL-29680
2987
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ELEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



ETATYYCAR IESIGTAYNFDY WGQGTMVTVSS



CL-29683
2988
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLGTSYSFDY WGQGTMFTVSS



CL-29688
2989
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLGTSYSFDY WGQGTMVTVSS



CL-29689
2990
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IEAKGTTYSFDY WGQGTMVTVSS



CL-29699
2991
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESRGTSYSFDY WGQGTMVTVSS



CL-29706
2992
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESMGPTYSFDY WGQGTMVTVSS



CL-29707
2993
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIETSYSFDY WGQGTMVTVSS



CL-29709
2994
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYRAR IESLGTTYSFDY WGQGTMVTVSS



CL-29711
2995
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRHPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESMGTSYSFDY WGQGTMVTVSS



CL-29713
2996
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESMGTTYSFDY WGQGTMVTVSS



CL-29714
2997
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAL IESSGTTYSFDY WGQGTMVTVSS



CL-29720
2998
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESKGVSYSFDY WGQGTMVTVSS



CL-29721
2999
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIPTTYSFDY WGQGTMVTVSS



CL-29727
3000
EVTLRESXPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ELEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLGTTYSFDY WGQGTMVTVSS



CL-29728
3001
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLGITYSFDY WGQGTMVTVSS



CL-29730
3002
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESMGRSYSFDY WGQGTMVTVSS



CL-29731
3003
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIATSYSFDY WGQGTMVTVSS



CL-29732
3004
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYNFDY WGQGTMVTVSS



CL-29735
3005
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESMGPMYSFDY WGQGTMVTVSS



CL-29736
3006
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTAYSFDY WGQGTMVTVSS



CL-29738
3007
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR MESSWTTYSFDY WGQGTMVTVSS



CL-29739
3008
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESTGATYSFDY WGQGTMVTVSS



CL-29740
3009
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESMGPKYSFDY WGQGTMVTVSS



CL-29742
3010
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESMGMSYSFDY WGQGTMVTVSS



CL-29744
3011
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGLSYSFDY WGQGTMVTVSS



CL-29745
3012
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYRAR IESLGMSYSFDY WGQGTMVTVSS



CL-29746
3013
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR LXSTGTNYSFDY WGQGTMVTVSS



CL-29748
3014
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSDTIYSFDY WGQGTMVTVSS



CL-29749
3015
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGMGVD WIRQPPGK



ALEWLA LIDWDDDIHYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-29751
3016
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESVGTTYSFDY WGQGTMVTVSS



CL-29753
3017
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWYDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESTGTTYSFDY WGQGTMVTVSS



CL-29756
3018
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR NESFGRMYXFDY WGQGTMVTVSS



CL-29757
3019
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR XESIGTTYSFDY WGQGTMVTVSS



CL-29758
3020
EVTLRESGPSLVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESFGTTYSFDY WGQGTMVTVSS



CL-29759
3021
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IETLGTAYSFDY WGQGTMVTVSS



CL-29761
3022
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESFGSSYSFDY WGQGTMVTVSS



CL-29763
3023
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESGPTTYSFDY WGQGTMVTVSS



CL-29765
3024
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTMYSFDY WGQGTMVTVSS



CL-29771
3025
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESTXTTYSXDYWGQGTMVTVSS



CL-29772
3026
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGITYSFDY WGQGTMVTVSS



CL-29773
3027
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESMETTYSFDY WGQGTMVTVSS



CL-29776
3028
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESNAITYSFDY WGQGTMVTVSS



CL-29777
3029
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSETTYMFDY WGQGTMVTVSS



CL-29780
3030
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLT NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESMGTSYSFDY WGQGTMVTVSS



CL-29786
3031
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IYSIGTSYSFDY WGQGTMVTVSS



CL-33292
3032
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSPWTYSFDY WGQGTMVTVSS



CL-33332
3033
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESRPDTYSFDY WGQGTMVTVSS



CL-33361
3034
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IQSSASNYEFDY WGQGTMVTVSS



CL-33368
3035
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCARIQSGWTNXEFDYWGQGTMVTVSS



CL-33583
3036
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IQSIWTRYDFDY WGQGTMVTVSS



CL-33588
3037
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IQSFATNYEFDY WGQGTMVTVSS



CL-33591
3038
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESVPWSYSFDY WGQGTMVTVSS



CL-33592
3039
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESTPFSYSFDY WGQGTMVTVSS



CL-33599
3040
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWTSYDFDY WGQGTMVTVSS



CL-33601
3041
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IQSSSTNYEFDY WGQGTMVTVSS



CL-33612
3042
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IQSSWRRYEFDY WGQGTMVTVSS



CL-33616
3043
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IKTSATNYDFDY WGQGTMVTVSS



CL-33618
3044
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSAFSYNFDY WGQGTMVTVSS



CL-33626
3045
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVFLTMTNMDPV



DTATYYCAR IVSSLTEYNFDY WGQGTMVTVSS



CL-33627
3046
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESRVDSYSFDY WGQGTMVTVSS



CL-33628
3047
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESTWTSYDFDY WGQGTMVTVSS



CL-33654
3048
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESVAWRYDFDY WGQGTMVTVSS



CL-33657
3049
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLPTSYNFDY WGQGTMVTVSS



CL-33663
3050
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSPFTYSFDY WGQGTMVTVSS



CL-33665
3051
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESDYTKYDFDY WGQGTMVTVSS



CL-33667
3052
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLPTRYDFDY WGQGTMVTVSS



CL-33674
3053
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWMA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIPTSYSFDY WGQGTMVTVSS



CL-33679
3054
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESKPTSYSFDY WGQGTMVTVSS



CL-33680
3055
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWTTYSFDY WGQGTMVTVSS



CL-33687
3056
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTSYSFDY WGQGTMVTVSS



CL-33688
3057
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTFKNQVVLTMTNMDPV



DTATYYCAR IESIPTSYSFDY WGQGTMVTVSS



CL-33690
3058
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDETYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESDFTSYMFDY WGQGTMVTVSS



CL-33693
3059
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESNWWSYSFDY WGQGTMVTVSS



CL-33696
3060
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSFTTYSFDY WGQGTMVTVSS



CL-33698
3061
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESXGXSYSFDY WGQGTMVTVSS



CL-33705
3062
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESRLDTYSFDY WGQGTMVTVSS



CL-33707
3063
EVTLRESGPALVKPTQTLTLTCTFS GFSLDTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTSYSFDY WGQGTMVTVSS



CL-33709
3064
EVTLRESGPALVKPTQTLTLTCTFS GFSLATSGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIPWSYSFDY WGQGTMVTVSS



CL-33711
3065
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESTGYSYSFDY WGQGTMVTVSS



CL-33712
3066
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRKPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWTSYSFDY WGQGTMVTVSS



CL-33722
3067
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSFFSYSFDY WGQGTMVTVSS



CL-33725
3068
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDEYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLGTSYSFDY WGQGTMVTVSS



CL-33734
3069
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLPGSYDFDY WGQGTMVTVSS



CL-33735
3070
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ELEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESNPLTYSFDY WGQGTMVTVSS



CL-33741
3071
EVTLRESGPALVKPTKTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGISYSFDY WGQGTMVTVSS



CL-33743
3072
EVTLRESGPALVKPTQTLTLTCTFS GFSLATYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLPTSYSFDY WGQGTMVTVSS



CL-33745
3073
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSPFAYSFDY WGQGTMVTVSS



CL-33746
3074
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWFTYAFDY WGQGTMVTVSS



CL-33747
3075
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IETIXPKYSFDY WGQGTMVTVSS



CL-33754
3076
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWTTYAFDY WGQGTMVTVSS



CL-33755
3077
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSEWTYSFDY WGQGTMVTVSS



CL-33756
3078
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IQSSWTTYEFDY WGQGTMVTVSS



CL-33760
3079
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IETLGSSYSFDY WGQGTMVTVSS



CL-33766
3080
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRKPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSFTSYSFDY WGQGTMVTVSS



CL-33770
3081
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESGGISYSFDY WGQGTMVTVSS



CL-33773
3082
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLPTTYSFDY WGQGTMVTVSS



CL-33777
3083
EVTLRESGPALVKPTQTLTLTCTFS GFSLYTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESVGTSYSFDY WGQGTMVTVSS



CL-33781
3084
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWYSYNFDY WGQGTMVTVSS



CL-33782
3085
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWRSYCFDY WGQGTMVTVSS



CL-33784
3086
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSPMSYSFDY WGQGTMVTVSS



CL-33789
3087
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLPTSYCFDY WGQGTMVTVSS



CL-33791
3088
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWWTYSFDY WGQGTMVTVSS



CL-33794
3089
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESRPTSYCFDY WGQGTMVTVSS



CL-33795
3090
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESVPTSYSFDY WGQGTMVTVSS



CL-33798
3091
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTSGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IQSDGPMYSFDY WGQGTMVTVSS



CL-33802
3092
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESTGASYSFDY WGQGTMVTVSS



CL-33813
3093
EVTLRESGPALVKPTQTLTLTCTFS GFSLYTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLPTSYSFDY WGQGTMVTVSS



CL-33814
3094
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDTV



DTATYYCAR IESTPWSYSFDY WGQGTMVTVSS



CL-33816
3095
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWTSYAFDY WGQGTMVTVSS



CL-33823
3096
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ELEWLA NIWWDDDKYYNPSLNN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSGPKYSFDY WGQGTMVTVSS



CL-33833
3097
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGWSYSFDY WGQGTMVTVSS



CL-33840
3098
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSAWTYSFDY WGQGTMVTVSS



CL-33842
3099
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESYGPKYSFDY WGQGTMVTVSS



CL-33844
3100
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKT RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IETSWWKYSFDY WGQGTMVTVSS



CL-33847
3101
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNLSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSPTSYSFDY WGQGTMVTVSS



CL-33849
3102
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IVSSYFTYSFDY WGQGTMVTVSS



CL-33858
3103
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDEEYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGISYSFDY WGQGTMVTVSS



CL-33861
3104
EVTLRESGPALVKPTQTLTLTCTFS GFSLYTSGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWTTYSFDY WGQGTMVTVSS



CL-33862
3105
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIPTRYDFDY WGQGTMVTVSS



CL-41180
3106
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNRVVLTMTNMDPV



DTATYYCAR IVSDWTTYSFDY WGQGTMVTVSS



CL-41185
3107
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTDMDPV



DTATYYCAR IESSWTTYSFDY WGQGTMVTVSS



CL-41193
3108
RXHWRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IETFGPKYSFDY WGQGTMVTVSS



CL-41204
3109
RGNTEESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTTTYYCAR IESLPTSYSFDY WGQGTMVTVSS



CL-41213
3110
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLXTNYSFDY WGQGTMVTVSS



CL-41224
3111
EVTLREGGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESHWWSYAFDY WGQGTMVTVSS



CL-41229
3112
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSFTSYSFDY WGQGTMVTEXC



CL-41232
3113
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESHWWSYAFDY WGQGTMVTVSS



CL-41233
3114
RXHXGESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWTTYSFDY WGQGTMVTVSS



CL-41246
3115
EVTLRESGPALAKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESHWWSYAFDY WGQGTMVTVSS



CL-41252
3116
EVTLRESGPALVKPTQTLTLTCAFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWTTYSFDY WGQGTMVTVSS



CL-41255
3117
EVTLRESGPALVEPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESNPWKYSFDY WGQGTMVTVSS



CL-41257
3118
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESNWRTYSFDY WGQGTMVTVSS



CL-41260
3119
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSFTSYSFDY WGQGTMVTVSS



CL-41261
3120
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESHWWSYAFDY WGQGTMVTVSI



CL-41262
3121
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IVSDWTTYSFDY WGQGTMVTVSS



CL-41268
3122
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLGWSYSFDY WGQGTMVTVSS



CL-41269
3123
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLPTSYSFDY WGQGTMVTVSS



CL-41270
3124
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWTTYSFDY WGQGTMVTVSS



CL-41272
3125
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESNPWKYSFDY WGQGTMVTVSS



CL-41273
3126
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IETFGPKYSFDY WGQGTMVTVSS



CL-41276
3127
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGIG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESMGPKYAFDY WGQGTMVTVSS



CL-41283
3128
EVTLRESGPALVKPTQTLTLTRTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIPTSYSFDY WGQGTMVTVSS



CL-41325
3129
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRKPPGK



ALEWLA NIWWDGDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSGPKYSFDY WGQGTMVTVSS



CL-41342
3130
EVTLRESGPALVKPTQTLTLACTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESVWTKYYFDX GGQGTMVTVSS



CL-41348
3131
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYEMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTPKNQVVLTMTNMDPV



DTATYYCAR IESVWTRYDFDY WGQGTMVKXVV



CL-41353
3132
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESLGTSYSFDY WGQGTMVTVSS



CL-41358
3133
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGPKYSFDY WGQGTMVTVSS



CL-41361
3134
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESVWTRYDFDY WGQGTMVTVSS



CL-41362
3135
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IETMGPKYSFDY WGQGTMVTVSS



CL-41365
3136
RGNTRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALKWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGPKYSFDY WGQGTMVTVSS



CL-41366
3137
EVTLRESGPAQVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIPTSYSFDY WGQGTMVTVSS



CL-41367
3138
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRKPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSGPKYSFDY WGQGTMVTVSS



CL-41368
3139
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGPKYSFDX GGQGTMVTVSS



CL-41369
3140
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIPTSYSFDY WGQGTMVTVSS



CL-41376
3141
EVKLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCARIQTIGTNYSFDYWGQGTMVTVSS



CL-41377
3142
EGQLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWTSYSFDY WGQGTMVTVSS



CL-41381
3143
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWTSYSFDY WGQSTMVTVSS



CL-41385
3144
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWTSYSFDY WGQGTIVTVSS



CL-41399
3145
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKS RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWTSYSFDY WGQGTMVTVSS



CL-41405
3146
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTAAYYCAR IETIGPKYSFDY WGQGTMVTVSS



CL-41411
3147
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IQSGWTNYEFDY WGQGTMVTVVV



CL-41420
3148
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IQSMWTRYDFDY WGQGTMVTVSS



CL-41425
3149
RXHXRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSGPKYSFDY WGQGTMVTVSS



CL-41427
3150
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DAATYYCAR IQSGWTNYEFDY WGQGTMVTVSS



CL-41436
3151
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWTSYSFDY WSQGTMVTVSS



CL-41439
3152
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IETIGPKYSFDY WGQGTMVTVSS



CL-41443
3153
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSGPKYSFDY WGQGTMVTVSS



CL-41446
3154
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWTSYSFDY WGQGTMVTVSS



CL-41447
3155
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQAVLTMTNMDPV



DTATYYCAR IQSGWTNYEFDY WGQGTMVTVSS



CL-41448
3156
RGNTEKSGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSWTSYSFDY WGQGTMVTVSS



CL-41449
3157
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IQSGWTNYEFDY WGQGTMVTVSS



CL-41452
3158
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMEXVVR



CL-41459
3159
EVTLRESGPALVKPTQTLTLTCTFSGFILSTYGMGVGWIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-41463
3160
EVTLRESGPALVKSTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS



CL-41465
3161
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESIGTTYSFDY WGQGTMVTVSS




















































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































Table 47 provides a list of amino acid sequences of VL regions of affinity matured humanized PDGF antibodies derived from hBDI-9E8.4. Amino acid residues of individual CDRs of each VL sequence are indicated in bold.





TABLE 47



List of Amino Acid Sequences Of Affinity

Matured hBDI-9E8.4 VL Variants





Clone
SEQ ID NO:
VL



CL-22656
3162
EIVLTQSXGTLSLSPGXRXTLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-22715
3163
EIVLXQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-22747
3164
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWYSYVS WYQQKPGQ



APRLVIY ADDQRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINKDLT FGGGTKVEIK



CL-22748
3165
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGYSYVS WYQQKPGQ



APRLVIY AADQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGIIIDIT FGGGTKVEIK



CL-22749
3166
EIVLTQSPGTLSLSPGERATLSC ERSSGSIEHAYVS WYQQKPGQ



APRLLIY GADHRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDFNNTIT FGGGTKVEIK



CL-22750
3167
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGHCYVS WYQQKPGQ



APRLVIY AADHRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGKNIDGT FGGGTKVEIK



CL-22752
3168
EIVLTQSPGTLSLSPGERATLSC RASSGDIGDFCVS WYQQKPGQ



APRLLIY VDDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGRRLDIT FGGGTKVEIK



CL-22753
3169
EIVLTQSPGTLSLSPGERATLSC ERSSGDIVLPYVS WYQQKPGQ



APRLVIY AADWRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDITIDTV FGGGTKVEIK



CL-22754
3170
EIVLTQSPGTLSLSPGERATLSC RASSGSIGYECVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDRQIV FGGGTKVEIK



CL-22755
3171
EIVLTQSPGTLSLSPGERATLSC RASSGSIVGSYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGVHIDIT FGGGTKVEIK



CL-22756
3172
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGHSDVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIGQV FGGGTKVEIK



CL-22758
3173
EIVLTQSPGTLSLSPGERATLSC RASSGSIGHPYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGCHIYNV FGGGTKVEIK



CL-22759
3174
EIVLTQSPGTLSLSPGERATLSC ERSSGSICDTYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIYIHIV FGGGTKVEIK



CL-22760
3175
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYSCVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGIDIVIV FGGGTKVEIK



CL-22761
3176
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGYSDVS WYQQKPGQ



APRLLIY ADDKRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDKYIV FGGGTKVEIK



CL-22763
3177
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWHFYVS WYQQKPGQ



APRLVIY AADHRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGTNIEIV FGGGTKVEIK



CL-22764
3178
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGXADVS WYQQKPGQ



APRLVIY VDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGEYIDRT FGGGTKVEIK



CL-22765
3179
EIVLTQSPGTLSLSPGERATLSC RASSGSIGGSYVS WYQQKPGQ



APRLLIY ADDHRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGINIGTV FGGGTKVEIK



CL-22766
3180
EIVLTQSPGTLSLSPGERATLSC ERSSGDIECDFVS WYQQKPGQ



APRLVIY ADDHRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGINNDIT FGGGTKVEIK



CL-22767
3181
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGCSYVS WYQQKPGQ



APRLVIY GDDQRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINKEIT FGGGTKVEIK



CL-22768
3182
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGHSRVS WYQQKPGQ



APRLVIY VDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDNNIATV FGGGTKVEIK



CL-22769
3183
EIVLTQSPGTLSLSPGERATLSC ERSSGSINHCHVS WYQQKPGQ



APRLVIY AADXRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIILDIT FGGGTKVEIK



CL-22770
3184
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDHRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDFDIDIT FGGGTKVEIK



CL-22771
3185
EIVLTQSPGTLSLSPGERATLSC RASSGSIRYTYVS WYQQKPGQ



APRLVIY AADEPPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINRNIV FGGGTKVEIK



CL-22772
3186
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGCTYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGISTVLV FGGGTKVEIK



CL-22773
3187
EIVLTQSPGTLSLSPGERATLSC ERSSGDIRYCYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDVDIV FGGGTKVEIK



CL-22774
3188
EIVLTQSPGTLSLSPGERATLSC RASSGSISQSYVS WYQQKPGQ



APRLVIY ADDLRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGINIDIT FGGGTKVEIK



CL-22775
3189
EIVLTQSPGTLSLSPGERATLSC ERSSGSIFYGCVS WYQQKPGQ



APRLLIY ADDQRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDINIVIT FGGGTKVEIK



CL-22776
3190
EIVLTQSPGTLSLSPGERATLSC RASSGSIWYSYVS WYQQKPGQ



APRLVIY AADQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINKYAV FGGGTKVEIK



CL-22777
3191
EIVLTQSPGTLSLSPGERATLSC RASSGDISYSYVS WYQQKPGQ



APRLVIY VDDERAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDIYKDLT FGGGTKVEIK



CL-22778
3192
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDXRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDSNIDIV FGGGTKVEIK



CL-22779
3193
EIVLTQSPGTLSLSPGERATLSC ERSSGSICYXYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDVNLEHT FGGGTKVEIK



CL-22780
3194
EIVLTQSPGTLSLSPGERATLSC RASSGDIRHCYVS WYQQKPGQ



APRLLIY PDDLRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-22781
3195
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY VDDHRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGTSLDNT FGGGTKVEIK



CL-22782
3196
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGHSYVS WYQQKPGQ



APRLVIY AADHRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGVNIYIT FGGGTKVEIK



CL-22783
3197
EIVLTQSPGTLSLSPGERATLSC RASSGSIRYSYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDINKVIV FGGGTKVEIK



CL-22784
3198
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGKPTSP WYQQKPGQ



APRLVIY SADERPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGVNRDIV FGGGTKVEIK



CL-22785
3199
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGPCYVS WYQQKPGQ



APRLVIY ADDHRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDINLVIT FGGGTKVEIK



CL-22786
3200
EIVLTQSPGTLSLSPGERATLSC ERSSGSIHYSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGISIDIT FGGGTKVEIK



CL-22787
3201
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDPYVS WYQQKPGQ



APRLVIY AADPRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDISIYIV FGGGTKVEIK



CL-22788
3202
EIVLTQSPGTLSLSPGERATLSC ERSSGDIKHCCVS WYQQKPGQ



APRLVIY LDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDISIDIT FGGGTKVEIK



CL-22789
3203
EIVLTQSPGTLSLSPGERATLSC RASSGSIVQSYVS WYQQKPGQ



APRLLIY SDDPRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGLYRDIT FGGGTKVEIK



CL-22790
3204
EIVLTQSPGTLSLSPGERATLSC RASSGSISYSYVS WYQQKPGQ



APRLLIY ADDXRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QHYDIHINIT FGGGTKVEIK



CL-22791
3205
EIVLTQSPGTLSLSPGERATLSC RASSGDIGYAHVS WYQQKPGQ



APRLLIY GDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGKNSEIT FGGGTKVEIK



CL-22792
3206
EIVLTQSPGTLSLSPGERATLSC RASSGSIGHSYVS WYQQKPGQ



APRLLIY DDDPRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGINVDIV FGGGTKVEIK



CL-22794
3207
EIVLTQSPGTLSLSPGERATLSC RASSGSIGHSCVS WYQQKPGQ



APRLVIY SADERAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDLNTLFV FGGGTKVEIK



CL-22795
3208
EIVLTQSPGTLSLSPGERATLSC RASSGDIGHXYVS WYQQKPGQ



APRLVIY AADHRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGISIAVV FGGGTKVEIK



CL-22796
3209
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGLSYVS WYQQKPGQ



APRLVIY AADQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDRHLDAT FGGGTKVEIK



CL-22797
3210
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGCSYVS WYQQKPGQ



APRLLIY GADHRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGIDIDIT FGGGTKVEIK



CL-22798
3211
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDASVS WYQQKPGQ



APRLLIY AADQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDITIGVV FGGGTKVEIK



CL-22799
3212
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYCFVS WYQQKPGQ



APRLVIY AADLRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIKIGIT FGGGTKVEIK



CL-22800
3213
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYWDVS WYQQKPGQ



APRLLIY ADDERAS GIPDRFSGSGSGTDFTLTISRLEPEDFSVY



YC QSYGINKDFV FGGGTKVEIK



CL-22801
3214
EIVLTQSPGTLSLSPGERATLSC RASSGDIGHTYVS WYQQKPGQ



APRLVIY TDDLRAS GIPDRFSGSGSGTDFTLTISRLDPEDFAVY



YC QQYDLNIDIV FGGGTKVEIK



CL-22802
3215
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGXSHVS WYQQKPGQ



APRLLIY VDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIKKGXT FGGGTKVEIK



CL-22803
3216
EIVLTQSPGTLSLSPGERATLSC RASSGDIGHSFVS WYQQKPGQ



APRLVIY ADDHRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGVNIDIT FGGGTKVEIK



CL-22804
3217
EIVLTQSPGTLSLSPGERATLSC RASSGSIFQSDVS WYQQKPGQ



APRLVIY ADDHRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGKNIYIV FGGGTKVEIK



CL-22805
3218
EIVLTQSPGTLSLSPGERATLSC RASSGDIGYSAVS WYQQKPGQ



APRLVXY VDDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIKLDFV FGGGTKVEIK



CL-22806
3219
EIVLTQSPGTLSLSPGERATLSC RASSGSIVYSSVS WYQQKPGQ



APRLVIY VXDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDIHIDIT FGGGTKVEIK



CL-22807
3220
EIVLTQSPGTLSLSPGERATLSC RASSGSIRDFYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGINLDNT FGGGTKVEIK



CL-22808
3221
EIVLTQSPGTLSLSPGERATLSC ERSSGDISDSHVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIT FGGGTKVEIK



CL-22811
3222
EIVLTQSPGTLSLSPGERATLSC ERSSGSIALSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINLDIV FGGGTKVEIK



CL-22812
3223
EIVLTQSPGTLSLSPGERATLSC ERSSGDMRYSDVS WYQQKPGQ



APRMVIY AVDQRAS GIPDRLSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDVGMVLT FGGGTKVEIK



CL-22813
3224
EIVLTQSPGTLSLSPGERATLSC RASSGDIGHFYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGISIDLT FGGGTKVEIK



CL-22815
3225
EIVLTQSPGTLSLSPGERATLSC ERSSGDIDHSYVS WYQQKPGQ



APRLVIY ADDPRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGLNIDLT FGGGTKVEIK



CL-22816
3226
EIVLTQSPGTLSLSPGERATLSC ERSSGSIRHSCVS WYQQKPGQ



APRLVIY ADDHRAS GIPDRFSDSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-22818
3227
EIVLTQSPGTLSLSPGERATLSC RASSGDIWHSYVS WYQQKPGQ



APRLVIY TDDHRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGCDKDIT FGGGTKVEIK



CL-22819
3228
EIVLTQSPGTLSLSPGERATLSC RASSGSIGDFYVS WYQQKPGQ



APRLVIY ADDQRPT GIPDRLSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGIHIEIV FGGGTKVEIK



CL-22820
3229
EIVLTQSPGTLSLSPGERATLSC RASSGDIGHSAVS WYQQKPGQ



APRLLIY ADDPRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGKNKELV FGGGTKVEIK



CL-22821
3230
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGINSYLV FGGGTKVEIK



CL-22822
3231
EIVLTQSPGTLSLSPGERATLSC RASSGDIGPSYVS WYQQKPGQ



APRLLIY PDDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDINKELV FGGGTKVEIK



CL-22823
3232
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWYSYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGKNVDIV FGGGTKVEIK



CL-22824
3233
EIVLTQSPGTLSLSPGERATLSC RASSGSILDTYVS WYQQKPGQ



APRLVIY ADDSRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDVNVDIV FGGGTKVEIK



CL-22825
3234
EIVLTQSPGTLSLSPGERATLSC RASSGSISQSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDXTIGIV FGGGTKVEIK



CL-22826
3235
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGFSYVS WYQQKPGQ



APRLVIY EDDPRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGANIEIV FGGGTKVEIK



CL-22827
3236
EIVLTQSPGTLSLSPGERATLSC RASSGYISHEYVS WYQQKPGQ



APRLVIY AADQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGIHIHVT FGGGTKVEIK



CL-22828
3237
EIVLTQSPGTLSLSPGERATLSC RASSGDIGHSYVS WYQQKPGQ



APRLVIY EDDQRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGGNIGIV FGGGTKVEIK



CL-22829
3238
EIVLTQSPGTLSLSPGERATLSC RASSGSIDASYVS WYQQKPGQ



APRLLIY TDDRRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGIILDIV FGGGTKVEIK



CL-22830
3239
EIVLTQSPGTLSLSPGERATLSC RASSGSIGYSYVS WYQQKPGQ



APRLLIY ADDHRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGVIIYIT FGGGTKVEIK



CL-22832
3240
EIVLTQSPGTLSLSPGERATLSC RASSGDIFYSYVS WYQQKPGQ



APRLVIY ADDXRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-22833
3241
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYLYVS WYQQKPGQ



APXLVIY PDDXRAS GIPDRFSGSGSGXDFTLTISRLEPEDXAVY



YC QQYDKTIDIV FGGGTKVEIK



CL-22834
3242
EIVLTQSPGTLSLSPGERATLSC RASSGDICESCVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINKDIV FGGGTKVEIK



CL-22835
3243
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYSNVS WYQQKPGQ



APRLLIY EDDKRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGXLVPIV FGGGTKVEIK



CL-22836
3244
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGHSYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYGIKVDST FGGGTKVEIK



CL-22837
3245
EIVLTQSPGTLSLSPGERATLSC ERSSGSIQSLHVS WYQQKPGQ



APRLLIY ADDXRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGRHIGLV FGGGTKVEIK



CL-22838
3246
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGYCYVS WYQQKPGQ



APRLVIY ADDHRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDLCIYIT FGGGTKVEIK



CL-22839
3247
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSHVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIAIT FGGGTKVEIK



CL-22840
3248
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYTYVS WYQQKPGQ



APRLLIY PDDKRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIRPTT FGGGTKVEIK



CL-22841
3249
EIVLTQSPGTLSLSPGERATLSC ERSSGDIAHSYVS WYQQKPGQ



APRLVIY AADYRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDSHNNIV FGGGTKVEIK



CL-22842
3250
EIVLTQSPGTLSLSPGERATLSC RASSGSIRGLRVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGLNFDIV FGGGTKVEIK



CL-25631
3251
EIVLTQSPGTLSLSPGERATLSC RASSGSITYYYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINTDIV FGGGTKVEIK



CL-25634
3252
EFVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-25648
3253
EIVLTQSPGTLSLSPGEXATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY VDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-25655
3254
EIVLTQSPGTLSLSPGERXTLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-25666
3255
EIVLTQXPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-25690
3256
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY SDDQRPG GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-25721
3257
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGYGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-25724
3258
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLLIY VDDWRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDIDVV FGGGTKVEIK



CL-25725
3259
EIVLTQSPGTLSLSPGERATLSC ERSSGDIDYSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDIV FGGGTKVEIK



CL-25726
3260
EIVLTQSPGTLSLSPGERATLSC RASSGSIGYSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINTDVV FGGGTKVEIK



CL-25727
3261
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWYSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIYIDVT FGGGTKVEIK



CL-25728
3262
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGYSYVS WYQQKPGQ



APRLVIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDIV FGGGTKVEIK



CL-25729
3263
EIVLTQSPGTLSLSPGERATLSC ERSSGDIAGYYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIT FGGGTKVEIK



CL-25730
3264
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGESYVS WYQQKPGQ



APRLVIY ADDLRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIVIDIX FGGGTKVEIK



CL-25731
3265
EIVLTQSPGTLSLSPGERATLSC RASSGSIVYSYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIYIDIT FGGGTKVEIK



CL-25732
3266
EIVLTQSPGTLSLSPGERATLSC RASSGDIVYSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDIDVT FGGGTKVEIK



CL-25733
3267
EIVLTQSPGTLSLSPGERATLSC RASSGDIWDAYVS WYQQKPGQ



APRLLIY ADDHRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIT FGGGTKVEIK



CL-25734
3268
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYAYVS WYQQKPGQ



APRLVIY ADDYRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDVDIV FGGGTKVEIK



CL-25735
3269
EIVLTQSPGTLSLSPGERATLSC RASSGDILDSYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDTIIDIT FGGGTKVEIK



CL-25736
3270
EIVLTQSPGTLSLSPGERATLSC ERSSGDIDDYYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIYIDVT FGGGTKVEIK



CL-25737
3271
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDFYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDVTIDVT FGGGTKVEIK



CL-25738
3272
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGLSYVS WYQQKPGQ



APRLVIY SDDLRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDVDIDVT FGGGTKVEIK



CL-25739
3273
EIVLTQSPGTLSLSPGERATLSC ERSSGDIFYTYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLDIDIT FGGGTKVEIK



CL-25740
3274
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLLIY ADDQRAI GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIYVDVV FGGGTKVEIK



CL-25741
3275
EIVLTQSPGTLSLSPGERATLSC RASSGDIEGSYVS WYQQKPGQ



APRLVIY SDDLRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIV FGGGTKVEIK



CL-25742
3276
EIVLTQSPGTLSLSPGERATLSC RASSGDISCSYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINTDIV FGGGTKVEIK



CL-25743
3277
EIVLTQSPGTLSLSPGERATLSC RASSGSIGSYYVS WYQQKPGQ



APRLVIY SDDQRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIYIDVV FGGGTKVEIK



CL-25745
3278
EIVLTQSPGTLSLSPGERATLSC RASSGDIWYSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIEIDVT FGGGTKVEIK



CL-25747
3279
EIVLTQSPGTLSLSPGERATLSC RASSGDIGYSYVS WYQQKPGQ



APRLLIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIISDIT FGGGTKVEIK



CL-25748
3280
EIVLTQSPGTLSLSPGERATLSC RASSGSIDYAYVS WYQQKPGQ



APRLVIY ADDQRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGITIDVV FGGGTKVEIK



CL-25749
3281
EIVLTQSPGTLSLSPGERATLSC RASSGSIYFAYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGITIDVV FGGGTKVEIK



CL-25751
3282
EIVLTQSPGTLSLSPGERATLSC RASSGSIWYSYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINVDIV FGGGTKVEIK



CL-25752
3283
EIVLTQSPGTLSLSPGERATLSC RASSGDIAHSYVS WYQQKPGQ



APRLVIY TDDARAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIVDIV FGGGTKVEIK



CL-25754
3284
EIVLTQSPGTLSLSPGERATLSC ERSSGDICQYYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLNIDVT FGGGTKVEIK



CL-25756
3285
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGDSYVS WYQQKPGQ



APRLLIY NDDDRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLTIDVT FGGGTKVEIK



CL-25758
3286
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYSYVS WYQQKPGQ



APRLVIY ADDQRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIV FGGGTKVEIK



CL-25759
3287
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGHSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDVDIV FGGGTKVEIK



CL-25760
3288
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWDMYVS WYQQKPGQ



APRLVIY ADDQRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIEIDIT FGGGTKVEIK



CL-25761
3289
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY GDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIT FGGGTKVEIK



CL-25763
3290
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWESYVS WYQQKPGQ



APRLVIY ADDERAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDIV FGGGTKVEIK



CL-25765
3291
EIVLTQSPGTLSLSPGERATLSC RASSGDIAYSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-25767
3292
EIVLTQSPGTLSLSPGERATLSC RASSGSIFGAYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIITDIV FGGGTKVEIK



CL-25769
3293
EIVLTQSPGTLSLSPGERATLSC RASSGSIADSLVS WYQQKPGQ



APRLVIY TDDWRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-25770
3294
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGDSYVS WYQQKPGQ



APRLLIY TDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDITIDIV FGGGTKVEIK



CL-25771
3295
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDYYVS WYQQKPGQ



APRLVIY SDDQRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLDIDIT FGGGTKVEIK



CL-25772
3296
EIVLTQSPGTLSLSPGERATLSC ERSSGSIVHSYVS WYQQKPGQ



APRLVXY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIXVDIV FGGGTKVEIK



CL-25773
3297
EIVLTQSPGTLSLSPGERATLSC RASSGDIWYSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGITVDIV FGGGTKVEIK



CL-25775
3298
EIVLTQSPGTLSLSPGERATLSC ERSSGDIFYSYVS WYQQKPGQ



APRLVIY ADDERAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIEIDIV FGGGTKVEIK



CL-25776
3299
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDVDIV FGGGTKVEIK



CL-25778
3300
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGLSYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLIIDIV FGGGTKVEIK



CL-25779
3301
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYSYVS WYQQKPGQ



APRLVIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDIV FGGGTKVEIK



CL-25780
3302
EIVLTQSPGTLSLSPGERATLSC RASSGDIGYSYVS WYQQKPGQ



APRLVIY ADDERAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIEIDIT FGGGTKVEIK



CL-25782
3303
EIVLTQSPGTLSLSPGERATLSC RASSGDIGYSYVS WYQQKPGQ



APRLLIY FDDYRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIEIDIV FGGGTKVEIK



CL-25783
3304
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYYYVS WYQQKPGQ



APRLVIY ADDERAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIYIDVV FGGGTKVEIK



CL-25784
3305
EIVLTQSPGTLSLSPGERATLSC RASSGDISDSYVS WYQQKPGQ



APRLVIY TDDHRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDIV FGGGTKVEIK



CL-25785
3306
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGDSYVS WYQQKPGQ



APRLVIY VDDWRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDVDIV FGGGTKVEIK



CL-25786
3307
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGHSYVS WYQQKPGQ



APRLVIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIV FGGGTKVEIK



CL-25787
3308
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWYSYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDIIDDIV FGGGTKVEIK



CL-25788
3309
EIVLTQSPGTLSLSPGERATLSC RASSGDIGYSYVS WYQQKPGQ



APRLLIY ADDFRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIITDIT FGGGTKVEIK



CL-25789
3310
EIVLTQSPGTLSLSPGERATLSC ERSSGDIYYSYVS WYQQKPGQ



APRLVIY SDDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDVT FGGGTKVEIK



CL-25790
3311
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYSYVS WYQQKPGL



APRLLIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGTYVDIV FGGGTKVEIK



CL-25791
3312
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDTYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRXSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDXV FGGGTKVEIK



CL-25792
3313
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWQYYVS WYQQKPGQ



APRLVIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-25793
3314
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDWRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIYIDIV FGGGTKVEIK



CL-25794
3315
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGHSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDTIIDIV FGGGTKVEIK



CL-25795
3316
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDYYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVV FGGGTKVEIK



CL-25796
3317
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDTIIDIV FGGGTKVEIK



CL-25797
3318
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWQYYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLNIDIT FGGGTKVEIK



CL-25798
3319
EIVLTQSPGTLSLSPGERATLSC RASSGDIGESYVS WYQQKPGQ



APRLVIY SDDSRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIV FGGGTKVEIK



CL-25799
3320
EIVLTQSPGTLSLSPGERATLSC RASSGDIGYSYVS WYQQKPGQ



APRLVIY ADDLRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIIDIV FGGGTKVEIK



CL-25800
3321
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDYYVS WYQQKPGQ



APRLVIY WDDYRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDVILDIT FGGGTKVEIK



CL-25801
3322
EIVLTQSPGTLSLSPGERATLSC ERSSGDISYTYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIITDIV FGGGTKVEIK



CL-25802
3323
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGESYVS WYQQKPGQ



APRLVIY TDDWRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGSNIDVV FGGGTKVEIK



CL-25803
3324
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDYYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGILTDIT FGGGTKVEIK



CL-25804
3325
EIVLTQSPGTLSLSPGERATLSC RASSGSIAHSYVS WYQQKPGQ



APRLVIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIVDIV FGGGTKVEIK



CL-25805
3326
EIVLTQSPGTLSLSPGERATLSC RASSGSIVYSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIITDIV FGGGTKVEIK



CL-25806
3327
EIVLTQSPGTLSLSPGERATLSC ERSSGDISYSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDIT FGGGTKVEIK



CL-25807
3328
EIVLTQSPGTLSLSPGERATLSC RASSGSIGDTYVS WYQQKPGQ



APRLLIY ADDWRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIEIDIV FGGGTKVEIK



CL-25808
3329
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDTYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDIV FGGGTKVEIK



CL-25809
3330
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGETYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGTIIDIV FGGGTKVEIK



CL-25810
3331
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDTYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIV FGGGTKVEIK



CL-25812
3332
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWYSYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIV FGGGTKVEIK



CL-25813
3333
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLLIY ADDYRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIVDIT FGGGTKVEIK



CL-25814
3334
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGQSYVS WYQQKPGQ



APRLVIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIV FGGGTKVEIK



CL-25815
3335
EIVLTQSPGTLSLSPGERATLSC RESSGDILYTYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIEIDIT FGGGTKVEIK



CL-25816
3336
EIVLTQSPGTLSLSPGERATLSC RASSGDIGHSYVS WYQQKPGQ



APRLVIY ADDQRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIIDVT FGGGTKVEIK



CL-25818
3337
EIVLTQSPGTLSLSPGERATLSC RASSGDISDSYVS WYQQKPGQ



APRLLIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIIDIV FGGGTKVEIK



CL-25819
3338
EIVLTQSPGTLSLSPGERATLSC RASSGSIGHSYVS WYQQKPGQ



APRLVIY GDDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDVDIDVV FGGGTKVEIK



CL-28175
3339
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY VDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-28178
3340
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV CGGGTKVEIK



CL-28195
3341
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPGRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-28212
3342
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDFYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-28215
3343
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDYYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTINRMEPEDFAVY



YC QSYDINMDIV FGGGTKVEIK



CL-28233
3344
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY GDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-29595
3345
EIVLTQSPGTLSLSPGERATLSC RASSGSISYSYVS WYQQKPGQ



APRLVIY ADDLRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-29596
3346
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWYSYVS WYQQKPGQ



APRLLIY ADDQRAS GIPYRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINVDTV FGGGTKVEIK



CL-29597
3347
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGDAYVS WYQQKPGQ



APRLVIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIVDVV FGGGTKVEIK



CL-29598
3348
EIVLTQSPGTLSLSPGERATLSC RASSGSIGDSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIAIDIV FGGGTKVEIK



CL-29599
3349
EIVLTQSPGTLSLSPGERATLSC RASSGSIEYSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIVDIV FGGGTKVEIK



CL-29600
3350
EIVLTQSPGTLSLSPGERATLSC RASSGSIEGAYVS WYQQKPGQ



APRLVIY SDDERAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIITDIV FGGGTKVEIK



CL-29601
3351
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGGTYVS WYQQKPGQ



APRLVIY ADDLRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIEIDIT FGGGTKVEIK



CL-29602
3352
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGSCYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVV FGGGTKVEIK



CL-29603
3353
EIVLTQSPGTLSLSPGERATLSC RASSGDIGYTYVS WYQQKPGQ



APRLVIY ADDVRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDVDIV FGGGTKVEIK



CL-29604
3354
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWGYYVS WYQQKPGQ



APRLVIY ADDHRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIT FGGGTKVEIK



CL-29605
3355
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGEAYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIT FGGGTKVEIK



CL-29606
3356
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYSYVS WYQQKPGQ



APRLLIY SDDNRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGTIIDIT FGGGTKVEIK



CL-29607
3357
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDITIDIV FGGGTKVEIK



CL-29608
3358
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWYSYVS WYQQKPGQ



APRLLIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLIIDVV FGGGTKVEIK



CL-29609
3359
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWHSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIT FGGGTKVEIK



CL-29610
3360
EIVLTQSPGTLSLSPGERATLSC RASSGDIGDSYVS WYQQKPGQ



APRLVIY ADDDRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDVDVT FGGGTKVEIK



CL-29611
3361
EIVLTQSPGTLSLSPGERATLSC RASSGDIAHSYVS WYQQKPGQ



APRLLIY VDDLRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDITIDIV FGGGTKVEIK



CL-29612
3362
EIVLTQSPGTLSLSPGERATLSC ERSSGDIYSYYVS WYQQKPGQ



APRLLIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLNIDVV FGGGTKVEIK



CL-29613
3363
EIVLTQSPGTLSLSPGERATLSC RASSGDISESYVS WYQQKPGQ



APRLLIY TDDLRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDTDIV FGGGTKVEIK



CL-29614
3364
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSLVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGVIVDIV FGGGTKVEIK



CL-29615
3365
EIVLTQSPGTLSLSPGERATLSC RASSGDIYESYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDVTIDIV FGGGTKVEIK



CL-29617
3366
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGFAYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDIDIV FGGGTKVEIK



CL-29618
3367
EIVLTQSPGTLSLSPGERAPLSC ERSSGSIWDSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDVDIDIV FGGGTKVEIK



CL-29620
3368
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDSYVS WYQQKPGQ



APRLVIY SDDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIIDIT FGGGTKVEIK



CL-29621
3369
EIVLTQSPGTLSLSPGERATLSC RASSGSIGYSYVS WYQQKPGQ



APRLVIY ADDRRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIRDIV FGGGTKVEIK



CL-29622
3370
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIVDIV FGGGTKVEIK



CL-29623
3371
EIVLTQSPGTLSLSPGERATLSC RASSGSIWYSYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVT FGGGTKVEIK



CL-29624
3372
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDSYVS WYQQKPGQ



APRLVIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIIDIV FGGGTKVEIK



CL-29625
3373
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYFYVS WYQQKPGQ



APRLVIY VDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-29626
3374
EIVLTQSPGTLSLSPGERATLSC RASSGSIGDTYVS WYQQKPGQ



APRLLIY SDDHRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-29627
3375
EIVLTQSPGTLSLSPGERATLSC RASSGDIWYSFVS WYQQKPGQ



APRLLIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIISDIV FGGGTKVEIK



CL-29628
3376
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGETYVS WYQQKPGQ



APRLVIY ADDLRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIVDIV FGGGTKVEIK



CL-29629
3377
EIVLTQSPGTLSLSPGERATLSC RASSGDIGDCFVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-29630
3378
EIVLTQSPGTLSLSPGERATLSC RASSGDIRHSFVS WYQQKPGQ



APRLVIY WDDYRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVT FGGGTKVEIK



CL-29631
3379
EIVLTQSPGTLSLSPGERATLSC ERSSGSIDECYVS WYQQKPGQ



APRLVIY ADDDRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVV FGGGTKVEIK



CL-29632
3380
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGESYVS WYQQKPGQ



APRLVIY TDDRRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGSNIDVV FGGGTKVEIK



CL-29634
3381
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QQYDIDTDIV FGGGTKVEIK



CL-29635
3382
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGHSYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIT FGGGTKVEIK



CL-29636
3383
EIVLTQSPGTLSLSPGERATLSC RASSGDICHSYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIVDIV FGGGTKVEIK



CL-29637
3384
EIVLTQSPGTLSLSPGERATLSC ERSSGSINESYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDIDIV FGGGTKVEIK



CL-29638
3385
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWYSYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVT FGGGTKVEIK



CL-29639
3386
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDTYVS WYQQKPGQ



APRLLIY ADDERAS RIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDIDVV FGGGTKVEIK



CL-29640
3387
EIVLTQSPGTLSLSPGERATLSC RASSGDIWYSYVS WYQQKPGQ



APRLVIY ADDQRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDIT FGGGTKVEIK



CL-29641
3388
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWQSYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIVIDIT FGGGTKVEIK



CL-29642
3389
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWYSYVS WYQQKPGQ



APRLLIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIV FGGGTKVEIK



CL-29643
3390
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDYYVS WYQQKPGQ



APRLVIY SDDQRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLIIDIT FGGGTKVEIK



CL-29644
3391
EIVLTQSPGTLSLSPGERATLSC RASSGDIGYTYVS WYQQKPGQ



APRLVIY SDDHRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIVDIV FGGGTKVEIK



CL-29645
3392
EIVLTQSPGTLSLSPGERATLSC ERSSGDISGAYVS WYQQKPGQ



APRLVIY GDDERAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDVT FGGGTKVEIK



CL-29646
3393
EIVLTQSPGTLSLSPGERATLSC RASSGDIGRSYVS WYQQKPGQ



APRLVIY ADDLRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDVNTDIV FGGGTKVEIK



CL-29647
3394
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWHTYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIIDIT FGGGTKVEIK



CL-29648
3395
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYAYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIILDVT FGGGTKVEIK



CL-29649
3396
EIVLTQSPGTLSLSPGERATLSC RASSGDIEHSYVS WYQQKPGQ



APRLLIY VDDQRPT GIPDRFSGSGSGTDFTLTISRLXPEDFAVY



YC QSYGIREDIV FGGGTKVEIK



CL-29650
3397
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGFSYVS WYQQKPGQ



APRLVIY ADDLRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGTYVDVV FGGGTKVEIK



CL-29651
3398
EIVLTQSPGTLSLSPGERATLSC RASSGDIWYSYVS WYQQKPGQ



APRLVIY SDDERPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGVDVDVV FGGGTKVEIK



CL-29652
3399
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIV FGGGTKVEIK



CL-29653
3400
EIVLTQSPGTLSLSPGERATLSC RASSGDIEHSYVS WYQQKPGQ



APRLLIY ADDYRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDPDIT FGGGTKVEIK



CL-29654
3401
EIVLTQSPGTLSLSPGERATLSC RASSGDISHSYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDIT FGGGTKVEIK



CL-29655
3402
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDAYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIFIDIV FGGGTKVEIK



CL-29656
3403
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGEYYVS WYQQKPGQ



APRLVIY ADDRRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVT FGGGTKVEIK



CL-29657
3404
EIVLTQSPGTLSLSPGERATLSC ERSSGSIDYAYVS WYQQKPGQ



APRLVIY SDDYRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDIT FGGGTKVEIK



CL-29658
3405
EIVLTQSPGTLSLSPGERATLSC RASSGDIWYSYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIVIDIV FGGGTKVEIK



CL-29659
3406
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGYSYVS WYQQKPGQ



APRLVMY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDVIIDVV FGGGTKVEIK



CL-29660
3407
EIVLTQSPGTLSLSPGERATLSC RASSGDIGYSYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDVT FGGGTKVEIK



CL-29661
3408
EIVLTQSPGTLSLSPGERATLSC RASSGSIWHSYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC KSYGINIDVT FGGGTKVEIK



CL-29662
3409
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYSYVS WYQQKPGQ



APRLVIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDVV FGGGTKVEIK



CL-29663
3410
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDTYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDIDIT FGGGTKVEIK



CL-29664
3411
EIVLTQSPGTLSLSPGERATLSC RASSGDIRHSYVS WYQQKPGQ



APRLVIY ADDDRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINTDIV FGGGTKVEIK



CL-29665
3412
EIVLTQSPGTLSLSPGERATLSC RASSGDIGGSYVS WYQQKPGQ



APRLVIY TDDWRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-29666
3413
EIVLTQSPGTLSLSPGERATLSC RASSGDISYSYVS WYQQKPGQ



APRLLIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIIDVV FGGGTKVEIK



CL-29667
3414
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDMYVS WYQQKPGQ



APRLVIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIV FGGGTKVEIK



CL-29668
3415
EIVLTQSPGTLSLSPGERATLSC ERSSGDIDYTYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLTLDIT FGGGTKVEIK



CL-29669
3416
EIVLTQSPGTLSLSPGERATLSC ERSSSSIWHSYVS WYQQKPGQ



APRLVIY ADDYRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVV FGGGTKVEIK



CL-29670
3417
EIVLTQSPGTLSLSPGERATLSC RASSGSIDYSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIYIDVV FGGGTKVEIK



CL-29671
3418
EIVLTQSPGTLSLSPGERATLSC RASSGSIWYSFVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGQYIDVV FGGGTKVEIK



CL-29672
3419
EIVLTQSPGTLSLSPGERATLSC RASSGDIDESYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIIDIV FGGGTKVEIK



CL-29673
3420
EIVLTQSPGTLSLSPGERATLSC RASSGDIXYSYVS WYQQKPGQ



APRLVIY SDDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDSIIDVT FGGGTKVEIK



CL-29674
3421
EIVLTQSPGTLSLSPGERATLSC RASSGDIWYSYVS WYQQKPGQ



APRLLIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINVDIV FGGGTKVEIK



CL-29675
3422
EIVLTQSPGTLSLSPGERATLSC ERSSGSIMYAYVS WYQQKPGQ



APRLVIY ADDQRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLIIDVT FGGGTKVEIK



CL-29676
3423
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDTYVS WYQQKPGQ



APRLVIY ADDARAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLDIDIT FGGGTKVEIK



CL-29677
3424
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWHSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDISIDVT FGGGTKVEIK



CL-29678
3425
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGETYVS WYQQKPGQ



APRLLIY SDDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDIDIV FGGGTKVEIK



CL-29679
3426
EIVLTQSPGTLSLSPGERATLSC RASSGSIGDSYVS WYQQKPGQ



APRLLIY SDDDRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGISIDVT FGGGTKVEIK



CL-29681
3427
EIVLTQSPGTLSLSPGERATLSC RASSGDIGHSYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIT FGGGTKVEIK



CL-29682
3428
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDTYVS WYQQKPGQ



APRLVIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIIDIV FGGGTKVEIK



CL-29683
3429
EIVLTQSPGTLSLSPGERATLSC ERSSGDIYSYYVS WYQQKPGQ



APRLLIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVT FGGGTKVEIK



CL-29684
3430
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWHSYVS WYQQKPGQ



APRLVIY SDDQQAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIV FGGGTKVEIK



CL-29685
3431
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYSYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIVIDIV FGGGTKVEIK



CL-29686
3432
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDTYVS WYQQKPGQ



APRLVIY ADDQRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLTIDIV FGGGTKVEIK



CL-29687
3433
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDICIDVT FGGGTKVEIK



CL-29688
3434
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLLIY SDDHRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIIDIV FGGGTKVEIK



CL-29689
3435
EIVLTQSPGTLSLSPGERATLSC ERSSGSIGGYYVS WYQQKPGQ



APRLLIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIIDIV FGGGTKVEIK



CL-29690
3436
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYSYVS WYQQKPGQ



APRLVIY GADLRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDIDIV FGGGTKVEIK



CL-29722
3437
EIVLTQSPGTLSLSPGERATLSC ERSXGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-29732
3438
EIVLTQSPGTLSLSPGERATLSC ERSSVDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-29741
3439
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIH ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-29746
3440
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPVQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-29756
3441
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



ATRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-29759
3442
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY AYDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-29765
3443
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-29771
3444
EXXLTQSPGTLSLSPGERATXSC ERSSGDXGDSYVS WYQQKPGQ



APRLVIY XDDQRPS GIPDRFSGSGSGTDFTLTISGLEPEDFAVY



YC QSXDINMDIV FGGGTKVEIK



CL-29780
3445
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGVGTKVEIK



CL-29781
3446
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFVVY



YC QSYDINIDIV FGGGTKVEIK



CL-33580
3447
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY XDDQRPS GIPDRFSGSGSGGDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-33673
3448
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWEYYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLEVDIV FGGGTKVEIK



CL-33674
3449
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWDTYVS WYQQKPGQ



APRLVIY SDDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINVDIV FGGGTKVEIK



CL-33676
3450
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWGYYVS WYQQKPGQ



APRLLIY ADDLRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDVV FGGGTKVEIK



CL-33677
3451
EIVLTQSPGTLSLSPGERATLSC ERSSGSIYYTYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDVDVV FGGGTKVEIK



CL-33678
3452
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWGYYVS WYQQKPGQ



APRLLIY ADDLRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDIDIT FGGGTKVEIK



CL-33679
3453
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDTYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGLNVDVV FGGGTKVEIK



CL-33680
3454
EIVLTQSPGTLSLSPGERATLSC ERSSGDIYETYVS WYQQKPGQ



APRLVIY SDDHRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVV FGGGTKVEIK



CL-33681
3455
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWYSYVS WYQQKPGQ



APRLLIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIITDVT FGGGTKVEIK



CL-33684
3456
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWGYYVS WYQQKPGQ



APRLLIY ADDLRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDVV FGGGTEVEIK



CL-33685
3457
EIVLTQSPGTLSLSPGERATLSC ERSSGDIYYTYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-33687
3458
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDYYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLDIDVV FGGGTKVEIK



CL-33688
3459
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWQSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIV FGGGTKVEIK



CL-33690
3460
EIVLTQSPGTLSLSPGERATLSC KRSSGSIYDTYVS WYQQKPGQ



APRLVIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDVDSDIV FGGGTKVEIK



CL-33691
3461
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDYYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDIDVT FGGGTKVEIK



CL-33692
3462
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDYYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLDIDVT FGGGTKVEIK



CL-33693
3463
EIVLTQSPGTLSLSPGERATLSC ERSSGSIYESYVS WYQQKPGQ



APRLLIY SDDQRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDIDVV FGGGTKVEIK



CL-33694
3464
EIVLTQSPGTLSLSPGERATLSC ERSSGSIYHTYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLDIDVT FGGGTKVEIK



CL-33695
3465
EIVLTQSPGTLSLSPGERATLSC ERSSGSIYDTYVS WYQQKPGQ



APRLVIY SDDQRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLDIDIV FGGGTKVEIK



CL-33697
3466
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWQTYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDVDIV FGGGTKVEIK



CL-33698
3467
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWXYYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLFIDVT FGGGTKVEIK



CL-33700
3468
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWHYYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLEIDVT FGGGTKVEIK



CL-33704
3469
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWSYYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLTVDVV FGGGTKVEIK



CL-33707
3470
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWSYYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLDIDVT FGGGTKVEIK



CL-33708
3471
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDYYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVT FGGGTKVEIK



CL-33709
3472
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWQTYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVT FGGGTKVEIK



CL-33710
3473
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWEYYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLDIDVV FGGGTKVEIK



CL-33712
3474
EIVLTQSPGTLSLSPGERATLSC RASSGSIYYSYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVV FGGGTKVEIK



CL-33713
3475
EIVLTQSPGTLSLSPGERATLSC ERYSGDIWYTYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDVDVV FGGGTKVEIK



CL-33716
3476
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWEYYVS WYQQKPGQ



APRLVIY ADDLRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLDIDVT FGGGTKVEIK



CL-33718
3477
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWEYYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLNIDVV FGGGTKVEIK



CL-33719
3478
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWEYYVS WYQQKPGQ



APRLVIY ADDLRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLDIDVT FGGGTKVEIK



CL-33720
3479
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWEYYVS WYQQKPGQ



APRLVIY TDDLRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIETDIV FGGGTKVEIK



CL-33721
3480
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWYSYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDVDVT FGGGTKVEIK



CL-33722
3481
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWYSYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIYIDVV FGGGTKVEIK



CL-33723
3482
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWEYYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDVCIDVV FGGGTKVEIK



CL-33725
3483
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWEYYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLDIDVV FGGGTKVEIK



CL-33726
3484
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWYSYVS WYQQKPGQ



APRLVIY SDDLRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDVV FGGGTKVEIK



CL-33727
3485
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY WDDYRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDVDIV FGGGTKVEIK



CL-33729
3486
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWSYYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLDIDIT FGGGTKVEIK



CL-33730
3487
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWSYYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLNIDTV FGGGTKVEIK



CL-33732
3488
EIVLTQSPGTLSLSPGERATLSC ERSSCDIWQYYVS WYQQKPGQ



APRLLIY ADDQRAT GIPDRFSGSGSGTDFTLIISRLEPEDFAVY



YC QSYDLDIDVV FGGGTKVEIK



CL-33733
3489
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWEYYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIITDVV FGGGTKVEIK



CL-33734
3490
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWHTYVS WYQQKPGQ



APRLVIY ADDQRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDVNIDVV FGGGTKVEIK



CL-33740
3491
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWSTYVS WYQQKPGQ



APRLLIY SDDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDVVIDIV FGGGTKVEIK



CL-33741
3492
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWEYYVS WYQQKPGQ



APRLLIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLIIDIV FGGGTKVEIK



CL-33742
3493
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWHYYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLDIDVT FGGGTKVEIK



CL-33743
3494
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWGYYVS WYQQKPGQ



APRLVIY ADDHRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDETIDIV FGGGTKVEIK



CL-33745
3495
EIVLTQSPGTLSLSPGERATLSC ERSSGDIYYTYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDIT FGGGTKVEIK



CL-33746
3496
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWQSYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDVDIV FGGGTKVEIK



CL-33747
3497
EIVLTQSPGTLSLSPGERATLSC RASSGSIWYSFVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-33755
3498
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY SDDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGTNIDVV FGGGTKVEIK



CL-33756
3499
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWESYVS WYQQKPGQ



APRLVIY ADDQRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIDDIV FGGGTKVEIK



CL-33757
3500
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWETYVS WYQQKPGQ



APRLVIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVT FGGGTKVEIK



CL-33758
3501
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWQTYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVV FGGGTKVEIK



CL-33760
3502
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGLNIDVV FGGGTKVEIK



CL-33761
3503
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWSYYVS WYQQKPGQ



APRLLIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDICIDVT FGGGTKVEIK



CL-33763
3504
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWEYYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDIV FGGGTKVEIK



CL-33766
3505
EIVLTQSPGTLSLSPGERATLSC ERSSGDIYDAYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDVDVV FGGGTKVEIK



CL-33768
3506
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWDTYVS WYQQKPGQ



APRLVIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVV FGGGTKVEIK



CL-33771
3507
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWQYYVS WYQQKPGQ



APRLLIY ADDKRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDEDIDIT FGGGTKVEIK



CL-33773
3508
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWSYYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLNIDVT FGGGTKVEIK



CL-33774
3509
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWSYYVS WYQQKPGQ



APRLLIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLYIDIV FGGGTKVEIK



CL-33775
3510
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWQTYVS WYQQKPGQ



APRLVIY ADDMRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLNIDVT FGGGTKVEIK



CL-33776
3511
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGYSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIIDIV FGGGTKVEIK



CL-33777
3512
EIVLTQSPGTLSLSPGERATLSC ERSSGDIYETYVS WYQQKPGQ



APRLLIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVV FGGGTKVEIK



CL-33778
3513
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWEYYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGLITDVT FGGGTKVEIK



CL-33779
3514
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWETYVS WYQQKPGQ



APRLVIY ADDRRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDIDVV FGGGTKVEIK



CL-33781
3515
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWEYYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDTDIV FGGGTKVEIK



CL-33782
3516
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDTYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-33785
3517
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWQTYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIVIDVV FGGGTKVEIK



CL-33787
3518
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWQYYVS WYQQKPGQ



APRLVIY ADDHRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLDIDVT FGGGTKVEIK



CL-33790
3519
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWHTYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDVDIDIT FGGGTKVEIK



CL-33791
3520
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWQAYVS WYQQKPGQ



APRLVIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIEDIT FGGGTKVEIK



CL-33792
3521
EIVLTQSPGTLSLSPGERATLSC ERSSGDIYETYVS WYQQKPGQ



APRLVIY SDDHRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIITDIV FGGGTKVEIK



CL-33794
3522
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWDYYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLITDIV FGGGTKVEIK



CL-33795
3523
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWQTYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-33796
3524
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWEYYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLIRDIV FGGGTKVEIK



CL-33799
3525
EIVLTQSPGTLSLSPGERATLSC ERSSGSIYETYVS WYQQKPGQ



APRLLIY ADDWRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDITVDVV FGGGTKVEIK



CL-33801
3526
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWESYVS WYQQKPGQ



APRLVIY SDDQRPT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIIDDIV FGGGTKVEIK



CL-33802
3527
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWEYYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLDIDIT FGGGTKVEIK



CL-33813
3528
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWQTYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDIDVV FGGGTKVEIK



CL-33814
3529
EIVLTQSPGTLSLSPGERATLSC RASSGSIWYSYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-33815
3530
EIVLTQSPGTLSLSPGERATLSC ERSSGDIYETYVS WYQQKPGQ



APRLVIY SDDHRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDVDVV FGGGTKVEIK



CL-33816
3531
EIVLTQSPGTLSLSPGERATLSC ERSSGDIYETYVS WYQQKPGQ



APRLVIY SDDHRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINVDVV FGGGTKVEIK



CL-33817
3532
EIVLTQSPGTLSLSPGERATLSC RASSGDISDKYVS WYQQKPGQ



APRLVIY ADDYRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLCIDVT FGGGTKVEIK



CL-33819
3533
EIVLTQSPGTLSLSPGERATLSC RASSGDISDKYVS WYQQKPGQ



APRLLIY ADDWRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDVDVV FGGGTKVEIK



CL-33825
3534
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWQYYVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLDIDVT FGGGTKVEIK



CL-33826
3535
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDYYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLEIDVV FGGGTKVEIK



CL-33828
3536
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDTYVS WYQQKPGQ



APRLLIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDITVDVV FGGGTKVEIK



CL-33829
3537
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWYSYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVT FGGGTKVEIK



CL-33832
3538
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDYYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLIIDVT FGGGTKVEIK



CL-33833
3539
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWETYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDVDIV FGGGTKVEIK



CL-33834
3540
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWYSYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDSDIV FGGGTKVEIK



CL-33836
3541
EIVLTQSPGTLSLSPGERATLSC RASSGSIWYSFVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINVDIV FGGGTKVEIK



CL-33837
3542
EIVLTQSPGTLSLSPGERATLSC ERSSGDIYQTYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDIDVV FGGGTKVEIK



CL-33839
3543
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWETYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGVDIDVV FGGGTKVEIK



CL-33840
3544
EIVLTQSPGTLSLSPGERATLSC ERSSGDIYETYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVV FGGGTKVEIK



CL-33841
3545
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWQYYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLFIDVT FGGGTKVEIK



CL-33844
3546
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDTYVS WYQQKPGQ



APRLLIY SDDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIYVDIV FGGGTKVEIK



CL-33847
3547
EIVLTQSPGTLSLSPGERATLSC ERSSGSIYYTYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIEIDIT FGGGTKVEIK



CL-33848
3548
EIVLTQSPGTLSLSPGERATLSC ERSSGDIYETYVS WYQQKPGQ



APRLVIY SDDHRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDTDIV FGGGTKVEIK



CL-33849
3549
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWYSYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-33854
3550
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWHTYVS WYQQKPGQ



APRLLIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINVDVV FGGGTKVEIK



CL-33857
3551
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWESYVS WYQQKPGQ



APRLLIY SDDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-33858
3552
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGHTYVS WYQQKPGQ



APRLVIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIISDVV FGGGTKVEIK



CL-33862
3553
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWGTYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVT FGGGTKVEIK



CL-41468
3554
EIVLTQSPGTLSLPPGERATLSC KRSSGSIYDTYVS WYQQKPGQ



APRLVIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLTIDIT FGGGTKVEIK



CL-41469
3555
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWHSYVS WYQQKPGQ



APRLLIY SDDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIYIDVV FGGGTRSKLS



CL-41472
3556
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDTYVS WYQQKPGQ



APRLLIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLTIDIT FGGGTKVEIK



CL-41477
3557
EIVLTQSPGTLSLSPGERATPSC RASSGSIWYSFVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-41479
3558
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDYYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QPYDLFIDVT FGGGTKVEIK



CL-41480
3559
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWQSYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAGY



YC QSYGINIDVV FGGGTKVEIK



CL-41486
3560
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDYYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLFIDVT FGGGTKVEIK



CL-41505
3561
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWHSYVS WYQQKPGQ



APRLLIY SDDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIETDIV FGGGTKVEIK



CL-41509
3562
EIVLTQSPGTWSLSPGERATLSC ERSSGSNYDTYVS WYQQKPGQ



APRLLIY ADDLRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIETDIV FGGGTKVEIK



CL-41528
3563
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWHSYVS WYQQKPGQ



APRLLIY SDDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIYIDVV FGGDTKVEIK



CL-41529
3564
EIVLTQSPGTLSLSSGERATLSC ERSSGSNYDTYVS WYQQKPGQ



APRLLIY ADDLRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIETDIV FGGGTKVEIK



CL-41532
3565
EIVLTQSPGTLSLSPGERATLSC RASSGSTWYSFVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-41535
3566
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDYYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLTIDIT FGGGTKVEIK



CL-41536
3567
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDYYVS WYQQKPGQ



APRLVIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLFIDXT FGGGTKVEIK



CL-41539
3568
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDTYVS WYQQKPGQ



APRLLIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEGFAVY



YC QSYDIIIDIV FGGGTKVEIK



CL-41543
3569
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDTYVS WYQQKPGQ



ASRLLIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIV FGGGTKVEIK



CL-41547
3570
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWHSYVS WYQQKPGQ



APRLLIY SDDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIYIDVV FGGGTNVEIK



CL-41550
3571
EIVLTQSPGTLSLSPGERATLSC KRSSGSIYDTYVS WYQQKPGQ



APRLVIY SDDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLTIDIT FGGGTKVEIK



CL-41554
3572
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWQSYVS WYQQKPGQ



APRLVIY SDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-41556
3573
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWHSYVS WYQQKPGQ



APRLLIY SDDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIYIDVV FGGGTKVEIK



CL-41557
3574
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDTYVS WYQQKPGQ



APRLLIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIIIDIV FGGGTKVEIK



CL-41560
3575
EIFLTQSPGTLSLSPGKKATLSG KRSSGSIYNTYFS GYQQKPGQ



APKRVIY SDDRRPS GIPDRFSGSGXGTDFTLTISXLEPKDFAVY



YC QSYDLTINLX FGGGTKVXIX



CL-41561
3576
EIVLTQSPGTLSLSPGERATLSC ERSSGSNYDTYVS WYQQKPGQ



APRLLIY ADDLRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIETDIV FGGGTKVEIK



CL-41562
3577
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



SPRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-41569
3578
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPR GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-41577
3579
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWQSYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVV FGGGTKVEIS



CL-41581
3580
EIVLTQSPGTLSLSPGERATLSC RASSGSIWYSFVS RYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-41591
3581
EIVLTQSPGTLSLSPGERATLSC RASSGSIWYSFVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGIDIDVV FGGGTKVEIK



CL-41599
3582
KSSLTQSPGTLSLSPGERATLSC RASSGSIWYSFVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-41600
3583
EIVLTQSLGTLSLSPGERATLSC RASSGSIWYSFVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-41615
3584
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWQMYVS WYQQKPGQ



APRLVIY GDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDIT FGGGTKVEIK



CL-41616
3585
EIVLTQSPGTLSLPPGERATLSC ERSSGDIWQTYVS WYQQKPGQ



APRLVIY GDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDIT FGGGHKGRNX



CL-41639
3586
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDYYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDSAVY



YC QSYDLFIDVT FGGGTKVEIK



CL-41642
3587
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDYYVS WYQRKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-41645
3588
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWQTYVS WYQQKPGQ



APRLVIY GDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDIT FGGGTKVEIK



CL-41646
3589
EIVLTQSPGTLSLSPGERATLSC ERSSGSIWQSYVS WYQQKPGQ



APRLVIY ADDQRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDIDIDVV FGGGTKVEIK



CL-41649
3590
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWDYYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDLFIDVT FGGGTKVEIK



CL-41654
3591
EIVLTQSPGTLSLSPGERATLSC RASSGSIWYSFVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVH



YC QSYGINIDVV FGGGTKVEIK



CL-41655
3592
EIVLTQSPGTLSLSPGERATLSC ERSSGDIWQTYVS WYQQKPGQ



APRLVIY GDDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-41668
3593
EIVLTQSPGTLSLSPGERATLSC RASSGSIWYSFVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVC



YC QSYGINIDVV FGGGTKVEIK



CL-41673
3594
EIVLTQSPGTLSLSPGERAPLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIX



CL-41685
3595
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTINRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-41705
3596
EIVLTQSPGTLSLSPGERATLSC RASSGSIWYSFVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRLSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-41707
3597
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADGQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-41710
3598
EIVLTQSPSTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-41713
3599
EIVLTQSPGTLSLSPGERATLSC RASSGSIWYSFVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIN



CL-41714
3600
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVELS



CL-41720
3601
EIVLTQIPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-41725
3602
EIVLTQSPGTLSLSPGERATLSC ERSSGSNYDTYVS WYQQKPGQ



APRLLIY ADDLRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-41727
3603
EIVLTQSPGTLSLSPGERATLSC RASSGSIWYSFVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YR QSYGINIDVV FGGGTKVEIK



CL-41729
3604
EIVLTQSPGTLSLSPGERATLSC RASSGSIWYSFVS WYQQKPGQ



APRLLIY ADDQRAS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYGINIDVV FGGGTKVEIK



CL-41732
3605
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPI GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-41735
3606
EIVLTQSPGTLSLSPVERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-41737
3607
EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFAVY



YC QSYDINIDIV FGGGTKVEIK



CL-41738
3608
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQAP



RLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC



QQSWYDPLT FGQGTKLEIK



CL-41739
3609
EIVLTQSPATLSLSPGERAALSC RASQSVSTHMH WYQQKPGQAP



RLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC



QQSWYDPLT FGQGTKLEIK



CL-41740
3610
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQAP



RLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC



QQSRYDPLT FGQGTKLEIK



CL-41742
3611
EIVLTQSPGTLSLSPGERATLSC RASQSVSTHMH WYQQKPGQAP



RLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC



QQSWYDPLT FGQGTKLEIK



CL-41751
3612
AKLCXPVPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQAP



RLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC



QQSWYDPLT FGQGTKLEIK



CL-41752
3613
EIVLTQSPATLSLSPGERATLSC RASQSVSTHMH WYQQKPGQAP



RLLIY GASNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC



QQSWYDPLT FGQGTKLRSN









































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































TABLE 48



Amino Acid Residues Found In Each Position Of The Heavy

Chain Variable Region During The Affinity Maturation

Of Anti-PDGF-BB Antibody hBDI-9E8.4

hBDI-9E8.4-2I|CL-22843 Heavy Chain Variable Region




SEQ ID NO:
Sequence



3614
1 2 3 4 5 6


123456789012345678901234567890123456789012345678901234567890


EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGKALEWLA NIWWDDDKY


I Y SEVSID L L DCYGEEH


R A R L C NNGTC


D A G HHVID


T C V AQN


M V E HVS


R Y I YNA


L R P NRF


C T A QYG


F E C SL


W S G LM


P C




7 8 9 10 11 12


12345678901234567890123456789012345678901234567890123456789012


YNPSLKN RLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSS


SL NS LYQTGWPN E Y


T T NVASPWS D


LKYMFRK Y


MYWVCIR A


VLPLYFM C


RDLFAAA N


KGVNEME M


FAEDLYI W


CMKHVSV T


TRFYSLL Q


ESCTDGW G


RRDP I


Q KQ L


K V P


E N


P E






























































TABLE 49



Amino Acid Residues Found In Each Position Of The Light Chain

Variable Region During The Affinity Maturation

Of Anti-PDGF Antibody hBDI-9E8.4

hBDI-9E8.4-2I|CL-22843 Light Chain Variable Region




SEQ ID NO:
Sequence



3615
1 2 3 4 5 6


123456789012345678901234567890123456789012345678901234567890


EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDS YVSWYQQKPGQAPRLVIY ADDQRPS GI


F RAY CSNWYTFFP R R MH GYGLQAI R


KE VYTYQYLS G SA RP T


S MSNMR WV H R


MHKH T W G


HGAN L Y


DECC V M


RSFA F K


EKLD N D


NFES P A


CRWT E E


ALD D N


LCP V


VAG S


FP F


T P


Q


K




7 8 9 10 11


12345678901234567890123456789012345678901234567890


PDRFSGSGSGTDFTLTISRLEFEDFAVYYC QSYDINIDIV FGGGTKVEIK


R KP GLFTNVT


Q VDSPL


H EEVAG


TTDYT


SIRGS


QYEHN


RCMEF


NVLVA


KSPLH


GRFQR


AANTQ


CLK


FG


H


K



































































TABLE 50



Variable Region Sequences of h9E8.4 Affinity

Matured Clones Converted to IgG








Protein
V Region

SEQ ID NO:
Clone
Region
123456789012345678901234567890



3616
CL-33578 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IQSGW




TNYEFDY WGQGTMVTVSS



3617
CL-33578
CDR-H1

GFSLSTYGMGVG




3618
CL-33578
CDR-H2

NIWWDDDKYYNPSLKN




3619
CL-33578
CDR-H3

IQSGWTNYEFDY




3620
CL-33578 VL

EIVLTQSPGTLSLSPGERATLSC ERS




SGDIGDSYVS WYQQKPGQAPRLVIY A




DDQRPS GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYDINIDIV FGGG




TKVEIK



3621
CL-33578
CDR-L1

ERSSGDIGDSYVS




3622
CL-33578
CDR-L2

ADDQRPS




3623
CL-33578
CDR-L3

QSYDINIDIV




3624
CL-33587 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IQSMW




TRYDFDY WGQGTMVTVSS



3625
CL-33587
CDR-H1

GFSLSTYGMGVG




3626
CL-33587
CDR-H2

NIWWDDDKYYNPSLKN




3627
CL-33587
CDR-H3

IQSMWTRYDFDY




3628
CL-33587 VL

EIVLTQSPGTLSLSPGERATLSC ERS




SGDIGDSYVS WYQQKPGQAPRLVIY A




DDQRPS GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYDINIDIV FGGG




TKVEIK



3629
CL-33587
CDR-L1

ERSSGDIGDSYVS




3630
CL-33587
CDR-L2

ADDQRPS




3631
CL-33587
CDR-L3

QSYDINIDIV




3632
CL-33675 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IESSG




PKYSFDY WGQGTMVTVSS



3633
CL-33675
CDR-H1

GFSLSTYGMGVG




3634
CL-33675
CDR-H2

NIWWDDDKYYNPSLKN




3635
CL-33675
CDR-H3

IESSGPKYSFDY




3636
CL-33675 VL

EIVLTQSPGTLSLSPGERATLSC RAS




SGSIWYSFVS WYQQKPGQAPRLLIY A




DDQRAS GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYGINIDVV FGGG




TKVEIK



3637
CL-33675
CDR-L1

RASSGSIWYSFVS




3638
CL-33675
CDR-L2

ADDQRAS




3639
CL-33675
CDR-L3

QSYGINIDVV




3640
CL-33682 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTIKDTSKN




QVVLTMTNMDPVDTATYYCAR IESSW




TSYSFDY WGQGTMVTVSS



3641
CL-33682
CDR-H1

GFSLSTYGMGVG




3642
CL-33682
CDR-H2

NIWWDDDKYYNPSLKN




3643
CL-33682
CDR-H3
IESSWTSYSFDY



3644
CL-33682 VL

EIVLTQSPGTLSLSPGERATLSC ERS




SGSNYDTYVS WYQQKPGQAPRLLIY A




DDLRAS GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYGINIDVV FGGG




TKVEIK



3645
CL-33682
CDR-L1

ERSSGSNYDTYVS




3646
CL-33682
CDR-L2

ADDLRAS




3647
CL-33682
CDR-L3

QSYGINIDVV




3648
CL-33683 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IETIG




PKYSFDY WGQGTMVTVSS



3649
CL-33683
CDR-H1

GFSLSTYGMGVG




3650
CL-33683
CDR-H2

NIWWDDDKYYNPSLKN




3651
CL-33683
CDR-H3

IETIGPKYSFDY




3652
CL-33683 VL

EIVLTQSPGTLSLSPGERATLSC RAS




SGSIWYSFVS WYQQKPGQAPRLLIY A




DDQRAS GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYGINIDVV FGGG




TKVEIK



3653
CL-33683
CDR-L1

RASSGSIWYSFVS




3654
CL-33683
CDR-L2

ADDQRAS




3655
CL-33683
CDR-L3

QSYGINIDVV




3656
CL-33699 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGIG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IESMG




PKYAFDY WGQGTMVTVSS



3657
CL-33699
CDR-H1

GFSLSTYGMGIG




3658
CL-33699
CDR-H2

NIWWDDDKYYNPSLKN




3659
CL-33699
CDR-H3

IESMGPKYAFDY




3660
CL-33699 VL

EIVLTQSPGTLSLSPGERATLSC RAS




SGSIWYSFVS WYQQKPGQAPRLLIY A




DDQRAS GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYGINIDVV FGGG




TKVEIK



3661
CL-33699
CDR-L1

RASSGSIWYSFVS




3662
CL-33699
CDR-L2

ADDQRAS




3663
CL-33699
CDR-L3

QSYGINIDVV




3664
CL-33701 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IESLG




TSYSFDY WGQGTMVTVSS



3665
CL-33701
CDR-H1

GFSLSTYGMGVG




3666
CL-33701
CDR-H2

NIWWDDDKYYNPSLKN




3667
CL-33701
CDR-H3
IESLGTSYSFDY



3668
CL-33701 VL

EIVLTQSPGTLSLSPGERATLSC ERS




SGDIWDYYVS WYQQKPGQAPRLVIYA




DDQRPS GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYDLFIDVT FGGG




TKVEIK



3669
CL-33701
CDR-L1

ERSSGDIWDYYVS




3670
CL-33701
CDR-L2

ADDQRPS




3671
CL-33701
CDR-L3

QSYDLFIDVT




3672
CL-33706 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IETMG




PKYSFDY WGQGTMVTVSS



3673
CL-33706
CDR-H1

GFSLSTYGMGVG




3674
CL-33706
CDR-H2

NIWWDDDKYYNPSLKN




3675
CL-33706
CDR-H3

IETMGPKYSFDY




3676
CL-33706 VL

EIVLTQSPGTLSLSPGERATLSC RAS




SGSIWYSFVS WYQQKPGQAPRLLIY A




DDQRAS GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYGINIDVV FGGG




TKVEIK



3677
CL-33706
CDR-L1

RASSGSIWYSFVS




3678
CL-33706
CDR-L2

ADDQRAS




3679
CL-33706
CDR-L3

QSYGINIDVV




3680
CL-33731 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IESIP




TSYSFDY WGQGTMVTVSS



3681
CL-33731
CDR-H1

GFSLSTYGMGVG




3682
CL-33731
CDR-H2

NIWWDDDKYYNPSLKN




3683
CL-33731
CDR-H3

IESIPTSYSFDY




3684
CL-33731 VL

EIVLTQSPGTLSLSPGERATLSC ERS




SGSIWQSYVS WYQQKPGQAPRLVIY A




DDQRAT GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYDIDIDVV FGGG




TKVEIK



3685
CL-33731
CDR-L1

ERSSGSIWQSYVS




3686
CL-33731
CDR-L2

ADDQRAT




3687
CL-33731
CDR-L3

QSYDIDIDVV




3688
CL-33737 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRKPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IESSG




PKYSFDY WGQGTMVTVSS



3689
CL-33737
CDR-H1

GFSLSTYGMGVG




3690
CL-33737
CDR-H2

NIWWDDDKYYNPSLKN




3691
CL-33737
CDR-H3
IESSGPKYSFDY



3692
CL-33737 VL

EIVLTQSPGTLSLSPGERATLSC RAS




SGSIWYSFVS WYQQKPGQAPRLLIY A




DDQRAS GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYGINIDVV FGGG




TKVEIK



3693
CL-33737
CDR-L1

RASSGSIWYSFVS




3694
CL-33737
CDR-L2

ADDQRAS




3695
CL-33737
CDR-L3

QSYGINIDVV




3696
CL-33759 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IESVW




TRYDFDY WGQGTMVTVSS



3697
CL-33759
CDR-H1

GFSLSTYGMGVG




3698
CL-33759
CDR-H2

NIWWDDDKYYNPSLKN




3699
CL-33759
CDR-H3

IESVWTRYDFDY




3700
CL-33759 VL

EIVLTQSPGTLSLSPGERATLSC ERS




SGDIWQTYVS WYQQKPGQAPRLVIY G




DDQRAS GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYDIDIDIT FGGG




TKVEIK



3701
CL-33759
CDR-L1

ERSSGDIWQTYVS




3702
CL-33759
CDR-L2

GDDQRAS




3703
CL-33759
CDR-L3

QSYDIDIDIT




3704
CL-33767 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IESIG




PKYSFDY WGQGTMVTVSS



3705
CL-33767
CDR-H1

GFSLSTYGMGVG




3706
CL-33767
CDR-H2

NIWWDDDKYYNPSLKN




3707
CL-33767
CDR-H3

IESIGPKYSFDY




3708
CL-33767 VL

EIVLTQSPGTLSLSPGERATLSC RAS




SGSIWYSFVS WYQQKPGQAPRLLIY A




DDQRAS GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYGINIDVV FGGG




TKVEIK



3709
CL-33767
CDR-L1

RASSGSIWYSFVS




3710
CL-33767
CDR-L2

ADDQRAS




3711
CL-33767
CDR-L3

QSYGINIDVV




3712
CL-33769 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IESIG




PKYSFDY WGQGTMVTVSS



3713
CL-33769
CDR-H1

GFSLSTYGMGVG




3714
CL-33769
CDR-H2

NIWWDDDKYYNPSLKN




3715
CL-33769
CDR-H3

IESIGPKYSFDY




3716
CL-33769 VL

EIVLTQSPGTLSLSPGERATLSC RAS




SGSIWYSFVS WYQQKPGQAPRLLIY A




DDQRAS GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYGINIDVV FGGG




TKVEIK



3717
CL-33769
CDR-L1

RASSGSIWYSFVS




3718
CL-33769
CDR-L2

ADDQRAS




3719
CL-33769
CDR-L3

QSYGINIDVV




3720
CL-33797 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IESLG




WSYSFDY WGQGTMVTVSS



3721
CL-33797
CDR-H1

GFSLSTYGMGVG




3722
CL-33797
CDR-H2

NIWWDDDKYYNPSLKN




3723
CL-33797
CDR-H3

IESLGWSYSFDY




3724
CL-33797 VL

EIVLTQSPGTLSLSPGERATLSC ERS




SGDIWDYYVS WYQQKPGQAPRLVIY A




DDQRPS GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYDLFIDVT FGGG




TKVEIK



3725
CL-33797
CDR-L1

ERSSGDIWDYYVS




3726
CL-33797
CDR-L2

ADDQRPS




3727
CL-33797
CDR-L3

QSYDLFIDVT




3728
CL-33803 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IESLP




TSYSFDY WGQGTMVTVSS



3729
CL-33803
CDR-H1

GFSLSTYGMGVG




3730
CL-33803
CDR-H2

NIWWDDDKYYNPSLKN




3731
CL-33803
CDR-H3

IESLPTSYSFDY




3732
CL-33803 VL

EIVLTQSPGTLSLSPGERATLSC ERS




SGDIWDTYVS WYQQKPGQAPRLLIY A




DDQRPS GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYDIIIDIV FGGG




TKVEIK



3733
CL-33803
CDR-L1

ERSSGDIWDTYVS




3734
CL-33803
CDR-L2

ADDQRPS




3735
CL-33803
CDR-L3

QSYDIIIDIV




3736
CL-33805 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IESHW




WSYAFDY WGQGTMVTVSS



3737
CL-33805
CDR-H1

GFSLSTYGMGVG




3738
CL-33805
CDR-H2

NIWWDDDKYYNPSLKN




3739
CL-33805
CDR-H3

IESHWWSYAFDY




3740
CL-33805 VL

EIVLTQSPGTLSLSPGERATLSC ERS




SGSNYDTYVS WYQQKPGQAPRLLIY A




DDLRAS GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYGIETDIV FGGG




TKVEIK



3741
CL-33805
CDR-L1

ERSSGSNYDTYVS




3742
CL-33805
CDR-L2

ADDLRAS




3743
CL-33805
CDR-L3

QSYGIETDIV




3744
CL-33811 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IESSW




TTYSFDY WGQGTMVTVSS



3745
CL-33811
CDR-H1

GFSLSTYGMGVG




3746
CL-33811
CDR-H2

NIWWDDDKYYNPSLKN




3747
CL-33811
CDR-H3

IESSWTTYSFDY




3748
CL-33811 VL

EIVLTQSPGTLSLSPGERATLSC ERS




SGSIWHSYVS WYQQKPGQAPRLLIYS




DDQRAT GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYGIYIDVV FGGG




TKVEIK



3749
CL-33811
CDR-L1

ERSSGSIWHSYVS




3750
CL-33811
CDR-L2

SDDQRAT




3751
CL-33811
CDR-L3

QSYGIYIDVV




3752
CL-33812 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IESNP




WKYSFDY WGQGTMVTVSS



3753
CL-33812
CDR-H1

GFSLSTYGMGVG




3754
CL-33812
CDR-H2

NIWWDDDKYYNPSLKN




3755
CL-33812
CDR-H3

IESNPWKYSFDY




3756
CL-33812 VL

EIVLTQSPGTLSLSPGERATLSC ERS




SGDIWQSYVS WYQQKPGQAPRLVIY S




DDQRAS GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYGINIDVV FGGG




TKVEIK



3757
CL-33812
CDR-L1

ERSSGDIWQSYVS




3758
CL-33812
CDR-L2

SDDQRAS




3759
CL-33812
CDR-L3

QSYGINIDVV




3760
CL-33820 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IESSF




TSYSFDY WGQGTMVTVSS



3761
CL-33820
CDR-H1

GFSLSTYGMGVG




3762
CL-33820
CDR-H2

NIWWDDDKYYNPSLKN




3763
CL-33820
CDR-H3

IESSFTSYSFDY




3764
CL-33820 VL

EIVLTQSPGTLSLSPGERATLSC KRS




SGSIYDTYVS WYQQKPGQAPRLVIY S




DDQRPS GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYDLTIDIT FGGG




TKVEIK



3765
CL-33820
CDR-L1

KRSSGSIYDTYVS




3766
CL-33820
CDR-L2

SDDQRPS




3767
CL-33820
CDR-L3

QSYDLTIDIT




3768
CL-33845 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IVSDW




TTYSFDY WGQGTMVTVSS



3769
CL-33845
CDR-H1

GFSLSTYGMGVG




3770
CL-33845
CDR-H2

NIWWDDDKYYNPSLKN




3771
CL-33845
CDR-H3

IVSDWTTYSFDY




3772
CL-33845 VL

EIVLTQSPGTLSLSPGERATLSC RAS




SGSIWYSFVS WYQQKPGQAPRLLIY A




DDQRAS GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYGINIDVV FGGG




TKVEIK



3773
CL-33845
CDR-L1

RASSGSIWYSFVS




3774
CL-33845
CDR-L2

ADDQRAS




3775
CL-33845
CDR-L3

QSYGINIDVV




3776
CL-33855 VH

EVTLRESGPALVKPTQTLTLTCTFS G




FSLSTYGMGVG WIRQPPGKALEWLA N




IWWDDDKYYNPSLKN RLTISKDTSKN




QVVLTMTNMDPVDTATYYCAR IETFG




PKYSFDY WGQGTMVTVSS



3777
CL-33855
CDR-H1

GFSLSTYGMGVG




3778
CL-33855
CDR-H2

NIWWDDDKYYNPSLKN




3779
CL-33855
CDR-H3

IETFGPKYSFDY




3780
CL-33855 VL

EIVLTQSPGTLSLSPGERATLSC RAS




SGSIWYSFVS WYQQKPGQAPRLLIY A




DDQRAS GIPDRFSGSGSGTDFTLTIS




RLEPEDFAVYYC QSYGINIDVV FGGG




TKVEIK



3781
CL-33855
CDR-L1

RASSGSIWYSFVS




3782
CL-33855
CDR-L2

ADDQRAS




3783
CL-33855
CDR-L3

QSYGINIDVV



















































































































































































































































































































































































































































































































































TABLE 51



Summary of Protein Expression And Purification Of

Affinity Matured Humanized Anti-Human PDGF-BB

Antibodies









Octet Titer
~Yield
SEC (%


Name
(mg/L) 1
(mg/L) 2
monomer) 3











CL-33578-IgG
176.5
98.9
91.3


CL-33587-IgG
155.7
109.1
94.2


CL-33675-IgG
275.2
57.7
96.9


CL-33682-IgG
203.6
80.7
94.6


CL-33683-IgG
136.7
24.5
48.1


CL-33701-IgG
114.9
79.2
97.9


CL-33706-IgG
169.8
25.8
100.0


CL-33731-IgG
137.0
73.6
95.8


CL-33803-IgG
98.0
50.5
96.7


CL-33805-IgG
227.5
66.5
97.9


CL-33811-IgG
190.2
31.7
99.0


CL-33812-IgG
171.0
76.4
96.7


CL-33820-IgG
135.3
75.0
95.7


CL-33855-IgG
50.9
13.8
94.3


CL-33699-IgG
ND
10.5
81.7


CL-33737-IgG
ND
5.0
88.0


CL-33759-IgG
ND
18.5
100.0


CL-33767-IgG
ND
16.5
50.9


CL-33845-IgG
ND
0.8
60.6





ND = Not Determined


1 Octet titer is the amount of IgG in the unpurified supernatant as determined by protein A binding compared to a standard curve using an Octet instrument.


2 Yield is determined by the total amount of purified protein in mg divided by the total cell culture volume in liters.


3 SEC % monomer is determined using HPLC size exclusion chromatography.




















































TABLE 52



Biacore Binding of Affinity-Matured Humanized

Anti-PDGF Antibodies








Antibody
k on (M−1 s−1)
k off (M−1)
K D (M)





CL-33578
≧9.0E+07
2.70E−05
≦3.0E−13


CL-33587
≧9.0E+07
2.00E−05
≦2.2E−13


CL-33675
3.60E+07
2.20E−05
6.10E−13


CL-33682
≧9.0E+07
2.20E−05
≦2.4E−13


CL-33683
1.90E+07
8.20E−06
4.40E−13


CL-33701
7.30E+07
1.80E−05
2.40E−13


CL-33706
1.80E+07
1.20E−05
6.90E−13


CL-33731
8.10E+07
1.60E−05
2.00E−13


CL-33803
≧9.0E+07
1.40E−05
≦1.6E−13


CL-33805
6.80E+07
1.50E−05
2.10E−13


CL-33811
2.70E+07
1.20E−05
4.50E−13


CL-33812
6.30E+07
1.90E−05
3.00E−13


CL-33820
≧9.8E+07
1.60E−05
≦1.6E−13


CL-33855
2.00E+07
≦1.0E−06
≦5.0E−14





*Heterogeneous off-rate


































Affinity matured humanized anti-PDGF-BB antibodies were characterized for PDGF-BB binding and potency. Human PDGF-BB binding affinity was determined by Biacore analysis (Example 1.1). Potency was evaluated in both cell-based and ELISA formats. The ability to block binding of hPDGF-BB to hPDGF-Rβ was tested in a competition ELISA format (Example 1.13) Inhibition of human and cynomolgus PDGF-BB-induced cell proliferation was assessed using NIH-3T3 cells (Examples 1.15 and 1.16). The data is summarized in Table 53 below.





TABLE 53



Summary of Characterization of Affinity Matured Humanized

Anti-Human PDGF-BB Antibodies





PDGF-BB IC 50 Potency (nM)







hPDGF-BB
cynoPDGF-BB
hPDGF-BB/

Affinity Matured
NIH-3T3
NIH-3T3
hPDGFR□

Humanized IgG
Proliferation
Proliferation
Competition








CL-33578-Ig
0.033
0.023
0.049

CL-33587-Ig
0.046
0.029
<0.1

CL-33675-Ig
0.04
0.024
0.054

CL-33682-Ig
0.03
0.019
0.069

CL-33683-Ig
0.029
0.028
0.126

CL-33699-Ig
0.033
0.016
0.072

CL-33706-Ig
0.035
0.019
0.081

CL-33731Ig
0.036
0.023
0.068

CL-33759-Ig
0.293
0.18
1.267

CL-33811-Ig
0.032
0.012
0.1

CL-33812-Ig
0.033
0.028
0.043

CL-33820-Ig
0.017
0.013
0.066

CL-33855-Ig
0.037
0.019
0.162

CL-33701-Ig
0.056
0.012
0.059

CL-33737-Ig
0.03
0.024
0.092

CL-33803-Ig
0.024
0.018
0.044

C-L33767-Ig
0.09
0.042
0.114

CL-33845-Ig
0.171
0.073
0.409

CL-33805-Ig
0.039
0.018
0.063

















































Example 9
Methods of Selecting Preferred Humanized Antibodies as DVD-Ig Building Blocks
Example 9.1
A Technique for Assessing the Stability of Regions of the Parental Antibodies Intended for DVD-Ig Protein Incorporation
The technique of differential scanning calorimetry (DSC) can be used to determine the thermal stabilities of the different domains of an antibody (e.g. CH2, CH3, CH1-CL, and VH-VL). The temperature of the highest peak in a DSC thermogram (plotted as heat capacity versus temperature) of an antibody has been shown to correspond to the midpoint of the unfolding transition or process of that antibody's VH-VL region due to increasing temperature. This may be interpreted as a measure of VH-VL thermal stability. VH-VL regions with high thermal stability in the antibody format will also likely have high thermal stability when incorporated into the DVD-Ig format as one of the binding domains. Therefore, antibodies can be screened to determine those with VH-VL regions of high thermal stability. Those regions can then be incorporated into the DVD-Ig format to increase the probability of generating a more stable DVD-Ig molecule.
Example 9.2
Determination of the Thermal Stability of the VH-VL Regions of Anti-VEGF mAbs and Anti-PDGF mAbs by Differential Scanning Calorimetry
A total of 73 mAbs (45 anti-VEGF and 28 anti-PDGF) were selected and analyzed by DSC (Example 2.2) and the thermal stabilities of their VH-VL regions were quantitated by determining the temperature of the highest peak in the DSC thermograms as detailed in Example 9.1 (Table 54).





TABLE 54



Thermal Stability of Anti-VEGF and Anti-PDGF Antibodies







Temperature of highest peak in

Name
Target Antigen
DSC thermogram (° C.)







hBDB-4G8.1
VEGF
71.97

hBDB-4G8.2
VEGF
69.13

hBDB-4G8.3
VEGF
65.65

hBDB-4G8.4
VEGF
75.27

hBDB-4G8.5
VEGF
73.07

hBDB-4G8.6
VEGF
68.68

hBDB-4G8.7
VEGF
76.27

hBDB-4G8.8
VEGF
73.16

hBDB-4G8.9
VEGF
68.95

hBDB-4G8.10
VEGF
73.44

hBDB-4G8.11
VEGF
69.77

hBDB-4G8.12
VEGF
67.48

hBDB-4G8.13
VEGF
67.12

hBDB-4G8.14
VEGF
63.4

hBDB-4G8.15
VEGF
69.41

h4G8.3 EI
VEGF
68.31

h4G8 CL-32416
VEGF
68.95

h4G8 CL-34449
VEGF
72.7

h4G8 CL-34455
VEGF
70.69

h4G8 CL-34469
VEGF
70.23

h4G8 CL-34475
VEGF
70.69

h4G8 CL-34522
VEGF
67.49

h4G8 CL-34540
VEGF
69.87

h4G8 CL-34633
VEGF
69.22

h4G8 CL-34538
VEGF
71.15

h4G8 CL-34570
VEGF
66.84

h4G8 CL-34565
VEGF
71.15

hBEW-9A8.17
VEGF
64.56

hBEW-9A8.21
VEGF
54.25

hBEW-5C3.4
VEGF
66.94

hBEW-9E10.1
VEGF
71.88

hBEW-9E10.3
VEGF
71.24

hBEW-9E10.4
VEGF
71.77

hBEW-9E10.6
VEGF
71.24

hBEW-9A8.20
VEGF
61.85

hBEW-5C3.1
VEGF
63.15

hBEW-5C3.5
VEGF
64.83

hBEW-9E10.2
VEGF
71.37

hBEW-9E10.5
VEGF
71.24

hBEW-1B10.1
VEGF
87.95

hBEW-1B10.2
VEGF
86.38

hBEW-1E3.1
VEGF
62.74

hBEW-1E3.2
VEGF
66.29

hBEW-1E3.4
VEGF
66.11

hBEW-1E3.5
VEGF
68.83

hBDI-9E8.1
PDGF
77.6

hBDI-9E8.2
PDGF
76.28

hBDI-9E8.3
PDGF
87.4

hBDI-9E8.4
PDGF
84.2

hBDI-9E8.5
PDGF
77.69

hBDI-9E8.6
PDGF
75.91

hBDI-9E8.7
PDGF
87.4

hBDI-9E8.8
PDGF
84.29

hBDI-9E8.9
PDGF
82.09

hBDI-9E8.10
PDGF
83.37

hBDI-9E8.11
PDGF
80.9

hBDI-9E8.12
PDGF
82.64

hBDI-9E8.13
PDGF
85.39

CL-33578-IgG
PDGF
75.03

CL-33587-IgG
PDGF
76.37

CL-33675-IgG
PDGF
87.4

CL-33682-IgG
PDGF
78.52

CL-33683-IgG
PDGF
82.55

CL-33701-IgG
PDGF
73.62

CL-33706-IgG
PDGF
86.85

CL-33731-IgG
PDGF
77.33

CL-33803-IgG
PDGF
74.26

CL-33805-IgG
PDGF
80.35

CL-33811-IgG
PDGF
79.71

CL-33812-IgG
PDGF
78.15

CL-33820-IgG
PDGF
78.88

CL-33855-IgG
PDGF
82.18

hBFU-3E2.1
PDGF
68.31

































































































Example 10
Generation of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules
The variable domain sequences from humanized anti-human VEGF-A and anti-human PDGF-BB mAbs were used to design the VH and VL domains of anti-human VEGF-A/anti-human PDGF-BB DVD-Ig molecules. In some cases, variable regions were synthesized using two-step PCR. Primers were designed with homologous flanking regions to the cloning vector and the linker region between each DVD variable pair. In some cases, variable regions were generated using gene synthesis. Bacterial transformations were performed to identify positive clones and constructs were harvested and purified for use in mammalian transfection using standard protocols known in the art.
The variable domains of the heavy and light chain were cloned in-frame into mutant human IgG1 (L234, 235A) heavy-chain or mutant human IgG1 (L234, 235A, H435A) heavy-chain, and kappa light-chain constant regions, respectively, into pHybE vectors to generate anti-human VEGF-A/anti-human PDGF-BB DVD-Ig molecules.





TABLE 55



Amino Acid Sequences of DVD-Ig Linkers





Seq ID



No
Name
Sequence



3784
HG-short
ASTKGP



3785
HG-long
ASTKGPSVFPLAP



3786
GS-H10
GGGGSGGGGS



3787
LK-short
RTVAAP



3788
LK-long
RTVAAPSVFIFPP



3789
GS-L10
RGGSGGGGSG



3790
GS-L10(dR)
GGSGGGGSGG



3791
GS-L11
RGGSGGGGSGG



3792

AKTTPKLEEGEFSEAR



3793

AKTTPKLEEGEFSEARV



3794

AKTTPKLGG



3795

SAKTTPKLGG



3796

SAKTTP



3797

RADAAP



3798

RADAAPTVS



3799

RADAAAAGGPGS



3800

RADAAAA(G 4 S) 4



3801

SAKTTPKLEEGEFSEARV



3802

ADAAP



3803

ADAAPTVSIFPP



3804

TVAAP



3805

TVAAPSVFIFPP



3806

QPKAAP



3807

QPKAAPSVTLFPP



3808

AKTTPP



3809

AKTTPPSVTPLAP



3810

AKTTAP



3811

AKTTAPSVYPLAP



3812

ASTKGP



3813

ASTKGPSVFPLAP



3814

GGGGSGGGGSGGGGS



3815

GENKVEYAPALMALS



3816

GPAKELTPLKEAKVS



3817

GHEAAAVMQVQYPAS



3818

TVAAPSVFIFPPTVAAPSVFIFPP



3819

ASTKGPSVFPLAPASTKGPSVFPLAP



3820

GGGGSGGGGS



3821

GGSGGGGSG



G/S based sequences



(e.g., G4S (SEQ ID NO: 3822)



and G4S repeats (“G4S”



disclosed as SEQ ID NO: 3822))









































































































TABLE 56



Heavy (H) and Light Chain (L) Composition of Anti-VEGF-A/Anti-PDGF-BB DVD-

Ig Molecules (first and second polypeptide chains are listed in alternating rows of the table)















SEQ ID NO







VD1-X1-

SEQ ID

DVD-Ig Variable Domain
Outer Variable

Inner Variable
VD2

NO
Corporate ID
Name
Domain Name
Linker
Domain Name
Formula




NA
AB014-GS-9E8.4 a
AB014 VH
GS-H10
hBDI-9E8.4 VH





AB014 VL
GS-L10
hBDI-9E8.4 VL


NA
9E8.4-GS-AB014 a
hBDI-9E8.4 VH
GS-H10
AB014 VH




hBDI-9E8.4 VL
GS-L10
AB014 VL


NA
AB014-SS-9E8.4 a
AB014 VH
HG-short
hBDI-9E8.4 VH




AB014 VL
LK-short
hBDI-9E8.4 VL


NA
9E8.4-SS-AB014 a
hBDI-9E8.4 VH
HG-short
AB014 VH




hBDI-9E8.4 VL
LK-short
AB014 VL


NA
AB014-SL-9E8.4 a
AB014 VH
HG-short
hBDI-9E8.4 VH




AB014 VL
LK-long
hBDI-9E8.4 VL


NA
9E8.4-SL-AB014 a
hBDI-9E8.4 VH
HG-short
AB014 VH




hBDI-9E8.4 VL
LK-long
AB014 VL


NA
AB014-LS-9E8.4 a
AB014 VH
HG-long
hBDI-9E8.4 VH




AB014 VL
LK-short
hBDI-9E8.4 VL


NA
9E8.4-LS-AB014 a
hBDI-9E8.4 VH
HG-long
AB014 VH




hBDI-9E8.4 VL
LK-short
AB014 VL


PR-1563988
9E8.4-GS-4G8.3 a
hBDI-9E8.4 VH
GS-H10
hBDB-4G8.3 VH




hBDI-9E8.4 VL
GS-L10
hBDB-4G8.3 VL


PR-1563990
9E8.4-SS-4G8.3 a
hBDI-9E8.4 VH
HG-short
hBDB-4G8.3 VH




hBDI-9E8.4 VL
LK-short
hBDB-4G8.3 VL


PR-1563998
9E8.4-SL-4G8.3 a
hBDI-9E8.4 VH
HG-short
hBDB-4G8.3 VH




hBDI-9E8.4 VL
LK-long
hBDB-4G8.3 VL


PR-1564009
9E8.4-LS-4G8.3 a
hBDI-9E8.4 VH
HG-long
hBDB-4G8.3 VH




hBDI-9E8.4 VL
LK-short
hBDB-4G8.3 VL


PR-1564010
4G8.3-GS-9E8.4 a
hBDB-4G8.3 VH
GS-H10
hBDI-9E8.4 VH




hBDB-4G8.3 VL
GS-H10
hBDI-9E8.4 VL


PR-1564011
4G8.3-SS-9E8.4 a
hBDB-4G8.3 VH
HG-short
hBDI-9E8.4 VH




hBDB-4G8.3 VL
LK-short
hBDI-9E8.4 VL


PR-1564012
4G8.3-SL-9E8.4 a
hBDB-4G8.3 VH
HG-short
hBDI-9E8.4 VH




hBDB-4G8.3 VL
LK-long
hBDI-9E8.4 VL


PR-1564013
4G8.3-LS-9E8.4 a
hBDB-4G8.3 VH
HG-long
hBDI-9E8.4 VH




hBDB-4G8.3 VL
LK-short
hBDI-9E8.4 VL


PR-1569574
9E8.4-GS-4G8.3
hBDI-9E8.4 VH
GS-H10
hBDB-4G8.3 VH




hBDI-9E8.4 VL
GS-L10
hBDB-4G8.3 VL


PR-1569579
9E8.4-SL-4G8.3
hBDI-9E8.4 VH
HG-short
hBDB-4G8.3 VH




hBDI-9E8.4 VL
LK-long
hBDB-4G8.3 VL


PR-1575573
9E8.4-LS-4G8.3
hBDI-9E8.4 VH
HG-long
hBDB-4G8.3 VH




hBDI-9E8.4 VL
LK-short
hBDB-4G8.3 VL


PR-1572102
4G8.3-GS-9E8.4 (g)
hBDB-4G8.3 VH
GS-H10
hBDI-9E8.4 VH




hBDB-4G8.3 VL
GS-L10
hBDI-9E8.4 VL


PR-1572103
4G8.3-GS(11)-9E8.4 (g)
hBDB-4G8.3 VH
GS-H10
hBDI-9E8.4 VH




hBDB-4G8.3 VL
GS-L11
hBDI-9E8.4 VL


PR-1572104
4G8.3-GS(noR)-9E8.4 (g)
hBDB-4G8.3 VH
GS-H10
hBDI-9E8.4 VH




hBDB-4G8.3 VL
GS-
hBDI-9E8.4 VL





L10 (dR)


PR-1572105
4G8.3-SL-9E8.4 (g)
hBDB-4G8.3 VH
HG-short
hBDI-9E8.4 VH




hBDB-4G8.3 VL
LK-long
hBDI-9E8.4 VL


PR-1572106
4G8.3-LS-9E8.4 (g)
hBDB-4G8.3 VH
HG-long
hBDI-9E8.4 VH




hBDB-4G8.3 VL
LK-short
hBDI-9E8.4 VL


PR-1575832
4G8.3-GS-9E8.4E
hBDB-4G8.3 VH
GS-H10
hBDI-9E8.4E VH




hBDB-4G8.3 VL
GS-L10
hBDI-9E8.4E VL


PR-1575834
4G8.3-SL-9E8.4E
hBDB-4G8.3 VH
HG-short
hBDI-9E8.4E VH




hBDB-4G8.3 VL
LK-long
hBDI-9E8.4E VL


PR-1575835
4G8.3-LS-9E8.4E
hBDB-4G8.3 VH
HG-long
hBDI-9E8.4E VH




hBDB-4G8.3 VL
LK-short
hBDI-9E8.4E VL


PR-1577165
9A8.12-GS-9E8.4E
hBEW-9A8.12
GS-H10
hBDI-9E8.4E VH




VH




hBEW-9A8.12 VL
GS-L10
hBDI-9E8.4E VL


PR-1577166
9A8.12-SL-9E8.4E
hBEW-9A8.12
HG-short
hBDI-9E8.4E VH




VH




hBEW-9A8.12 VL
LK-long
hBDI-9E8.4E VL


PR-1577547
9A8.12-LS-9E8.4E
hBEW-9A8.12
HG-long
hBDI-9E8.4E VH




VH




hBEW-9A8.12 VL
LK-short
hBDI-9E8.4E VL


PR-1578137
9E8.4E-GS-9A8.12
hBDI-9E8.4E VH
GS-H10
hBEW-9A8.12 VH




hBDI-9E8.4E VL
GS-L10
hBEW-9A8.12 VL


PR-1577548
9E8.4E-SL-9A8.12
hBDI-9E8.4E VH
HG-short
hBEW-9A8.12 VH




hBDI-9E8.4E VL
LK-long
hBEW-9A8.12 VL


PR-1577550
9E8.4E-LS-9A8.12
hBDI-9E8.4E VH
HG-long
hBEW-9A8.12 VH




hBDI-9E8.4E VL
LK-short
hBEW-9A8.12 VL


PR-1598261
4G8.2-GS-9E8.4
hBDB-4G8.2 VH
GS-H10
hBDI-9E8.4 VH




hBDB-4G8.2 VL
GS-L10
hBDI-9E8.4 VL


PR-1598262
4G8.4-GS-9E8.4
hBDB-4G8.4 VH
GS-H10
hBDI-9E8.4 VH




hBDB-4G8.4 VL
GS-L10
hBDI-9E8.4 VL


PR-1598263
4G8.5-GS-9E8.4
hBDB-4G8.5 VH
GS-H10
hBDI-9E8.4 VH




hBDB-4G8.5 VL
GS-L10
hBDI-9E8.4 VL


PR-1598264
4G8.12-GS-9E8.4
hBDB-4G8.12 VH
GS-H10
hBDI-9E8.4 VH




hBDB-4G8.12 VL
GS-L10
hBDI-9E8.4 VL


PR-1598265
4G8.13-GS-9E8.4
hBDB-4G8.13 VH
GS-H10
hBDI-9E8.4 VH




hBDB-4G8.13 VL
GS-L10
hBDI-9E8.4 VL


PR-1598266
4G8.14-GS-9E8.4
hBDB-4G8.14 VH
GS-H10
hBDI-9E8.4 VH




hBDB-4G8.14 VL
GS-L10
hBDI-9E8.4 VL


PR-1613183
CL-34565_GS_CL-33675
CL-34565 VH
GS-H10
CL-33675 VH




CL-34565 VL
GS-
CL-33675 VL





L10 (dR)


PR-1613184
CL-34565_GS_9E8.4
CL-34565 VH
GS-H10
hBDI-9E8.4 VH




CL-34565 VL
GS-
hBDI-9E8.4 VL





L10 (dR)


PR-1613185
CL-34565_GS_3E2.1
CL-34565 VH
GS-H10
hBFU-3E2.1 VH




CL-34565 VL
GS-
hBFU-3E2.1 VL





L10 (dR)


PR-1611291
4G8.5_GS_CL-33675
hBDB-4G8.5 VH
GS-H10
CL-33675 VH




hBDB-4G8.5 VL
GS-
CL-33675 VL





L10 (dR)


PR-1612489
4G8.5_GS_9E8.4
hBDB-4G8.5 VH
GS-H10
hBDI-9E8.4 VH




hBDB-4G8.5 VL
GS-
hBDI-9E8.4 VL





L10 (dR)


PR-1610560
4G8.5_GS_3E2.1
hBDB-4G8.5 VH
GS-H10
hBFU-3E2.1 VH




hBDB-4G8.5 VL
GS-
hBFU-3E2.1 VL





L10 (dR)


PR-1610561
9E10.1_GS_CL-33675
hBEW-9E10.1 VH
GS-H10
CL-33675 VH




hBEW-9E10.1 VL
GS-
CL-33675 VL





L10 (dR)


PR-1612491
9E10.1_GS_9E8.4
hBEW-9E10.1 VH
GS-H10
hBDI-9E8.4 VH




hBEW-9E10.1 VL
GS-
hBDI-9E8.4 VL





L10 (dR)


PR-1610562
9E10.1_GS_3E2.1
hBEW-9E10.1 VH
GS-H10
hBFU-3E2.1 VH




hBEW-9E10.1 VL
GS-
hBFU-3E2.1 VL





L10 (dR)


PR-1612492
9E10.6_GS_CL-33675
hBEW-9E10.6 VH
GS-H10
CL-33675 VH




hBEW-9E10.6 VL
GS-
CL-33675 VL





L10 (dR)


PR-1612493
9E10.6_GS_9E8.4
hBEW-9E10.6 VH
GS-H10
hBDI-9E8.4 VH




hBEW-9E10.6 VL
GS-
hBDI-9E8.4 VL





L10 (dR)


PR-1610563
9E10.6_GS_3E2.1
hBEW-9E10.6 VH
GS-H10
hBFU-3E2.1 VH




hBEW-9E10.6 VL
GS-
hBFU-3E2.1 VL





L10 (dR)


PR-1611292
1B10.1_GS_CL-33675
hBEW-1B10.1 VH
GS-H10
CL-33675 VH




hBEW-1B10.1 VL
GS-
CL-33675 VL





L10 (dR)


PR-1612494
1B10.1_GS_9E8.4
hBEW-1B10.1 VH
GS-H10
hBDI-9E8.4 VH




hBEW-1B10.1 VL
GS-
hBDI-9E8.4 VL





L10 (dR)


PR-1610564
1B10.1_GS_3E2.1
hBEW-1B10.1 VH
GS-H10
hBFU-3E2.1 VH




hBEW-1B10.1 VL
GS-
hBFU-3E2.1 VL





L10 (dR)


PR-1611293
1E3.4_GS_CL-33675
hBEW-1E3.4 VH
GS-H10
CL-33675 VH




hBEW-1E3.4 VL
GS-
CL-33675 VL





L10 (dR)


PR-1611294
1E3.4_GS_9E8.4
hBEW-1E3.4 VH
GS-H10
hBDI-9E8.4 VH




hBEW-1E3.4 VL
GS-
hBDI-9E8.4 VL





L10 (dR)


PR-1612495
1E3.4_GS_3E2.1
hBEW-1E3.4 VH
GS-H10
hBFU-3E2.1 VH




hBEW-1E3.4 VL
GS-
hBFU-3E2.1 VL





L10 (dR)


PR-1613186
CL-33675_GS_CL-34565
CL-33675 VH
GS-H10
CL-34565 VH




CL-33675 VL
GS-
CL-34565 VL





L10 (dR)


PR-1612496
CL-33675_GS_4G8.5
CL-33675 VH
GS-H10
hBDB-4G8.5 VH




CL-33675 VL
GS-
hBDB-4G8.5 VL





L10 (dR)


PR-1611295
CL-33675_GS_9E10.1
CL-33675 VH
GS-H10
hBEW-9E10.1 VH




CL-33675 VL
GS-
hBEW-9E10.1 VL





L10 (dR)


PR-1611296
CL-33675_GS_9E10.6
CL-33675 VH
GS-H10
hBEW-9E10.6 VH




CL-33675 VL
GS-
hBEW-9E10.6 VL





L10 (dR)


PR-1612498
CL-33675_GS_1B10.1
CL-33675 VH
GS-H10
hBEW-1B10.1 VH




CL-33675 VL
GS-
hBEW-1B10.1





L10 (dR)
VL


PR-1611297
CL-33675_GS_1E3.4
CL-33675 VH
GS-H10
hBEW-1E3.4






VH




CL-33675 VL
GS-
hBEW-1E3.4 VL





L10 (dR)


PR-1613187
9E8.4_GS_CL-34565
hBDI-9E8.4 VH
GS-H10
CL-34565 VH




hBDI-9E8.4 VL
GS-
CL-34565 VL





L10 (dR)


PR-1613188
9E8.4_GS_4G8.5
hBDI-9E8.4 VH
GS-H10
hBDB-4G8.5 VH




hBDI-9E8.4 VL
GS-
hBDB-4G8.5 VL





L10 (dR)


PR-1611298
9E8.4_GS_9E10.1
hBDI-9E8.4 VH
GS-H10
hBEW-9E10.1






VH





GS-
hBEW-9E10.1H





L10 (dR)
VL


PR-1611299
9E8.4_GS_9E10.6
hBDI-9E8.4 VH
GS-H10
hBEW-9E10.6






VH




hBDI-9E8.4 VL
GS-
hBEW-9E10.6





L10 (dR)
VL


PR-1611300
9E8.4_GS_1B10.1
hBDI-9E8.4 VH
GS-H10
hBEW-1B10.1 VH




hBDI-9E8.4 VL
GS-
hBEW-1B10.1





L10 (dR)
VL


PR-1611301
9E8.4_GS_1E3.4
hBDI-9E8.4 VH
GS-H10
hBEW-1E3.4






VH




hBDI-9E8.4 VL
GS-
hBEW-1E3.4 VL





L10 (dR)


PR-1613189
3E2.1_GS_CL-34565
hBFU-3E2.1 VH
GS-H10
CL-34565 VH




hBFU-3E2.1 VL
GS-
CL-34565 VL





L10 (dR)


PR-1612499
3E2.1_GS_4G8.5
hBFU-3E2.1 VH
GS-H10
hBDB-4G8.5 VH




hBFU-3E2.1 VL
GS-
hBDB-4G8.5 VL





L10 (dR)


PR-1612500
3E2.1_GS_9E10.1
hBFU-3E2.1 VH
GS-H10
hBEW-9E10.1






VH




hBFU-3E2.1 VL
GS-
hBEW-9E10.1





L10 (dR)
VL


PR-1612501
3E2.1_GS_9E10.6
hBFU-3E2.1 VH
GS-H10
hBEW-9E10.6






VH




hBFU-3E2.1 VL
GS-
hBEW-9E10.6





L10 (dR)
VL


PR-1612502
3E2.1_GS_1B10.1
hBFU-3E2.1 VH
GS-H10
hBEW-1B10.1 VH




hBFU-3E2.1 VL
GS-
hBEW-1B10.1





L10 (dR)
VL


PR-1613190
3E2.1_GS_1E3.4
hBFU-3E2.1 VH
GS-H10
hBEW-1E3.4






VH




hBFU-3E2.1 VL
GS-
hBEW-1E3.4 VL





L10 (dR)


PR-1629646
9E10.1_SL_CL-33675
hBEW-9E10.1 VH
HG-short
CL-33675 VH




hBEW-9E10.1 VL
LK-long
CL-33675 VL


PR-1629647
1B10.1_SL_CL-33675
hBEW-1B10.1 VH
HG-short
CL-33675 VH




hBEW-1B10.1 VL
LK-long
CL-33675 VL


PR-1629648
9E10.1_LS_CL-33675
hBEW-9E10.1 VH
HG-long
CL-33675 VH




hBEW-9E10.1 VL
LK-short
CL-33675 VL


PR-1629649
1B10.1_LS_CL-33675
hBEW-1B10.1 VH
HG-long
CL-33675 VH




hBEW-1B10.1 VL
LK-short
CL-33675 VL


PR-1564883
DVD3896 a
hBDI-5H1.9 VH
HG-short
hBDB-4G8.13






VH




hBDI-5H1.9 VL
LK-long
hBDB-4G8.13






VL


PR-1564893
DVD3897 a
hBDI-5H1.9 VH
HG-short
hBDB-4G8.14






VH




hBDI-5H1.9 VL
LK-long
hBDB-4G8.14






VL


PR-1564896
DVD3898 a
hBDI-5H1.9 VH
HG-short
hBDB-4G8.15






VH




hBDI-5H1.9 VL
LK-long
hBDB-4G8.15






VL


PR-1564898
DVD3899 a
hBDI-9E8.12 VH
HG-short
hBDB-4G8.14






VH




hBDI-9E8.12 VL
LK-long
hBDB-4G8.14






VL


PR-1564899
DVD3900 a
hBDI-9E8.12 VH
HG-short
hBDB-4G8.15






VH




hBDI-9E8.12 VL
LK-long
hBDB-4G8.15






VL


PR-1565023
DVD3901 a
hBDI-9E8.9 VH
HG-short
hBDB-4G8.13






VH




hBDI-9E8.9 VL
LK-long
hBDB-4G8.13






VL


PR-1565029
DVD3902 a
hBDI-9E8.9 VH
HG-short
hBDB-4G8.14






VH




hBDI-9E8.9 VL
LK-long
hBDB-4G8.14






VL


PR-1565030
DVD3903 a
hBDI-9E8.9 VH
HG-short
hBDB-4G8.15






VH




hBDI-9E8.9 VL
LK-long
hBDB-4G8.15






VL


PR-1565031
DVD3904 a
hBDI-5H1.13 VH
HG-short
hBDB-4G8.14






VH




hBDI-5H1.13 VL
LK-long
hBDB-4G8.14






VL


PR-1565032
DVD3905 a
hBDI-9E8.12 VH
HG-short
hBDB-4G8.15






VH




hBDI-9E8.12 VL
LK-long
hBDB-4G8.15






VL


PR-1565035
DVD3906 a
hBDI-5H1.13 VH
HG-short
hBDB-4G8.15






VH




hBDI-5H1.13 VL
LK-long
hBDB-4G8.15






VL


PR-1565033
DVD3907 a
hBDI-9E8.13 VH
HG-short
hBDB-4G8.15






VH




hBDI-9E8.13 VL
LK-long
hBDB-4G8.15






VL



a These DVDs were made with Ig gamma-1 constant region L234A, L235A, all other DVDs made with Ig gamma-1 constant region L234A, L235A, and H435A.

























































































































































































































































































TABLE 57



Heavy (H) and Light Chain (L) Amino Acid Composition of

Some Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules

(Linker sequence in italics; CDR sequences in bold;

HC = heavy chain and LC = light chain)





Sequence
DVD-Ig Variable
Sequence

Identifier
Domain (Corporate ID)
12345678901234567890123456789012



SEQ ID NO: 3823
4G8.3-GS-9E8.4 HC
EVQLVQSGSELKKPGASVKVSCKAS GYTFTNY


(PR-1569574)
GMY WVRQAPGQGLEWMG WINTETGKPTYADDF



KG RFVFSLDTSVSTAYLQISSLKAEDTAVYYC



AR TNYYYRSYIFYFDY WGQGTMVTVSS GGGGS



GGGGS EVTLRESGPALVKPTQTLTLTCTFS GF



SLSTYGMGVG WIRQPPGKALEWLA NIWWDDDK



YYNPSLKN RLTISKDTSKNQVVLTMTNMDPVD



TATYYCARIES IGTTYSFDY WGQGTMVTVSSA



STKGPSVFPLAPSSKSTSGGTAALGCLVKDYF



PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL



SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK



VEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPK



PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY



VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH



QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ



PREPQVYTLPPSREEMTKNQVSLTCLVKGFYP



SDIAVEWESNGQPENNYKTTPPVLDSDGSFFL



YSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQ



KSLSLSPGK



SEQ ID NO: 3824
4G8.3-GS-9E8.4 LC
DTVLTQSPATLSLSPGERATLSC RASESVSTH


(PR-1569574)
MH WYQQKPGQAPRLLIY GASNLES GVPARFSG



SGSGTDFTLTISSLEPEDFAVYFC QQSWNDPF



TFGQGTKLEIKR GGSGGGGSG EFVLTQSPGTL



SLSPGERATLSC ERSSGDIGDSYVS WYQQKPG



QAPRLVIY ADDQRPS GIPDRFSGSGSGTDFTL



TISRLEPEDFAVYYC QSYDINIDIV FGGGTKV



EIKGTVAAPSVFIFPPSDEQLKSGTASVVCLL



NNFYPREAKVQWKVDNALQSGNSQESVTEQDS



KDSTYSLSSTLTLSKADYEKHKVYACEVTHQG



LSSPVTKSFNRGEC



SEQ ID NO: 3825
4G8.3-SL-9E8.4 HC
EVQLVQSGSELKKPGASVKVSCKAS GYTFTNY


(PR-1569579)
GMY WVRQAPGQGLEWMG WINTETGKPTYADDF



KG RFVFSLDTSVSTAYLQISSLKAEDTAVYYC



AR TNYYYRSYIFYFDY WGQGTMVTVSS ASTKG



PE VTLRESGPALVKPTQTLTLTCTFS GFSLST



YGMGVG WIRQPPGKALEWLA NIWWDDDKYYNP



SLKN RLTISKDTSKNQVVLTMTNMDPVDTATY



YCARIES IGTTYSFDY WGQGTMVTVSSASTKG



PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV



TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV



TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK



SCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDT



LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV



EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL



NGKEYKCKVSNKALPAPIEKTISKAKGQPREP



QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA



VEWESNGQPENNYKTTPPVLDSDGSFFLYSKL



TVDKSRWQQGNVFSCSVMHEALHNAYTQKSLS



LSPGK



SEQ ID NO: 3826
4G8.3-SL-9E8.4 LC
DTVLTQSPATLSLSPGERATLSC RASESVSTH


(PR-1569579)
MH WYQQKPGQAPRLLIY GASNLES GVPARFSG



SGSGTDFTLTISSLEPEDFAVYFC QQSWNDPF



T FGQGTKLEIK RTVAAPSVFIFPP EFVLTQSP



GTLSLSPGERATLSC ERSSGDIGDSYVS WYQQ



KPGQAPRLVIY ADDQRPS GIPDRFSGSGSGTD



FTLTISRLEPEDFAVYYC QSYDINIDIV FGGG



TKVEIKGTVAAPSVFIFPPSDEQLKSGTASVV



CLLNNFYPREAKVQWKVDNALQSGNSQESVTE



QDSKDSTYSLSSTLTLSKADYEKHKVYACEVT



HQGLSSPVTKSFNRGEC



SEQ ID NO: 3827
4G8.3-LS-9E8.4 HC
EVQLVQSGSELKKPGASVKVSCKAS GYTFTNY


(PR-1575573)
GMY WVRQAPGQGLEWMG WINTETGKPTYADDF



KG RFVFSLDTSVSTAYLQISSLKAEDTAVYYC



AR TNYYYRSYIFYFDY WGQGTMVTVSS ASTKG



PSVFPLAP EVTLRESGPALVKPTQTLTLTCTF



S GFSLSTYGMGVG WIRQPPGKALEWLA NIWWD



DDKYYNPSLKN RLTISKDTSKNQVVLTMTNMD



PVDTATYYCAR IESIGTTYSFDY WGQGTMVTV



SSASTKGPSVFPLAPSSKSTSGGTAALGCLVK



DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL



YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV



DKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLF



PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF



NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT



VLHQDWLNGKEYKCKVSNKALPAPIEKTISKA



KGQPREPQVYTLPPSREEMTKNQVSLTCLVKG



FYPSDIAVEWESNGQPENNYKTTPPVLDSDGS



FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNA



YTQKSLSLSPGK



SEQ ID NO: 3828
4G8.3-LS-9E8.4 LC
DTVLTQSPATLSLSPGERATLSC RASESVSTH


(PR-1575573)
MH WYQQKPGQAPRLLIY GASNLES GVPARFSG



SGSGTDFTLTISSLEPEDFAVYFC QQSWNDPF



T FGQGTKLEIK RTVAAP EFVLTQSPGTLSLSP



GERATLSC ERSSGDIGDSYVS WYQQKPGQAPR



LVIY ADDQRPS GIPDRFSGSGSGTDFTLTISR



LEPEDFAVYYC QSYDINIDIV FGGGTKVEIKG



TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY



PREAKVQWKVDNALQSGNSQESVTEQDSKDST



YSLSSTLTLSKADYEKHKVYACEVTHQGLSSP



VTKSFNRGEC



SEQ ID NO: 3829
4G8.3-GS-9E8.4 (g)
EVQLVQSGSELKKPGASVKVSCKAS GYTFTNY


HC (PR-1572102)
GMY WVRQAPGQGLEWMG WINTETGKPTYADDF



KG RFVFSLDTSVSTAYLQISSLKAEDTAVYYC



AR TNYYYRSYIFYFDY WGQGTMVTVSS GGGGS



GGGGS EVTLRESGPALVKPTQTLTLTCTFS GF



SLSTYGMGVG WIRQPPGKALEWLA NIWWDDDK



YYNPSLKN RLTISKDTSKNQVVLTMTNMDPVD



TATYYCAR IESIGTTYSFDY WGQGTMVTVSSA



STKGPSVFPLAPSSKSTSGGTAALGCLVKDYF



PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL



SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK



VEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPK



PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY



VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH



QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ



PREPQVYTLPPSREEMTKNQVSLTCLVKGFYP



SDIAVEWESNGQPENNYKTTPPVLDSDGSFFL



YSKLTVDKSRWQQGNVFSCSVMHEALHNAYTQ



KSLSLSPGK



SEQ ID NO: 3830
4G8.3-GS-9E8.4 (g) LC
DTVLTQSPATLSLSPGERATLSC RASESVSTH


(PR-1572102)
MH WYQQKPGQAPRLLIY GASNLES GVPARFSG



SGSGTDFTLTISSLEPEDFAVYFC QQSWNDPF



T FGQGTKLEIK RGGSGGGGSG EFVLTQSPGTL



SLSPGERATLSC ERSSGDIGDSYVS WYQQKPG



QAPRLVIY ADDQRPS GIPDRFSGSGSGTDFTL



TISRLEPEDFAVYYC QSYDINIDIV FGGGTKV



EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLL



NNFYPREAKVQWKVDNALQSGNSQESVTEQDS



KDSTYSLSSTLTLSKADYEKHKVYACEVTHQG



LSSPVTKSFNRGEC



SEQ ID NO: 3831
4G8.3-SL-9E8.4 (g) HC
EVQLVQSGSELKKPGASVKVSCKAS GYTFTNY


(PR-1572105)
GMY WVRQAPGQGLEWMG WINTETGKPTYADDF



KG RFVFSLDTSVSTAYLQISSLKAEDTAVYYC



AR TNYYYRSYIFYFDY WGQGTMVTVSS ASTKG



P EVTLRESGPALVKPTQTLTLTCTFS GFSLST



YGMG VGWIRQPPGKALEWLANIWWDDDKYYNP



SLKN RLTISKDTSKNQVVLTMTNMDPVDTATY



YCAR IESIGTTYSFDY WGQGTMVTVSSASTKG



PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV



TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV



TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK



SCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDT



LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV



EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL



NGKEYKCKVSNKALPAPIEKTISKAKGQPREP



QVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA



VEWESNGQPENNYKTTPPVLDSDGSFFLYSKL



TVDKSRWQQGNVFSCSVMHEALHNAYTQKSLS



LSPGK



SEQ ID NO: 3832
4G8.3-SL-9E8.4 (g) LC
DTVLTQSPATLSLSPGERATLSC RASESVSTH


(PR-1572105)
MH WYQQKPGQAPRLLIY GASNLES GVPARFSG



SGSGTDFTLTISSLEPEDFAVYFC QQSWNDPF



T FGQGTKLEIK RTVAAPSVFIFPP EFVLTQSP



GTLSLSPGERATLSC ERSSGDIGDSYVS WYQQ



KPGQAPRLVIY ADDQRPS GIPDRFSGSGSGTD



FTLTISRLEPEDFAVYYC QSYDINIDIV FGGG



TKVEIKrTVAAPSVFIFPPSDEQLKSGTASVV



CLLNNFYPREAKVQWKVDNALQSGNSQESVTE



QDSKDSTYSLSSTLTLSKADYEKHKVYACEVT



HQGLSSPVTKSFNRGEC



SEQ ID NO: 3833
9E10.1_GS_CL-33675
EIQLVQSGSELKKPGASVKVSCKAS GYTFTNY


HC (PR-1610561)
GMY WVKQAPGQGLEYMG WIDTETGRPTYADDF



KG RFVFSLDTSVSTAYLQISSLKAEDTAVYFC



AR WSGDTTGIRGPWFAY WGQGTLVTVSS GGGG



SGGGGS EVTLRESGPALVKPTQTLTLTCTFS G



FSLSTYGMGVG WIRQPPGKALEWLA NIWWDDD



KYYNPSLKN RLTISKDTSKNQVVLTMTNMDPV



DTATYYCAR IESSGPKYSFDY WGQGTMVTVSS



ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY



FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS



LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK



KVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPP



KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW



YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL



HQDWLNGKEYKCKVSNKALPAPIEKTISKAKG



QPREPQVYTLPPSREEMTKNQVSLTCLVKGFY



PSDIAVEWESNGQPENNYKTTPPVLDSDGSFF



LYSKLTVDKSRWQQGNVFSCSVMHEALHNAYT



QKSLSLSPGK



SEQ ID NO: 3834
9E10.1_GS_CL-33675
DIRMTQSPSSLSASVGDRVTIEC LASEDIYSD


LC (PR-1610561)
LA WYQQKPGKSPKLLIY NANGLQN GVPSRFSG



SGSGTDYSLTISSLQPEDVATYFC QQYNYFPG



T FGQGTKLEIK GGSGGGGSGG EIVLTQSPGTL



SLSPGERATLSC RASSGSIWYSFVS WYQQKPG



QAPRLLIY ADDQRAS GIPDRFSGSGSGTDFTL



TISRLEPEDFAVYYC QSYGINIDVV FGGGTKV



EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLL



NNFYPREAKVQWKVDNALQSGNSQESVTEQDS



KDSTYSLSSTLTLSKADYEKHKVYACEVTHQG



LSSPVTKSFNRGEC



SEQ ID NO: 3835
1B10.1_GS_CL-33675
EVQLVESGGGLVQPGGSLRLSCAAS GFSFSKY


HC (PR-1611292)
DMA WFRQAPGKGLEWVA SITTSGVGTYYRDSV



KG RFTVSRDNAKSTLYLQMNSLRAEDTAVYYC



AR GYGAMDA WGQGTTVTVSSGGGGSGGGGSEV



TLRESGPALVKPTQTLTLTCTFS GFSLSTYGM



GVGW IRQPPGKALEWLA NIWWDDDKYYNPSLK



N RLTISKDTSKNQVVLTMTNMDPVDTATYYCA



R IESSGPKYSFDY WGQ



GTMVTVSSASTKGPSVFPLAPSSKSTSGGTAA



LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV



LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK



PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGG



PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE



DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR



VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE



KTISKAKGQPREPQVY



TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEW



ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD



KSRWQQGNVFSCSVMHEALHNAYTQKSLSLSP



GK



SEQ ID NO: 3836
1B10.1_GS_CL-33675
DIQMTQSPSSLSASVGDRVTITC KASQDIDDY


LC (PR-1611292)
LS WYQQKPGKSPKLVIY AATRLAD GVPSRFSG



SGSGTDYTLTISSLQPEDFATYYC LQSSSTPW



T FGGGTKVEIKGGSGGGGSGGEIVLTQSPGTL



SLSPGERATLSC RASSGSIWYSFVS WYQQKPG



QAPRLLIY ADDQRAS GIPDRFSGSGSGTDFTL



TISRLEPEDFAVYYC QSYGINIDVV FGGGTKV



EIKRTVAAPSVFIFPP



SDEQLKSGTASVVCLLNNFYPREAKVQWKVDN



ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA



DYEKHKVYACEVTHQGLSSPVTKSFNRGEC
























































































































































































































































Example 11
Generation of CO-DVD-Ig Molecules
Cross-over DVD-Ig binding proteins are constructed as shown below. Each of VD1, VD2, VD3 and VD4 could be the VH or VL from a mAb. In cross-over DVD-Ig, VD1 and VD4 form one antigen binding domain. VD2 and VD3 form another binding domain.














TABLE 58



Heavy Chain and Light Chain Amino Acid Sequences of Anti-Human

VEGF-A/Anti-Human PDGF-BB Cross-over DVD-Ig Molecules

(Linker sequence in italics; CDR sequences in bold)





Seq ID
Name (Corporate
Sequence

No
ID)
1234567890123456789012345678901234567890







3844
CODV001 HC
EVQLVESGGGLVQPGGSLRLSCAAS GYTFTNYGMN WVRQA


(PR-1565040)
PGKGLEWVG WINTYTGEPTYAADFKR RFTFSLDTSKSTAY



LQMNSLRAEDTAVYYCAK YPHYYGSSHWYFDV WGQGTLVT



VSS G EVTLKESGPALVKPTQTLTLTCTFS GFSLSTFGMGV



G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTISKDTS



KNQAVLTITNMDPVDTATYYCAR ISTGISSYYVMDA WGQG



TTVTVSS GG ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD



YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV



PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP



CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH



EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV



LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV



YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE



NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM



HEALHNHYTQKSLSLSPGK



3845
CODV001 LC
DFQLTQSPSSLSASVGDRVTITC ERSSGDIGDTYVS WYQQ


(PR-1565040)
KPGKAPKNVIY GNDQRPS GVPSRFSGSGSGNSATLTISSL



QPEDFATYFC QSYDSDIDIV FGQGTKVEIK GGGSGGG DIQ



MTQSPSSLSASVGDRVTITC SASQDISNYLN WYQQKPGKA



PKVLIY FTSSLHS GVPSRFSGSGSGTDFTLTISSLQPEDF



ATYYC QQYSTVPWT FGQGTKVEIK GGG SGRTVAAPSVFIF



PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN



SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH



QGLSSPVTKSFNRGEC



3837
CODV002 HC
EVTLKESGPALVKPTQTLTLTCTFS GFSLSTFGMGVG WIR


(PR-1565042)
QPPGKALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQA



VLTITNMDPVDTATYYCAR ISTGISSYYVMDA WGQGTTVT



VSS G EVQLVESGGGLVQPGGSLRLSCAAS GYTFTNYGMN W



VRQAPGKGLEWVG WINTYTGEPTYAADFKR RFTFSLDTSK



STAYLQMNSLRAEDTAVYYCAK YPHYYGSSHWYFDV WGQG



TLVTVSS GG ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD



YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV



PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP



CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH



EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV



LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV



YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE



NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM



HEALHNHYTQKSLSLSPGK



3838
CODV002 LC
DIQMTQSPSSLSASVGDRVTITC SASQDISNYLN WYQQKP


(PR-1565042)
GKAPKVLIY FTSSLHS GVPSRFSGSGSGTDFTLTISSLQP



EDFATYYC QQYSTVPWT FGQGTKVEIK GGGSGGG DFQLTQ



SPSSLSASVGDRVTITC ERSSGDIGDTYVS WYQQKPGKAP



KNVIY GNDQRPS GVPSRFSGSGSGNSATLTISSLQPEDFA



TYFC QSYDSDIDIV FGQGTKVEIK GGGSG RTVAAPSVFIF



PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN



SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH



QGLSSPVTKSFNRGEC



213
CODV003 HC
EVQLVESGGGLVQPGGSLRLSCAAS GYTFTNYGMN WVRQA


(PR-1565044)
PGKGLEWVG WINTYTGEPTYAADFKR RFTFSLDTSKSTAY



LQMNSLRAEDTAVYYCAK YPHYYGSSHWYFDV WGQGTLVT



VSS G EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGV



G WIRQPPGKGLEWLA NIWWDDDKYYNPSLKN RLTISKDTS



KNQAVLTITNMDPVDTATYYCAR IESIGTTYSFDY WGQGT



MVTVSS GG ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY



FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP



SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC



PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE



DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL



HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY



TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN



NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH



EALHNHYTQKSLSLSPGK



214
CODV003 LC
DFQLTQSPSSLSASVGDRVTITC ERSSGDIGDSYVS WYQQ


(PR-1565044)
KPGKAPKNVIY ADDQRPS GVPSRFSGSGSGNSASLTISSL



QPEDFATYFC QSYDINIDIV FGQGTKVEIK GGGSGGG DIQ



MTQSPSSLSASVGDRVTITC SASQDISNYLN WYQQKPGKA



PKVLIY FTSSLHS GVPSRFSGSGSGTDFTLTISSLQPEDF



ATYYC QQYSTVPWT FGQGTKVEIK GGGSG RTVAAPSVFIF



PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN



SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH



QGLSSPVTKSFNRGEC



215
CODV004 HC
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIR


(PR-1565051)
QPPGKGLEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQA



VLTITNMDPVDTATYYCAR IESIGTTYSFDY WGQGTMVTV



SS G EVQLVESGGGLVQPGGSLRLSCAAS GYTFTNYGMN WV



RQAPGKGLEWVG WINTYTGEPTYAADFKR RFTFSLDTSKS



TAYLQMNSLRAEDTAVYYCAK YPHYYGSSHWYFDV WGQGT



LVTVSS GG ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY



FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP



SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC



PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE



DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL



HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY



TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN



NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH



EALHNHYTQKSLSLSPGK



216
CODV004 LC
DIQMTQSPSSLSASVGDRVTITC SASQDISNYLN WYQQKP


(PR-1565051)
GKAPKVLIY FTSSLHS GVPSRFSGSGSGTDFTLTISSLQP



EDFATYYC QQYSTVPWT FGQGTKVEIK GGGSGGG DFQLTQ



SPSSLSASVGDRVTITC ERSSGDIGDSYVS WYQQKPGKAP



KNVIY ADDQRPS GVPSRFSGSGSGNSASLTISSLQPEDFA



TYFC QSYDINIDIV FGQGTKVEIK GGGSG RTVAAPSVFIF



PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN



SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH



QGLSSPVTKSFNRGEC



217
CODV005 HC
EVQLVESGGGLVQPGGSLRLSCAAS GYTFTNYGMY WVKQA


(PR-1565083)
PGKGLEYMG WINTETGKPTYADDFKG RFTFSLDTSKSTAY



LQMNSLRAEDTAVYFCAR TNYYYRSYIFYFDY WGQGTLVT



VSS G EVTLKESGPALVKPTQTLTLTCTFS GFSLSTFGMGV



G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTISKDTS



KNQAVLTITNMDPVDTATYYCAR ISTGISSYYVMDA WGQG



TTVTVSS GG ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD



YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV



PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP



CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH



EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV



LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV



YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE



NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM



HEALHNHYTQKSLSLSPGK



218
CODV005 LC
DFQLTQSPSSLSASVGDRVTITC ERSSGDIGDTYVS WYQQ


(PR-1565083)
KPGKAPKNVIY GNDQRPS GVPSRFSGSGSGNSATLTISSL



QPEDFATYFC QSYDSDIDIV FGQGTKVEIK GGGSGGG DTQ



LTQSPSSLSASVGDRVTISC RASESVSTHMH WYQQKPGKA



PKLLIY GASNLES GVPSRFSGSGSGTDFTLTISSLQPEDF



ATYFC QQSWNDPFT FGQGTKVEIK GGGSG RTVAAPSVFIF



PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN



SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH



QGLSSPVTKSFNRGEC



219
CODV006 HC
EVTLKESGPALVKPTQTLTLTCTFS GFSLSTFGMGVG WIR


(PR-1565084)
QPPGKALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQA



VLTITNMDPVDTATYYCAR ISTGISSYYVMDA WGQGTTVT



VSS G EVQLVESGGGLVQPGGSLRLSCAAS GYTFTNYGMY W



VKQAPGKGLEYMG WINTETGKPTYADDFKG RFTFSLDTSK



STAYLQMNSLRAEDTAVYFCAR TNYYYRSYIFYFDY WGQG



TLVTVSS GG ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD



YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV



PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP



CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH



EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV



LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV



YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE



NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM



HEALHNHYTQKSLSLSPGK



220
CODV006 LC
DTQLTQSPSSLSASVGDRVTISC RASESVSTHMH WYQQKP


(PR-1565084)
GKAPKLLIY GASNLES GVPSRFSGSGSGTDFTLTISSLQP



EDFATYFC QQSWNDPFT FGQGTKVEIK GGGSGGG DFQLTQ



SPSSLSASVGDRVTITC ERSSGDIGDTYVS WYQQKPGKAP



KNVIY GNDQRPS GVPSRFSGSGSGNSATLTISSLQPEDFA



TYFC QSYDSDIDIV FGQGTKVEIK GGGSG RTVAAPSVFIF



PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN



SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH



QGLSSPVTKSFNRGEC



221
CODV007 HC
EVQLVESGGGLVQPGGSLRLSCAAS GYTFTNYGMY WVKQA


(PR-1565085)
PGKGLEYMG WINTETGKPTYADDFKG RFTFSLDTSKSTAY



LQMNSLRAEDTAVYFCAR TNYYYRSYIFYFDY WGQGTLVT



VSS G EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGV



G WIRQPPGKGLEWLA NIWWDDDKYYNPSLKN RLTISKDTS



KNQAVLTITNMDPVDTATYYCAR IESIGTTYSFDY WGQGT



MVTVSS GG ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY



FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP



SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC



PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE



DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL



HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY



TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN



NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH



EALHNHYTQKSLSLSPGK



222
CODV007 LC
DFQLTQSPSSLSASVGDRVTITC ERSSGDIGDSYVS WYQQ


(PR-1565085)
KPGKAPKNVIY ADDQRPS GVPSRFSGSGSGNSASLTISSL



QPEDFATYFC QSYDINIDIV FGQGTKVEIK GGGSGGG DTQ



LTQSPSSLSASVGDRVTISC RASESVSTHMH WYQQKPGKA



PKLLIY GASNLES GVPSRFSGSGSGTDFTLTISSLQPEDF



ATYFC QQSWNDPFT FGQGTKVEIK GGGSG RTVAAPSVFIF



PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN



SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH



QGLSSPVTKSFNRGEC



223
CODV008 HC
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIR


(PR-1565086)
QPPGKGLEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQA



VLTITNMDPVDTATYYCAR IESIGTTYSFDY WGQGTMVTV



SS G EVQLVESGGGLVQPGGSLRLSCAAS GYTFTNYGMY WV



KQAPGKGLEYMG WINTETGKPTYADDFKG RFTFSLDTSKS



TAYLQMNSLRAEDTAVYFCAR TNYYYRSYIFYFDY WGQGT



LVTVSS GG ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY



FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP



SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC



PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE



DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL



HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY



TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN



NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH



EALHNHYTQKSLSLSPGK



224
CODV008 LC
DTQLTQSPSSLSASVGDRVTISC RASESVSTHMH WYQQKP


(PR-1565086)
GKAPKLLIY GASNLES GVPSRFSGSGSGTDFTLTISSLQP



EDFATYFC QQSWNDPFT FGQGTKVEIK GGGSGGG DFQLTQ



SPSSLSASVGDRVTITC ERSSGDIGDSYVS WYQQKPGKAP



KNVIY ADDQRPS GVPSRFSGSGSGNSASLTISSLQPEDFA



TYFC QSYDINIDIV FGQGTKVEIK GGGSG RTVAAPSVFIF



PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN



SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH



QGLSSPVTKSFNRGEC



225
CODV009 HC
EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQA


(PR-1571821)
PGQGLEWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAY



LQISSLKAEDTAVYYCAR TNYYYRSYIFYFDY WGQGTMVT



VSS G EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGV



G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTISKDTS



KNQVVLTMTNMDPVDTATYYCAR IESIGTTYSFDY WGQGT



MVTVSS GG ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY



FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP



SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC



PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE



DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL



HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY



TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN



NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH



EALHNAYTQKSLSLSPGK



226
CODV009 LC
EFVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQ


(PR-1571821)
KPGQAPRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRL



EPEDFAVYYC QSYDINIDIV FGGGTKVEIK GGGSGGG DTV



LTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDF



AVYFC QQSWNDPFT FGQGTKLEIK GGGSG RTVAAPSVFIF



PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN



SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH



QGLSSPVTKSFNRGEC



227
CODV010 HC
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIR


(PR-1571823)
QPPGKALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQV



VLTMTNMDPVDTATYYCAR IESIGTTYSFDY WGQGTMVTV



SS G EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WV



RQAPGQGLEWMG WINTETGKPTYADDFKG RFVFSLDTSVS



TAYLQISSLKAEDTAVYYCAR TNYYYRSYIFYFDY WGQGT



MVTVSS GG ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY



FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP



SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC



PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE



DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL



HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY



TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN



NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH



EALHNAYTQKSLSLSPGK



228
CODV010 LC
DTVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKP


(PR-1571823)
GQAPRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEP



EDFAVYFC QQSWNDPFT FGQGTKLEIK GGGSGGG EFVLTQ



SPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQAP



RLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFA



VYYC QSYDINIDIV FGGGTKVEIK GGGSG RTVAAPSVFIF



PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN



SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH



QGLSSPVTKSFNRGEC



229
CODV011 HC
EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQA


(PR-1575521)
PGQGLEWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAY



LQISSLKAEDTAVYYCAR TNYYYRSYIFYFDY WGQGTMVT



VSSG GGGSGGG GSEFVLTQSPGTLSLSPGERATLSC ERSS



GDIGDSYVS WYQQKPGQAPRLVIY ADDQRPS GIPDRFSGS



GSGTDFTLTISRLEPEDFAVYYC QSYDINIDIV FGGGTKV



EIK GGGSG ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY



FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP



SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC



PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE



DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL



HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY



TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN



NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH



EALHNAYTQKSLSLSPGK



230
CODV011 LC
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIR


(PR-1575521)
QPPGKALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQV



VLTMTNMDPVDTATYYCAR IESIGTTYSFDY WGQGTMVTV



SS GGGGSGGGGS DTVLTQSPATLSLSPGERATLSC RASES



VSTHMH WYQQKPGQAPRLLIY GASNLES GVPARFSGSGSG



TDFTLTISSLEPEDFAVYFC QQSWNDPFT FGQGTKLEIK G



GGSG RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE



AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK



ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



231
CODV012 HC
EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQA


(PR-1571824)
PGQGLEWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAY



LQISSLKAEDTAVYYCAR TNYYYRSYIFYFDY WGQGTMVT



VSSG GGGSGGG EFVLTQSPGTLSLSPGERATLSC ERSSGD



IGDSYVS WYQQKPGQAPRLVIY ADDQRPS GIPDRFSGSGS



GTDFTLTISRLEPEDFAVYYC QSYDINIDIV FGGGTKVEI



K GGGSG ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP



EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS



SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA



PEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP



EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ



DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL



PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY



KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA



LHNAYTQKSLSLSPGK



232
CODV012 LC
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIR


(PR-1571824)
QPPGKALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQV



VLTMTNMDPVDTATYYCAR IESIGTTYSFDY WGQGTMVTV



SSG GGGSGGG DTVLTQSPATLSLSPGERATLSC RASESVS



THMH WYQQKPGQAPRLLIY GASNLES GVPARFSGSGSGTD



FTLTISSLEPEDFAVYFC QQSWNDPFT FGQGTKLEIK GGG



SG RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK



VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD



YEKHKVYACEVTHQGLSSPVTKSFNRGEC



233
CODV013 HC
EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQA


(PR-1571825)
PGQGLEWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAY



LQISSLKAEDTAVYYCAR TNYYYRSYIFYFDY WGQGTMVT



VSSG GGGSGGG EFVLTQSPGTLSLSPGERATLSC ERSSGD



IGDSYVS WYQQKPGQAPRLVIY ADDQRPS GIPDRFSGSGS



GTDFTLTISRLEPEDFAVYYC QSYDINIDIV FGGGTKVEI



K GGS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP



VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL



GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE



AAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV



KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW



LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP



SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT



TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH



NAYTQKSLSLSPGK



234
CODV013 LC
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIR


(PR-1571825)
QPPGKALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQV



VLTMTNMDPVDTATYYCAR IESIGTTYSFDY WGQGTMVTV



SSG GGGSGGG DTVLTQSPATLSLSPGERATLSC RASESVS



THMH WYQQKPGQAPRLLIY GASNLES GVPARFSGSGSGTD



FTLTISSLEPEDFAVYFC QQSWNDPFT FGQGTKLEIK GGG



SG RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK



VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD



YEKHKVYACEVTHQGLSSPVTKSFNRGEC



235
CODV014 HC
EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQA


(PR-1571826)
PGQGLEWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAY



LQISSLKAEDTAVYYCAR TNYYYRSYIFYFDY WGQGTMVT



VSS GGGGS EFVLTQSPGTLSLSPGERATLSC ERSSGDIGD



SYV SWYQQKPGQAPRLVIY ADDQRPS GIPDRFSGSGSGTD



FTLTISRLEPEDFAVYYC QSYDINIDIV FGGGTKVEIK GG



S ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV



SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ



TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAG



GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN



WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG



KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE



EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP



VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNAY



TQKSLSLSPGK



236
CODV014 LC
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIR


(PR-1571826)
QPPGKALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQV



VLTMTNMDPVDTATYYCAR IESIGTTYSFDY WGQGTMVTV



SSG GGGSGGG DTVLTQSPATLSLSPGERATLSC RASESVS



THMH WYQQKPGQAPRLLIY GASNLES GVPARFSGSGSGTD



FTLTISSLEPEDFAVYFC QQSWNDPFT FGQGTKLEIK GGG



SG RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK



VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD



YEKHKVYACEVTHQGLSSPVTKSFNRGEC



237
CODV015 HC
EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQA


(PR-1571827)
PGQGLEWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAY



LQISSLKAEDTAVYYCAR TNYYYRSYIFYFDY WGQGTMVT



VSSG GGGSGGG EFVLTQSPGTLSLSPGERATLSC ERSSGD



IGDSYVS WYQQKPGQAPRLVIY ADDQRPS GIPDRFSGSGS



GTDFTLTISRLEPEDFAVYYC QSYDINIDIV FGGGTKVEI



K GGGSG ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP



EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS



SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA



PEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP



EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ



DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL



PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY



KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA



LHNAYTQKSLSLSPGK



238
CODV015 LC
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIR


(PR-1571827)
QPPGKALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQV



VLTMTNMDPVDTATYYCAR IESIGTTYSFDY WGQGTMVTV



SSG GGGSGGG DTVLTQSPATLSLSPGERATLSC RASESVS



THMH WYQQKPGQAPRLLIY GASNLES GVPARFSGSGSGTD



FTLTISSLEPEDFAVYFC QQSWNDPFT FGQGTKLEIK GGS



RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ



WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE



KHKVYACEVTHQGLSSPVTKSFNRGEC



239
CODV016 HC
EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQA


(PR-1571828)
PGQGLEWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAY



LQISSLKAEDTAVYYCAR TNYYYRSYIFYFDY WGQGTMVT



VSSG GGGSGGG EFVLTQSPGTLSLSPGERATLSC ERSSGD



IGDSYVS WYQQKPGQAPRLVIY ADDQRPS GIPDRFSGSGS



GTDFTLTISRLEPEDFAVYYC QSYDINIDIV FGGGTKVEI



K GGGSG ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP



EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS



SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA



PEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP



EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ



DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL



PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY



KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA



LHNAYTQKSLSLSPGK



240
CODV016 LC
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIR


(PR-1571828)
QPPGKALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQV



VLTMTNMDPVDTATYYCAR IESIGTTYSFDY WGQGTMVTV



SS GGGGS DTVLTQSPATLSLSPGERATLSC RASESVSTHM



H WYQQKPGQAPRLLIY GASNLES GVPARFSGSGSGTDFTL



TISSLEPEDFAVYFC QQSWNDPFT FGQGTKLEIK GGS RTV



AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV



DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK



VYACEVTHQGLSSPVTKSFNRGEC



241
CODV017 HC
DTVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKP


(PR-1571830)
GQAPRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEP



EDFAVYFC QQSWNDPFT FGQGTKLEIK GGGSGGG EFVLTQ



SPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQAP



RLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPEDFA



VYYC QSYDINIDIV FGGGTKVEIK GGGSG ASTKGPSVFPL



APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH



TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN



TKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPK



DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK



TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL



PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL



VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS



KLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPGK



242
CODV017 LC
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIR


(PR-1571830)
QPPGKALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQV



VLTMTNMDPVDTATYYCAR IESIGTTYSFDY WGQGTMVTV



SS G EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WV



RQAPGQGLEWMG WINTETGKPTYADDFKG RFVFSLDTSVS



TAYLQISSLKAEDTAVYYCAR TNYYYRSYIFYFDY WGQGT



MVTVSS GGR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNF



YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL



TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



243
CODV018 HC
EFVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQ


(PR-1571831)
KPGQAPRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRL



EPEDFAVYYC QSYDINIDIV FGGGTKVEIK GGGSGGG DTV



LTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKPGQA



PRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEPEDF



AVYFC QQSWNDPFT FGQGTKLEIK GGGSG ASTKGPSVFPL



APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH



TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN



TKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPK



DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK



TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL



PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCL



VKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS



KLTVDKSRWQQGNVFSCSVMHEALHNAYTQKSLSLSPGK



244
CODV018 LC
EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQA


(PR-1571831)
PGQGLEWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAY



LQISSLKAEDTAVYYCAR TNYYYRSYIFYFDY WGQGTMVT



VSS G EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGV



G WIRQPPGKALEWLA NIWWDDDKYYNPSLKN RLTISKDTS



KNQVVLTMTNMDPVDTATYYCAR IESIGTTYSFDY WGQGT



MVTVSS GG RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF



YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL



TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



245
CODV019 HC
DTVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKP


(PR-1571832)
GQAPRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEP



EDFAVYFC QQSWNDPFT FGQGTKLEIK GGGSGGG GEVTLR



ESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMT



NMDPVDTATYYCAR IESIGTTYSFDY WGQGTMVTVSS LGG



CGGGS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE



PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS



LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP



EAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE



VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP



PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK



TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL



HNAYTQKSLSLSPGK



246
CODV019 LC
EFVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQ


(PR-1571832)
KPGQAPRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRL



EPEDFAVYYC QSYDINIDIV FGGGTKVEIK GGGSGGG GEV



QLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPG



QGLEWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQ



ISSLKAEDTAVYYCAR TNYYYRSYIFYFDY WGQGTMVTVS



S LGGCGGGS RTVAAPSVFIFPPSDEQLKSGTASVVCLLNN



FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST



LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



247
CODV020 HC
EFVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQ


(PR-1571836)
KPGQAPRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRL



EPEDFAVYYC QSYDINIDIV FGGGTKVEIK GGGSGGG GEV



QLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQAPG



QGLEWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAYLQ



ISSLKAEDTAVYYCAR TNYYYRSYIFYFDY WGQGTMVTVS



S LGGCGGGS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKD



YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV



PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP



CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH



EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV



LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV



YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE



NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM



HEALHNAYTQKSLSLSPGK



248
CODV020 LC
DTVLTQSPATLSLSPGERATLSC RASESVSTHMH WYQQKP


(PR-1571836)
GQAPRLLIY GASNLES GVPARFSGSGSGTDFTLTISSLEP



EDFAVYFC QQSWNDPFT FGQGTKLEIK GGGSGGG GEVTLR



ESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGK



ALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMT



NMDPVDTATYYCAR IESIGTTYSFDY WGQGTMVTVSS LGG



CGGGS RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR



EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS



KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



249
CODV021 HC
EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQA


(PR-1577053)
PGQGLEWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAY



LQISSLKAEDTAVYYCAR TNYYYRSYIFYFDY WGQGTMVT



VSSG GGGSGGG EFVLTQSPGTLSLSPGERATLSCERSSGD



IGESYVSWYQQKPGQAPRLVIY ADDQRPS GIPDRFSGSGS



GTDFTLTISRLEPEDFAVYYC QSYDINIDIV FGGGTKVEI



K GGGSG ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP



EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS



SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA



PEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP



EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ



DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL



PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY



KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA



LHNAYTQKSLSLSPGK



250
CODV021 LC
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIR


(PR-1577053)
QPPGKALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQV



VLTMTNMDPVDTATYYCAR IESIGTTYSFDY WGQGTMVTV



SSG GGGSGGG DTVLTQSPATLSLSPGERATLSC RASESVS



THMH WYQQKPGQAPRLLIY GASNLES GVPARFSGSGSGTD



FTLTISSLEPEDFAVYFC QQSWNDPFT FGQGTKLEIK GGS



RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ



WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE



KHKVYACEVTHQGLSSPVTKSFNRGEC



251
CODV022 HC
EVQLVQSGSELKKPGASVKVSCKAS GYTFTNYGMY WVRQA


(PR-1577056)
PGQGLEWMG WINTETGKPTYADDFKG RFVFSLDTSVSTAY



LQISSLKAEDTAVYYCAR TNYYYRSYIFYFDY WGQGTMVT



VSSG GGGSGGG EFVLTQSPGTLSLSPGERATLSCERSSGD



IGESYVSWYQQKPGQAPRLVIY ADDQRPS GIPDRFSGSGS



GTDFTLTISRLEPEDFAVYYC QSYDINIDIV FGGGTKVEI



K GGGSG ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP



EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS



SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA



PEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP



EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ



DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL



PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY



KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA



LHNAYTQKSLSLSPGK



252
CODV022 LC
EVTLRESGPALVKPTQTLTLTCTFS GFSLSTYGMGVG WIR


(PR-1577056)
QPPGKALEWLA NIWWDDDKYYNPSLKN RLTISKDTSKNQV



VLTMTNMDPVDTATYYCAR IESIGTTYSFDY WGQGTMVTV



SS GGGGS DTVLTQSPATLSLSPGERATLSC RASESVSTHM



H WYQQKPGQAPRLLIY GASNLES GVPARFSGSGSGTDFTL



TISSLEPEDFAVYFC QQSWNDPFT FGQGTKLEIK GGS RTV



AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV



DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK



VYACEVTHQGLSSPVTKSFNRGEC



















































































































































































































































































































































































































































































































































































































Example 12
Generation of scFv-IgG Fusion Proteins
All Ig-scFv molecules used the same anti-VEGF-A mAb AB014 as the IgG molecule. A single chain Fv (scFv) anti-PDGF-BB antibody was fused to the C-terminus of AB014 heavy chain using various length of GS linker using standard molecular cloning techniques. Four different heavy chains and one common light chain were made, as shown in the table below. Each heavy chain and the common light chain were co-transfected into HEK293 cells and the resulting Ig-scFv fusion proteins were purified using rProtein-A chromatography.





TABLE 59



Heavy Chain and Light Chain Amino Acid Sequences of Anti-human

VEGF-A/anti-human PDGF-BB Ig-scFv Molecules

(Linker sequence in italics; CDR sequences in bold)





Seq ID
Name
Sequence

No
(Corporate ID)
1234567890123456789012345678901234567890



3839
AB014-GS6-9E8.4
EVQLVESGGGLVQPGGSLRLSCAAS GYTFTNYGMN WVRQA


VH-VK HC
PGKGLEWVG WINTYTGEPTYAADFKR RFTFSLDTSKSTAY


(PR-1599234)
LQMNSLRAEDTAVYYCAK YPHYYGSSHWYFDV WGQGTLVT



VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV



TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG



TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEA



AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK



FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL



NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS



REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT



PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN



AYTQKSLSLSPGK GGSGGG EVTLRESGPALVKPTQTLTLT



CTFS GFSLSTYGMGVG WIRQPPGKALEWLA NIWWDDDKYY



NPSLKN RLTISKDTSKNQVVLTMTNMDPVDTATYYCARIE



SIGTTYSFDY WGQGTMVTVSSGGGGSGGGGSGGGGSEIVL



TQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQKPGQ



APRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRLEPED



FAVYYC QSYDINIDIV FGGGTKVEIK



3940
AB014-GS10-9E8.4
EVQLVESGGGLVQPGGSLRLSCAAS GYTFTNYGMN WVRQA


VH-VK HC
PGKGLEWVG WINTYTGEPTYAADFKR RFTFSLDTSKSTAY


(PR-1599236)
LQMNSLRAEDTAVYYCAK YPHYYGSSHWYFDV WGQGTLVT



VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV



TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG



TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEA



AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK



FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL



NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS



REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT



PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN



AYTQKSLSLSPGK GGSGGGGSGG EVTLRESGPALVKPTQT



LTLTCTFS GFSLSTYGMGVGW IRQPPGKALEWLA NIWWDD



DKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPVDTATYYC



AR IESIGTTYSFDY WGQGTMVTVSSGGGGSGGGGSGGGGS



EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYVS WYQQ



KPGQAPRLVIY ADDQRPS GIPDRFSGSGSGTDFTLTISRL



EPEDFAVYYC QSYDINIDIV FGGGTKVEIK



3841
AB014-GS15-9E8.4
EVQLVESGGGLVQPGGSLRLSCAAS GYTFTNYGMN WVRQA


VH-VK HC
PGKGLEWVG WINTYTGEPTYAADFKR RFTFSLDTSKSTAY


(PR-1599239)
LQMNSLRAEDTAVYYCAK YPHYYGSSHWY FDVWGQGTLVT



VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV



TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG



TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEA



AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK



FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL



NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS



REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT



PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN



AYTQKSLSLSPGK GGSGGGGSGGGGSGG EVTLRESGPALV



KPTQTLTLTCTFS GFSLSTYGMGVGW IRQPPGKALEWLA N



IWWDDDKYYN PSLKNRLTISKDTSKNQVVLTMTNMDPVDT



ATYYCAR IESIGTTYSFDY WGQGTMVTVSS GGGGSGGGGS



GGGGS EIVLTQSPGTLSLSPGERATLSC ERSSGDIGDSYV



SWYQQKPGQAPRLVIY ADDQRPS GIPDRFSGSGSGTDFTL



TISRLEPEDFAVYYC QSYDINIDIV FGGGTKVEIK



3842
AB014-GS10-9E8.4
EVQLVESGGGLVQPGGSLRLSCAAS GYTFTNYGMN WVRQA


VK-VH HC
PGKGLEWVG WINTYTGEPTYAADFKR RFTFSLDTSKSTAY


(PR-1599240)
LQMNSLRAEDTAVYYCAK YPHYYGSSHWYFDV WGQGTLVT



VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV



TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG



TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEA



AGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK



FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL



NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS



REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT



PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN



AYTQKSLSLSPGK GGSGGGGSGG EIVLTQSPGTLSLSPGE



RATLSC ERSSGDIGDSYVS WYQQKPGQAPRLVIY ADDQRP



S GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QSYDINI



DIV FGGGTKVEIKGGGGSGGGGSGGGGSEVTLRESGPALV



KPTQTLTLTCTFS GFSLSTYGMGVG WIRQPPGKALEWLA N



IWWDDDKYYNPSLKN RLTISKDTSKNQVVLTMTNMDPVDT



ATYYCAR IESIGTTYSFDY WGQGTMVTVSS



3843
AB014 LC
DIQMTQSPSSLSASVGDRVTITC SASQDISNYLN WYQQKP



GKAPKVLIY FTSSLHS GVPSRFSGSGSGTDFTLTISSLQP



EDFATYYC QQYSTVPWT FGQGTKVEIKRTVAAPSVFIFPP



SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ



ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG



LSSPVTKSFNRGEC









































































































All HC use the exact same LC (last sequence in Table 59). The naming of the HC follows the following convention: VH name—Linker length (between Fc and scFv)—scFv name with orientation of scFv.
Example 13
In Vitro Characterization of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules and Other Bispecific Molecules
Example 13.1
Expression and Purification of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules and CO-DVD-Ig Molecules
All variants were transiently transfected into 200-500 mls of HEK 293 6e suspension cell cultures in a ratio of 60% to 40% light to heavy chain construct. 1 mg/ml PEI was used to transfect the cells. Alternatively variants were transiently transfected into 500 mls of Expi293 suspension cell cultures using the ExpiFectamine kit (LifeTechnologies A14524). Supernatants were harvested after six days in shaking flasks, spun down to pellet cells, and filtered through 0.22 μm filters to separate IgG from culture contaminates. All was purified via gravity flow using 1-2 ml of rProteinA sepharose fast flow beads (GE Healthcare, 17-1279-04) over poly prep chromatography columns (Bio Rad, 731-1550). Once supernatants had passed through the columns the beads were washed with 10 column volumes of binding buffer, and IgG was eluted with Immunopure IgG elution buffer (Pierce, 185 1520) and collected in 1 ml aliquots. Fractions containing DVD-Ig were pooled and dialyzed in PBS or 15 mM Histidine pH 6 overnight at 4° C.





TABLE 60



Expression Level and SEC Profile of Anti-VEGF-A/Anti-

PDGF-BB DVD-Ig, CO-DVD-Ig and IgG-scFv Fusion Proteins









Octet





Titer
Yield
SEC (%

Name
Corporate ID
(mg/L)
(mg/L)
monomer)









AB014-GS-9E8.4
NA
4.2
ND
ND

9E8.4-GS-AB014
NA
1.2
ND
ND

AB014-SS-9E8.4
NA
3.5
0.4
ND

9E8.4-SS-AB014
NA
3.5
0.6
ND

AB014-SL-9E8.4
NA
2.0
ND
ND

9E8.4-SL-AB014
NA
2.8
0.1
ND

AB014-LS-9E8.4
NA
3.3
ND
ND

9E8.4-LS-AB014
NA
3.6
ND
ND

9E8.4-GS-4G8.3
PR-1563988
6.5
2.8
94.5

9E8.4-SS-4G8.3
PR-1563990
5.9
4.5
92.1

9E8.4-SL-4G8.3
PR-1563998
3.4
2.0
94.0

9E8.4-LS-4G8.3
PR-1564009
10.7
8.0
93.3

4G8.3-GS-9E8.4
PR-1564010
3.6
2.1
98.4

4G8.3-SS-9E8.4
PR-1564011
5.7
3.1
99.4

4G8.3-SL-9E8.4
PR-1564012
2.6
0.7
99.4

4G8.3-LS-9E8.4
PR-1564013
6.7
3.1
99.2

DVD3896
PR-1564883
ND
2.8
100.0

DVD3897
PR-1564893
ND
2.7
79.1

DVD3898
PR-1564896
ND
22.0
93.0

DVD3899
PR-1564898
ND
14.7
87.4

DVD3900
PR-1564899
ND
12.1
72.4

DVD3901
PR-1565023
ND
1.3
99.1

DVD3902
PR-1565029
ND
3.2
98.3

DVD3903
PR-1565030
ND
2.9
98.0

DVD3904
PR-1565031
ND
13.8
97.8

DVD3905
PR-1565032
ND
15.1
92.5

DVD3906
PR-1565035
ND
28.2
85.5

DVD3907
PR-1565033
ND
0.5
ND

CODV001
PR-1565040
ND
88.4
87.6

CODV002
PR-1565042
ND
46.5
97.0

CODV003
PR-1565044
ND
37.3
77.3

CODV004
PR-1565051
ND
75.8
77.4

CODV005
PR-1565083
ND
104.5
86.9

CODV006
PR-1565084
ND
83.9
96.4

CODV007
PR-1565085
ND
43.9
77.4

CODV008
PR-1565086
ND
44.5
75.5

CODV009
PR-1571821
2.0
1.2
86.6

CODV010
PR-1571823
4.5
3.6
94.8

CODV011
PR-1575521
3.7
2.0
100.0

CODV012
PR-1571824
2.0
0.7
98.9

CODV013
PR-1571825
0.7
0.4
90.6

CODV014
PR-1571826
4.5
0.5
89.6

CODV015
PR-1571827
0.7
0.9
91.7

CODV016
PR-1571828
2.6
1.4
93.6

CODV017
PR-1571830
4.2
2.6
99.8

CODV018
PR-1571831
2.6
1.5
88.8

CODV019
PR-1571832
0.4
0.2
87.1

CODV020
PR-1571836
2.1
0.3
58.1

4G8.3-GS-9E8.4
PR-1569574
4.4
4.3
ND

4G8.3-SL-9E8.4
PR-1569579
0.7
0.5
ND

4G8.3-LS-9E8.4
PR-1575573
3.8
2.7
ND

4G8.3-GS-9E8.4 (g)
PR-1572102
2.5
0.4
98.8

4G8.3-GS(11)-9E8.4 (g)
PR-1572103
5.3
1.4
100.0

4G8.3-GS(noR)-9E8.4 (g)
PR-1572104
4.1
0.7
99.5

4G8.3-SL-9E8.4 (g)
PR-1572105
1.4
0.3
98.6

4G8.3-LS-9E8.4 (g)
PR-1572106
4.0
0.8
100.0

4G8.3-GS-9E8.4E
PR-1575832
9.8
8.1
99.2

4G8.3-SL-9E8.4E
PR-1575834
4.5
2.6
99.0

4G8.3-LS-9E8.4E
PR-1575835
16.0
9.7
99.6

CODV021
PR-1577053
2.6
0.3
92.8

CODV022
PR-1577056
2.0
0.2
93.2

9A8.12-GS-9E8.4E
PR-1577165
3.3
2.4
82.99

9A8.12-SL-9E8.4E
PR-1577166
1.1
0.2
51.54

9A8.12-LS-9E8.4E
PR-1577547
10.6
1.1
97.35

9E8.4E-GS-9A8.12
PR-1578137
12.0
3.8
97.3

9E8.4E-SL-9A8.12
PR-1577548
5.0
1.7
97.51

9E8.4E-LS-9A8.12
PR-1577550
2.5
2.5
96.96

AB014-GS6-9E8.4 VH-VK
PR-1599234
70.0
25.6
33.8

AB014-GS10-9E8.4 VH-
PR-1599236
70.0
24.3
34.7

VK

AB014-GS15-9E8.4 VH-
PR-1599239
70.0
29.3
39.3

VK

AB014-GS10-9E8.4 VK-
PR-1599240
47.0
21.4
33.2

VH

4G8.2-GS-9E8.4
PR-1598261
29.4
10.3
98.31

4G8.4-GS-9E8.4
PR-1598262
61.0
20.4
87.65

4G8.5-GS-9E8.4
PR-1598263
31.3
11.5
98.5

4G8.12-GS-9E8.4
PR-1598264
44.0
15.1
93.12

4G8.13-GS-9E8.4
PR-1598265
6.3
2.6
83.58

4G8.14-GS-9E8.4
PR-1598266
19.3
9.9
96.52

CL-34565_GS_CL-33675
PR-1613183
101.4
27.7
88.2

CL-34565_GS_9E8.4
PR-1613184
49.3
31.3
95.9

CL-34565_GS_3E2.1
PR-1613185
109.8
82.5
96.3

4G8.5_GS_CL-33675
PR-1611291
91.1
10.4
96.9

4G8.5_GS_9E8.4
PR-1612489
39.0
23.0
97.0

4G8.5_GS_3E2.1
PR-1610560
127.0
13.9
100.0

9E10.1_GS_CL-33675
PR-1610561
136.0
19.2
92.9

9E10.1_GS_9E8.4
PR-1612491
86.0
50.1
95.0

9E10.1_GS_3E2.1
PR-1610562
44.0
10.2
96.0

9E10.6_GS_CL-33675
PR-1612492
152.0
65.7
89.0

9E10.6_GS_9E8.4
PR-1612493
96.0
50.1
93.0

9E10.6_GS_3E2.1
PR-1610563
122.0
18.0
95.0

1B10.1_GS_CL-33675
PR-1611292
233.0
22.7
75.4

1B10.1_GS_9E8.4
PR-1612494
123.0
52.1
77.0

1B10.1_GS_3E2.1
PR-1610564
142.0
23.3
93.7

1E3.4_GS_CL-33675
PR-1611293
54.0
9.3
83.7

1E3.4_GS_9E8.4
PR-1611294
67.5
11.6
72.1

1E3.4_GS_3E2.1
PR-1612495
101.0
29.6
97.0

CL-33675_GS_CL-34565
PR-1613186
73.5
17.7
87.6

CL-33675_GS_4G8.5
PR-1612496
36.0
8.6
94.0

CL-33675_GS_9E10.1
PR-1611295
148.5
2.3
95.9

CL-33675_GS_9E10.6
PR-1611296
185.3
4.9
95.8

CL-33675_GS_1B10.1
PR-1612498
19.0
7.0
65.0

CL-33675_GS_1E3.4
PR-1611297
72.8
3.5
95.9

9E8.4_GS_CL-34565
PR-1613187
67.5
53.6
79.0

9E8.4_GS_4G8.5
PR-1613188
95.2
73.6
81.7

9E8.4_GS_9E10.1
PR-1611298
237.5
21.5
73.3

9E8.4_GS_9E10.6
PR-1611299
179.0
19.1
71.9

9E8.4_GS_1B10.1
PR-1611300
93.7
12.9
71.7

9E8.4_GS_1E3.4
PR-1611301
87.9
12.2
66.4

3E2.1_GS_CL-34565
PR-1613189
76.1
65.7
93.3

3E2.1_GS_4G8.5
PR-1612499
98.0
46.9
95.0

3E2.1_GS_9E10.1
PR-1612500
126.0
59.2
85.0

3E2.1_GS_9E10.6
PR-1612501
141.0
61.0
86.5

3E2.1_GS_1B10.1
PR-1612502
141.0
61.0
97.0

3E2.1_GS_1E3.4
PR-1613190
107.8
79.9
96.5

9E10.1_SL_CL-33675
PR-1629646
7.6
1.0
98.7

1B10.1_SL_CL-33675
PR-1629647
157.0
111.7
63.3

9E10.1_LS_CL-33675
PR-1629648
64.4
36.4
92.9

1B10.1_LS_CL-33675
PR-1629649
218.4
157.7
65.4


















































































































































Example 13.2
Binding Affinity of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules and CO-DVD-Ig Molecules
The binding affinity of anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules and CO-DVD-Ig molecules to VEGF-A and PDGF-BB were measured by Biacore using the method described in Example 1.1 and the data is summarized in Tables 61 and 62 below.





TABLE 61



Biacore Binding of Anti-VEGF/anti-PDGF DVD-Ig Molecules






VEGF
PDGF












k on
k off
K D
k on
k off
K D

DVD Name
Corporate ID
(M−1 s−1)
(M−1)
(M)
(M−1 s−1)
(M−1)
(M)












9E8.4-GS-4G8.3
PR-1563988
2.2E+05
6.3E−05
2.9E−10
1.0E+07
2.0E−04
2.0E−11

9E8.4-SS-4G8.3
PR-1563990
1.6E+05
1.2E−04
7.8E−10
1.0E+07
2.0E−04
2.0E−11

9E8.4-SL-4G8.3
PR-1563998
7.0E+05
8.0E−05
1.2E−10
1.0E+07
1.9E−04
1.9E−11

9E8.4-LS-4G8.3
PR-1564009
2.7E+05
5.5E−05
2.0E−10
1.0E+07
2.0E−04
2.0E−11

4G8.3-GS-9E8.4
PR-1564010
3.3E+06
5.7E−05
1.7E−11
1.0E+07
1.4E−04
1.3E−11

4G8.3-SS-9E8.4
PR-1564011
3.1E+06
4.1E−05
1.3E−11
7.5E+06
1.5E−04
1.9E−11

4G8.3-SL-9E8.4
PR-1564012
3.1E+06
4.1E−05
1.3E−11
1.4E+07
1.4E−04
9.9E−12

4G8.3-LS-9E8.4
PR-1564013
3.1E+06
3.9E−05
1.2E−11
1.7E+07
1.4E−04
8.6E−12

DVD3904
PR-1565031
6.1E+05
1.1E−04
1.9E−10
1.0E+07
9.0E−04
9.0E−11

DVD3905
PR-1565032
1.1E+06
1.0E−04
9.4E−11
1.0E+07
1.8E−03
1.8E−10

DVD3906
PR-1565035
9.2E+05
9.3E−05
1.0E−10
1.0E+07
7.2E−03
7.2E−10

4G8.3-GS(9)-9E8.4 (g)
PR-1572102
6.0E+06
7.6E−05
1.3E−11
1.3E+07
1.7E−04
1.3E−11

4G8.3-GS(11)-9E8.4
PR-1572103
6.3E+06
7.5E−05
1.2E−11
1.4E+07
1.7E−04
1.3E−11

(g)

4G8.3-GS(noR)-9E8.4
PR-1572104
6.1E+06
6.9E−05
1.1E−11
1.5E+07
1.4E−04
8.9E−12

(g)

4G8.3-SL-9E8.4 (g)
PR-1572105
5.6E+06
6.1E−05
1.1E−11
1.3E+07
1.7E−04
1.3E−11

4G8.3-LS-9E8.4 (g)
PR-1572106
6.3E+06
5.1E−05
8.1E−12
1.8E+07
2.0E−04
1.1E−11

4G8.3-GS-9E8.4E
PR-1575832
6.1E+06
8.0E−05
1.3E−11
1.3E+07
2.7E−04
2.0E−11

4G8.3-SL-9E8.4E
PR-1575834
6.2E+06
6.3E−05
1.0E−11
1.7E+07
2.5E−04
1.5E−11

4G8.3-LS-9E8.4E
PR-1575835
5.8E+06
5.9E−05
1.0E−11
2.0E+07
2.8E−04
1.4E−11

9A8.12-GS-9E8.4E
PR-1577165
7.7E+05
1.4E−04
1.8E−10
3.3E+07
2.6E−04
8.1E−12

9A8.12-SL-9E8.4E
PR-1577166
2.5E+05
1.2E−04
4.7E−10
2.7E+07
2.3E−04
8.3E−12

9A8.12-LS-9E8.4E
PR-1577547
2.7E+05
9.3E−05
3.5E−10
3.6E+07
2.3E−04
6.5E−12

9E8.4E-SL-9A8.12
PR-1577548
2.2E+06
3.4E−04
1.6E−10
5.0E+07
3.2E−04
6.4E−12

9E8.4E-LS-9A8.12
PR-1577550
6.4E+05
1.5E−04
2.3E−10
5.0E+07
2.5E−04
5.0E−12

9E8.4E-GS-9A8.12
PR-1578137
4.7E+05
1.8E−04
3.8E−10
5.0E+07
4.4E−04
8.8E−12

CL-34565_GS_CL-
PR-1613183
1.2E+07
2.0E−05
1.7E−12
6.0E+07
1.1E−05
1.9E−13

33675

CL-34565_GS_9E8.4
PR-1613184
1.5E+07
1.6E−05
1.1E−12
3.5E+07
1.9E−04
5.4E−12

CL-34565_GS_3E2.1
PR-1613185
1.2E+07
1.7E−05
1.4E−12
4.5E+07
5.2E−04
1.2E−11

4G8.5_GS_CL-33675
PR-1611291
4.7E+06
3.1E−05
6.6E−12
1.6E+07
1.2E−05
7.4E−13

4G8.5_GS_9E8.4
PR-1612489
5.4E+06
4.6E−05
8.5E−12
5.8E+06
1.6E−04
2.8E−11

4G8.5_GS_3E2.1
PR-1610560
4.8E+06
4.2E−05
8.7E−12
4.1E+07
5.5E−04
1.3E−11

9E10.1_GS_CL-33675
PR-1610561
9.7E+06
1.7E−05
1.8E−12
2.0E+07
9.1E−06
4.5E−13

9E10.1_GS_9E8.4
PR-1612491
1.1E+07
2.5E−05
2.2E−12
6.8E+06
1.7E−04
2.5E−11

9E10.1_GS_3E2.1
PR-1610562
9.3E+06
2.3E−05
2.4E−12
4.1E+07
8.5E−04
2.1E−11

9E10.6_GS_CL-33675
PR-1612492
1.1E+07
2.2E−05
2.0E−12
2.4E+07
2.8E−05
1.2E−12

9E10.6_GS_3E2.1
PR-1610563
8.6E+06
2.5E−05
3.0E−12
5.8E+06
2.1E−04
3.6E−11

1B10.1_GS_CL-33675
PR-1611292
2.1E+06
1.3E−04
6.2E−11
2.2E+07
1.2E−05
5.4E−13

1E3.4_GS_3E2.1
PR-1612495
5.3E+06
5.2E−05
9.8E−12
4.5E+07
5.1E−04
1.2E−11

CL-33675_GS_4G8.5
PR-1612496
2.3E+05
4.0E−05
1.8E−10
3.8E+07
9.0E−06
2.3E−13

3E2.1_GS_4G8.5
PR-1612499
2.4E+05
3.9E−05
1.7E−10
≧9.0E+07
3.4E−04
≦3.8E−12

3E2.1_GS_9E10.1
PR-1612500
6.3E+05
1.2E−05
1.9E−11
≧9.0E+07
3.9E−04
≦4.3E−12

3E2.1_GS_9E10.6
PR-1612501
5.7E+05
2.3E−05
4.1E−11
≧9.0E+07
4.5E−04
≦5.3E−12

3E2.1_GS_1B10.1
PR-1612502
3.5E+05
1.2E−04
3.2E−10
8.4E+07
1.5E−04
1.8E−12

3E2.1_GS_1E3.4
PR-1613190
3.6E+05
9.2E−05
2.6E−10
≧9.0E+07
4.8E−04
≦5.3E−12
















































































TABLE 62



Biacore Binding of Anti-VEGF/anti-PDGF CO-DVD-Ig Molecules






VEGF
PDGF










CO-DVD-Ig

k on
k off
K D
k on
k off
K D

Name
Corporate ID
(M−1 s−1)
(M−1)
(M)
(M−1 s−1)
(M−1)
(M)










CODV003
PR-1565044
no binding
2.3E+07
2.5E−04
1.1E−11

CODV004
PR-1565051
no binding
1.0E+07
8.7E−04
8.7E−11










CODV005
PR-1565083


3.5E−08
1.2E+07
1.3E−04
1.1E−11








CODV006
PR-1565084
no binding
2.2E+07
2.1E−04
9.7E−12










CODV007
PR-1565085


2.2E−08
2.9E+07
2.2E−04
7.3E−12








CODV008
PR-1565086
no binding
1.7E+07
1.3E−04
7.4E−12










CODV009
PR-1571821


2.6E−08
3.5E+07
2.0E−04
5.6E−12

CODV010
PR-1571823
5.7E+04
3.7E−04
6.6E−09
4.1E+07
1.6E−04
4.0E−12

CODV011
PR-1575521
1.1E+06
4.0E−05
3.8E−11
3.8E+07
6.9E−05
1.8E−12

CODV012
PR-1571824
2.7E+06
7.6E−05
2.8E−11
7.0E+07
1.0E−04
1.5E−12

CODV014
PR-1571826
2.2E+06
7.7E−05
3.6E−11
5.5E+07
1.3E−04
2.4E−12

CODV015
PR-1571827
2.7E+06
6.5E−05
2.4E−11
7.0E+07
9.1E−05
1.3E−12

CODV016
PR-1571828
2.9E+06
5.9E−05
2.0E−11
4.6E+07
1.1E−04
2.5E−12

CODV017
PR-1571830
—
—
5.7E−08
3.0E+07
2.0E−04
6.5E−12

CODV018
PR-1571831
—
—
3.1E−08
3.5E+07
1.9E−04
5.3E−12

CODV019
PR-1571832
2.9E+06
1.4E−04
5.0E−11
3.9E+07
1.7E−04
4.4E−12

CODV020
PR-1571836
3.1E+06
1.0E−04
3.3E−11
4.6E+07
1.6E−04
3.5E−12

CODV021
PR-1577053
3.8E+06
6.8E−05
1.8E−11
6.1E+07
1.2E−04
1.9E−12

CODV022
PR-1577056
4.5E+06
5.6E−05
1.3E−11
3.2E+07
1.3E−04
4.2E−12






























































Example 13.2.1
Binding of Anti-VEGF/anti-PDGF DVD-Ig Molecule (PR-1610561) to Various VEGF-A Isoforms and VEGF-A and PDGF-BB of Different Species
Binding of anti-VEGF/anti-PDGF DVD-Ig molecule (PR-1610561) and their parental monoclonal antibodies to various VEGF-A isoforms and VEGF-A and PDGF-BB of different species were measured by Biacore using the method described in Example 1.1 and the data is summarized in Table 63 below. Tables 63A-B summarize the high affinity for VEGF-A 165 (65 pM), VEGF-A 121 (230 pM), VEGF-A 111 (290 pM), isoforms and the high affinity for soluble PDGF-BB (5 pM), observed for PR-1610561. The data shows that PR-1610561binds to both soluble and extracellular-matrix (ECM) bound forms of PDGF-BB.





TABLE 63



Binding of Anti-VEGF/Anti-PDGF DVD-Ig Molecule (PR-1610561) and Parental mAbs to VEGF-A Isoforms and PDGF










human VEGF 165
human PDGF-B


PR-1350437, 1925483
PR-1373790, 1926007
















K a
K d
K D
K a
K d
K D

No

PR-
lot
(M −1 s −1 )
(s −1 )
(M)
(M −1 s −1 )
(s −1 )
(M)



1
9E10.1-GS-33675
PR-1610561
2213329
5.2E+05
3.4E−05
6.5E−11
≧1.0E+07
5.2E−05
≦5.2E−12

2
AB014 (Avastin)
PR-1545939
2129911
5.5E+05
4.1E−05
7.6E−11

3
AB642 (9E10.1)
PR-1594047
2169800
1.6E+07
2.8E−05
1.8E−12

4
CL-33675
PR-1593725
2178826



≧1.0E+07
5.8E−06
≦5.8E−13








human VEGF 121



PR-1515941, 2069355














K a
K d
K D


No

PR-
lot
(M −1 s −1 )
(s −1 )
(M)



1
9E10.1-GS-33675
PR-1610561
2213329
1.8E+05
4.1E−05
2.3E−10

2
AB014 (Avastin)
PR-1545939
2129911
1.8E+05
5.1E−05
2.8E−10

3
AB642 (9E10.1)
PR-1594047
2169800
3.2E+06
6.8E−05
2.1E−11

4
CL-33675
PR-1593725
2178826








human VEGF 111



PR-1520687, 2074657














K a
K d
K D


No

PR-
lot
(M −1 s −1 )
(s −1 )
(M)



1
9E10.1-GS-33675
PR-1610561
2213329
1.5E+05
4.3E−05
2.9E−10

2
AB014 (Avastin)
PR-1545939
2129911
1.4E+05
5.3E−05
3.8E−10

3
AB642 (9E10.1)
PR-1594047
2169800
1.8E+06
1.0E−04
5.8E−11

4
CL-33675
PR-1593725
2178826







cyno PDGF-B


PR-1575400, 2154322














cyno VEGF has similar
K a
K d
K D

No

PR-
lot
sequence as human
(M −1 s −1 )
(s −1 )
(M)



1
9E10.1-GS-33675
PR-1610561
2213329

≧1.0E+07
8.1E−06
≦8.1E−13

2
AB014 (Avastin)
PR-1545939
2129911

3
AB642 (9E10.1)
PR-1594047
2169800

4
CL-33675
PR-1593725
2178826

≧1.0E+07
1.3E−05
≦1.3E−12








mouse VEGF
mouse PDGF-B


PR-1578904, 2150241
PR-1577160, 2147923
















K a
K d
K D
K a
K d
K D

No

PR-
lot
(M −1 s −1 )
(s −1 )
(M)
(M −1 s −1 )
(s −1 )
(M)



1
9E10.1-GS-33675
PR-1610561
2213329


potentially
≧1.0E+07
5.2E−05
≦5.2E−12







very weak binding

2
AB014 (Avastin)
PR-1545939
2129911


no binding

3
AB642 (9E10.1)
PR-1594047
2169800


potentially







very weak binding

4
CL-33675
PR-1593725
2178826



≧1.0E+07
5.8E−06
≦5.8E−13








rat VEGF
rat PDGF-B


PR-1645045, 2235296
PR-1645048, 2235300
















K a
K d
K D
K a
K d
K D

No

PR-
lot
(M −1 s −1 )
(s −1 )
(M)
(M −1 s −1 )
(s −1 )
(M)



1
9E10.1-GS-33675
PR-1610561
2213329


potentially
≧1.0E+07
5.2E−05
≦5.2E−12







very weak binding

2
AB014 (Avastin)
PR-1545939
2129911


no binding

3
AB642 (9E10.1)
PR-1594047
2169800


potentially







very weak binding

4
CL-33675
PR-1593725
2178826



≧1.0E+07
5.8E−06
≦5.8E−13








rabbit VEGF



PR-1563693, 2130027














K a
K d
K D
rabbit PDGF-B has similar

No

PR-
lot
(M −1 s −1 )
(s −1 )
(M)
sequence as rat












1
9E10.1-GS-33675
PR-1610561
2213329
9.6E+05
4.0E−05
4.1E−11


2
AB014 (Avastin)
PR-1545939
2129911
9.4E+05
4.4E−05
4.7E−11

3
AB642 (9E10.1)
PR-1594047
2169800
1.6E+07
2.8E−05
1.8E−12

4
CL-33675
PR-1593725
2178826












































































































































TABLE 63A



Affinity of PR-1610561 to Various Isoforms of Human VEGF-A





Human VEGF-A


Isoforms







A 165
A 121
A 111











Affinity K D (pM)
65
230
290



































TABLE 63B



Affinity of PR-1610561 to Human PDGF-BB







Human PDGF-BB Forms
Soluble
ECM-associated





Affinity K D (pM)
5
n/t


Cell Staining
n/t
+























Example 13.3
Neutralization Potencies of Anti-VEGF-A/anti-PDGF-BB DVD-Ig Molecules and CO-DVD-Ig Molecules
The DVD-Ig molecules and CO-DVD-Ig molecules were evaluated for their potencies to block VEGF 165 /VEGFR2 interaction (Example 1.4) and neutralize VEGF 165 activity in HMVEC-d or VEGFR2-3T3 proliferation assays (Examples 1.10 and 1.7). The molecules were also characterized for the ability to block PDGF-BB/PDGF-Rβ interaction (Example 1.13) and inhibition of PDGF-BB induced proliferation of NIH-3T3 cells (Example 1.15). The data is summarized in Table 64 below. PR-1610561 exhibited neutralization activity against human VEGF-A (IC 50 of 145 pM) and human PDGF-BB (IC 50 of 34 pM), as summarized in Table 64A.





TABLE 64



Human VEGF-A and Human PDGF-BB Neutralization Potency of

Anti-VEGF-A/anti-PDGF-BB DVD-Ig and CO-DVD-Ig Proteins





Potency IC50 (nM)














hVEGFR2
hPDGF β




VEGFR2-

Competition
Competition



HMVEC-d
3T3
NIH-3T3
ELISA
ELISA

DVD-Ig
Corporate ID
hVEGF 165
hVEGF 165
hPDGF-BB
IC 50 nM
IC 50 nM











9E8.4-GS-4G8.3
PR-1563988
2.643
>5
0.076
NT
NT

9E8.4-SS-4G8.3
PR-1563990
NT
>5
0.094
NT
NT

9E8.4-SL-4G8.3
PR-1563998
NT
>5
0.091
NT
NT

9E8.4-LS-4G8.3
PR-1564009
NT
>5
0.104
NT
NT

4G8.3-GS-9E8.4
PR-1564010
0.096
NT
NT
0.126
NT

4G8.3-GS-9E8.4E
PR-1575832
NT
2.953
>5
NT
NT

4G8.3-SS-9E8.4
PR-1564011
NT
0.747
5.511
NT
NT

4G8.3-SL-9E8.4
PR-1564012
NT
NT
0.365
0.086
NT

4G8.3-SL-9E8.4E
PR-1575834
NT
3.090
0.572
NT
NT

4G8.3-LS-9E8.4
PR-1564013
0.060
NT
0.152
0.092
NT

CODV009
PR-1571821
NT
>5
>5
NT
NT

CODV010
PR-1571823
NT
>5
2.139
NT
NT

CODV011
PR-1575521
NT
2.553
0.043
NT
NT

CODV012
PR-1571824
NT
1.424
0.182
NT
NT

CODV013
PR-1571825
NT
0.785
0.11
NT
NT

CODV014
PR-1571826
NT
3.768
0.469
NT
NT

CODV015
PR-1571827
0.104
0.407
0.075
NT
NT

CODV021
PR-1577053
NT
>5
0.056
NT
NT

CODV016
PR-1571828
0.115
0.503
0.096
NT
NT

CODV022
PR-1577056
NT
1.462
0.059
NT
NT

CODV017
PR-1571830
NT
>5
>5
NT
NT

CODV018
PR-1571831
NT
>5
>5
NT
NT

DVD3904
PR-1565031
NT
>5
>5
NT
NT

DVD3905
PR-1565032
NT
>5
>5
NT
NT

DVD3906
PR-1565035
NT
>5
>5
NT
NT

CODV003
PR-1565044
NT
>5
>5
NT
NT

CODV004
PR-1565051
NT
>5
>5
NT
NT

CODV005
PR-1565083
NT
>5
>5
NT
NT

CODV006
PR-1565084
NT
>5
>5
NT
NT

CODV007
PR-1565085
NT
>5
>5
NT
NT

CODV008
PR-1565086
NT
>5
>5
NT
NT

4G8.3-GS(9)-9E8.4 (g)
PR-1572102
0.417
0.986
.528
0.157
>5

4G8.3-GS(11)-9E8.4 (g)
PR-1572103
NT
0.318
0.298
NT
NT

4G8.3-GS(noR)-9E8.4 (g)
PR-1572104
NT
0.217
0.095
NT
NT

4G8.3-SL-9E8.4 (g)
PR-1572105
0.347
1.603
0.290
0.111
>5

4G8.3-LS-9E8.4 (g)
PR-1572106
NT
0.203
0.109
NT
NT

4G8.3-LS-9E8.4E
PR-1575835
NT
2.852
0.176
NT
NT

9A8.12-GS-9E8.4E
PR-1577165
NT
2.992
0.204
NT
NT

9A8.12-SL-9E8.4E
PR-1577166
NT
5.536
0.148
NT
NT

9A8.12-LS-9E8.4E
PR-1577547
NT
4.13
0.133
NT
NT

9E8.4E−SL-9A8.12
PR-1577548
NT
>5
0.147
NT
NT

9E8.4E−LS-9A8.12
PR-1577550
NT
>5
0.066
NT
NT

9E8.4E−GS-9A8.12
PR-1578137
NT
>5
0.327
NT
NT

hVEGF 4G8.3-GS-hPDGF
PR-1569574
0.341
1.02
0.630
0.137
>5

9E8.4 [hu IgG1/k]

mut(234, 235) H435A

hVEGF 4G8.3-SL-hPDGF
PR-1569579
0.36
1.178
0.427
0.133
>5

9E8.4 [hu IgG1/k]

mut(234, 235) H435A

hVEGF 4G8.3-LS-hPDGF
PR-1575573
NT
NT
NT
0.131
>5

9E8.4 [hu IgG1/k]

mut(234, 235) H435A

AB014-GS6-9E8.4
PR-1599234
0.124
NT
0.222
NT
NT

VH-VK

AB014-GS10-9E8.4
PR-1599236
0.095
NT
0.063
NT
NT

VH-VK

AB014-GS15-9E8.4
PR-1599239
0.13
NT
0.066
NT
NT

VH-VK

AB014-GS10-9E8.4
PR-1599240
0.086
NT
0.074
NT
NT

VK-VH

4G8.2-GS10-9E8.4
PR-1598261
0.221
NT
>5
NT
NT

4G8.4-GS10-9E8.4
PR-1598262
0.281
NT
1.327
NT
NT

4G8.5-GS10-9E8.4
PR-1598263
0.079
NT
>5
NT
NT

4G8.12-GS10-9E8.4
PR-1598264
0.079
NT
0.227
NT
NT

4G8.13-GS10-9E8.4
PR-1598265
0.907
NT
0.255
NT
NT

4G8.14-GS10-9E8.4
PR-1598266
0.113
NT
0.459
NT
NT

4G8.5_GS_CL-33675
PR-1611291
0.076
NT
0.05
NT
NT

4G8.5_GS_3E2.1
PR-1610562
0.072
NT
1.398
NT
NT

9E10.1_GS_CL-33675
PR-1610561
0.145
0.433
0.034
0.045
0.09

9E10.1_GS_3E2.1
PR-1610562
0.054
NT
5.724
NT
NT

9E10.6_GS_3E2.1
PR-1610563
0.06
NT
1.317
NT
NT

1B10.1_GS_CL-33675
PR-1611292
0.05
NT
0.037
NT
NT

1B10.1_GS_3E2.1
PR-1610564
0.084
NT
1.545
NT
NT

1E3.4_GS_CL-33675
PR-1611293
0.067
NT
0.037
NT
NT

1E3.4_GS_9E8.4
PR-1611294
0.092
NT
0.329
NT
NT

CL-33675_GS_9E10.1
PR-1611295
0.064
NT
0.031
NT
NT

CL-33675_GS_9E10.6
PR-1611296
0.082
NT
0.037
NT
NT

CL-33675_GS_1E3.4
PR-1611297
0.372
NT
0.039
NT
NT

9E8.4_GS_9E10.1
PR-1611298
0.073
NT
0.317
NT
NT

9E8.4_GS_9E10.6
PR-1611299
0.132
NT
0.213
NT
NT

9E8.4_GS_1B10.1
PR-1611300
0.391
NT
0.109
NT
NT

9E8.4_GS_1E3.4
PR-1611301
0.897
NT
0.131
NT
NT

4G8.5_GS_9E8.4
PR-1612489
0.069
NT
4.829
NT
NT

9E10.1_GS_9E8.4
PR-1612491
0.059
NT
1.913
NT
NT

9E10.6_GS_CL-33675
PR-1612492
0.05
NT
0.037
NT
NT

9E10.6_GS_9E8.4
PR-1612493
0.049
NT
1.14
NT
NT

1B10.1_GS_9E8.4
PR-1612494
0.127
NT
0.678
NT
NT

1E3.4_GS_3E2.1
PR-1612495
0.043
NT
6.253
NT
NT

CL-33675_GS_4G8.5
PR-1612496
0.219
NT
0.035
NT
NT

CL-33675_GS_1B10.1
PR-1612498
0.265
NT
0.11
NT
NT

3E2.1_GS_4G8.5
PR-1612499
0.743
NT
0.38
NT
NT

3E2.1_GS_9E10.1
PR-1612500
0.133
NT
0.394
NT
NT

3E2.1_GS_9E10.6
PR-1612501
0.188
NT
0.377
NT
NT

3E2.1_GS_1B10.1
PR-1612502
1.78
NT
0.187
NT
NT

CL-34565_GS_CL-33675
PR-1613183
0.059
NT
0.052
NT
NT

CL-34565_GS_9E8.4
PR-1613184
0.065
NT
0.323
NT
NT

CL-34565_GS_3E2.1
PR-1613185
0.053
NT
6.005
NT
NT

CL-33675_GS_CL-34565
PR-1613186
0.05
NT
0.043
NT
NT

9E8.4_GS_CL-34565
PR-1613187
0.058
NT
0.134
NT
NT

9E8.4_GS_4G8.5
PR-1613188
0.354
NT
0.108
NT
NT

3E2.1_GS_CL-34565
PR-1613189
0.063
NT
1.157
NT
NT

3E2.1_GS_1E3.4
PR-1613190
0.709
NT
0.896
NT
NT



NT—Not tested









































































































































TABLE 64A



Neutralization Activities in Cellular Assays







Protein
Human VEGF-A
Human PDGF-BB





Potency IC 50 (pM)
145
34






















Selected DVD-Ig molecules were further characterized for the ability to neutralize human VEGF 111 and human VEGF 121 , isoforms of human VEGF-A. The molecules were tested for inhibition of VEGF 111 and human VEGF 121 induced proliferation of VEGFR2-3T3 cells (Example 1.8). Neutralization of non-human VEGF-A species was also evaluated. Molecules were tested for inhibition of rabbit VEGF 165 induced proliferation of VEGFR2-3T3 cells (Example 1.9). The data is summarized in Table 65 below. As noted, the amino acid sequence of cynomolgus monkey VEGF-A is identical to human VEGF-A. Parental antibodies had previously been examined for mouse VEGF 164 cross-reactivity in a competition ELISA and no blocking was observed (Example 1.5).





TABLE 65



Neutralization of Different VEGF-A Isoforms by Anti-VEGF-A/

Anti-PDGF-BB DVD-Ig Molecules





Potency IC50 (nM)









human
human
rabbit

DVD-Ig and Controls
Corporate ID
VEGF 111
VEGF 121
VEGF 165



4G8.3-GS(9)-9E8.4
PR-1572102
0.771
0.182
0.869

(g)

4G8.3-SL-9E8.4 (g)
PR-1572105
0.654
0.139
1.194

4G8.3-LS-9E8.4 (g)
PR-1572106
0.431
0.148
0.601

4G8.3-LS-9E8.4E
PR-1575835
NT
NT
1.534

hVEGF 4G8.3-GS-
PR-1569574
0.674
0.124
0.841

hPDGF 9E8.4

[hu IgG1/k]

mut(234, 235) H435A

hVEGF 4G8.3-SL-
PR-1569579
0.576
0.154
1.213

hPDGF 9E8.4

[hu IgG1/k]

mut(234, 235) H435A

9E10.1_GS_CL-
PR-1610561
0.213
0.097
0.520

33675



NT—Not tested








































Selected DVD-Ig molecules were further evaluated for their potencies to neutralize PDGF-BB of different species using the assay described in Examples 1.15-1.18. The data is summarized in Table 66 below. As noted, the amino acid sequence of rabbit PDGF-BB is identical to rat PDGF-BB.





TABLE 66



Neutralization of Different PDGF-BB Species by Anti-VEGF-

A/Anti-PDGF-BB DVD-Ig Molecules





Potency IC50 (nM)







DVD-Ig and
Corporate
cynoPDGF-
mPDGF-
ratPDGF-

Controls
ID
BB
BB
BB



4G8.3-GS-9E8.4
PR-1564010
NT
0.440
1.359

4G8.3-SL-9E8.4
PR-1564012
NT
0.290
0.650

4G8.3-SL-9E8.4E
PR-1575834
NT
0.772
NT

4G8.3-LS-9E8.4
PR-1564013
NT
0.110
0.210

4G8.3-GS(9)-9E8.4
PR-1572102
0.139
0.174
2.202

(g)

4G8.3-SL-9E8.4 (g)
PR-1572105
0.142
0.096
1.296

4G8.3-LS-9E8.4 (g)
PR-1572106
0.094
0.14
NT

hVEGF 4G8.3-GS-
PR-1569574
0.139
0.134
1.514

hPDGF 9E8.4

[hu IgG1/k]

mut(234, 235)

H435A

hVEGF 4G8.3-SL-
PR-1569579
0.144
0.150
0.994

hPDGF 9E8.4

[hu IgG1/k]

mut(234, 235)

H435A

9E10.1_GS_CL-
PR-1610561
0.035
0.032
0.038

33675



NT—Not tested













































Selected DVD-Ig molecules were evaluated for their ability to neutralize in the presence of a second ligand. To evaluate hPDGF-BB potency, the DVD-Ig molecules were pre-incubated with an excess of human VEGF 165 prior to testing in the NIH-3T3 proliferation assay (Example 1.21). To evaluate hVEGF 165 potency, the DVD-Ig molecules were pre-incubated with an excess of human hPDGF-BB prior to testing in the VEGFR2-3T3 (KDR/Flk-1) phosphorylation assay (Example 1.20). The data is summarized in Table 67 below.





TABLE 67



Simultaneous binding to VEGF and PDGF





Co-incubation Potency


IC50 (nM)






DVD-Ig
Corporate ID
hPDGF-BB
hVEGF 165



9E8.4-GS-4G8.3
PR-1563988
NT
NT

9E8.4-SS-4G8.3
PR-1563990
NT
NT

9E8.4-SL-4G8.3
PR-1563998
NT
NT

9E8.4-LS-4G8.3
PR-1563009
NT
NT

4G8.3-GS-9E8.4
PR-1564010
NT
NT

4G8.3-SS-9E8.4
PR-1564011
NT
NT

4G8.3-SL-9E8.4
PR-1564012
NT
NT

4G8.3-LS-9E8.4
PR-1564013
NT
NT

4G8.3-GS(9)-9E8.4 (g)
PR-1572102
0.051
0.701

4G8.3-SL-9E8.4 (g)
PR-1572105
0.047
0.773

hVEGF 4G8.3-GS-
PR-1569574
0.032
0.594

hPDGF 9E8.4 [hu

IgG1/k] mut(234, 235)

H435A

hVEGF 4G8.3-SL-
PR-1569579
0.038
0.789

hPDGF 9E8.4 [hu

IgG1/k] mut(234, 235)

H435A

9E10.1_GS_CL-33675
PR-1610561
0.04
0.464



NT—Not tested











































Selected DVD-Ig molecules were further evaluated for their ability to bind naturally derived human VEGF 165 (Example 1.11) and naturally derived human PDGF-BB (Example 1.19). The data is summarized in Table 68 below.





TABLE 68



Binding of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules to

hVEGF 165 and hPDGF-BB by ELISA





Binding








Platelet derived
Y-79 derived

DVD-Ig
Corporate ID
hPDGF-BB
hVEGF 165



4G8.3-GS(9)-9E8.4 (g)
PR-1572102
Yes
NT

4G8.3-SL-9E8.4 (g)
PR-1572105
Yes
NT

hVEGF 4G8.3-GS-
PR-1569574
Yes
NT

hPDGF 9E8.4 [hu

IgG1/k] mut(234, 235)

H435A

hVEGF 4G8.3-SL-
PR-1569579
Yes
NT

hPDGF 9E8.4 [hu

IgG1/k] mut(234, 235)

H435A

9E10.1_GS_CL-33675
PR-1610561
Yes
Yes



NT—Not tested




































Example 13.4
Species Cross-Reactivity of an Anti-VEGF/Anti-PDGF DVD-Ig Molecule (PR-1610561)
PR-1610561 was further evaluated for its ability to cross-react with cynomolgus monkey, mouse, rat, and rabbit using cell-based proliferation assays (Examples 1.6, 1.17, 1.18, and 1.25). The data is summarized in Table 69 below.





TABLE 69



Species Cross-Reactivity of Anti-VEGF/anti-

PDGF DVD-Ig Molecule (PR-1610561)






VEGF
PDGF











Protein
cyno
mo
rat
rab
cyno
mo
rat
rab



Affinity
65
—
—
41
0.8
0.3
3
3

K D (pM)



























Example 13.5
Reactivity of Anti-PDGF-BB Antibodies and Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules to ECM-Associated PDGF-BB
As described in Example 1.27, first recombinant cell line HEK293 cells over-expressing PDGFBB-RM and then HUVEC naturally expressing ECM-associated PDGF-BB cells were used for staining:
HEK293 Cell Staining: PDGFB-RM transient transfected HEK 293 cells and parental HEK293 cells were re-suspended at 1E6 cells/mL in PBS and fixed in 4% paraformaldehyde at RT for 10 minutes, washed with PBS and 2E5 cells/tube were incubated in blocking buffer (10% goat serum in PBS) for one hour on ice. Cells were washed with PBS and incubated with primary antibody or DVD at 33 nM in antibody dilution buffer (5% goat serum in PBS) for one hour on ice. Cells were washed three times with PBS and incubated with Alexa Fluo 488 conjugated Goat anti-Human IgG (Jackson Immune, code: 109-546-098; lot: 108427) 1:400 dilution in antibody dilution buffer, incubate on ice for 45 minutes. Cells were washed three times with PBS and cytospin onto glass slides and mounted with mounting media with DAPI. Pictures were taken by fluorescent microscopy. Anti-PDGF-BB parental and affinity matured mAbs and three DVD-Ig molecules all showed positive staining on PDGFB-RM transient transfected 293 cells ( FIG. 2A ) and no staining on parental HEK 293 cells except for the slightly positive staining of affinity matured anti-PDGF-BB mAb. It is unclear if parental HEK 293 cells express low level of PDGF-BB endogenously
HUVEC Staining:
HUVEC cells secrete PDGF-BB, and low level of PDGF-BB may be captured on the cell surface as ECM-associated PDGF-BB. Affinity matured anti-PDGF-BB mAb and anti-VEGF/anti-PDGF DVD-Ig built with affinity-matured anti-PDGF-BB mAb was further assessed for its staining on naturally derived ECM-associated PDGF-BB on HUVEC cells. HUVECs (Lonza, cat#: C2519A lot: 181607) were trypsinized, resuspended at 2E4 cells/mL in culture media (Lonza, EGM2 MV Bulletkit: CC-3202). Cells were plated at 10,000 cells/500 μl/well in 8-chamber glass slide and incubated for 16 hours at 37° C., 5% CO 2 . After incubation, cells were fixed with 200 μl 4% paraformaldehyde at RT for 10 minutes, washed with PBS and incubated in blocking buffer (10% goat serum in PBS) for one hour on ice. Cells were washed with PBS 3× and incubated with primary antibodies or DVD-Ig molecules at 33 nM in antibody dilution buffer (5% goat serum in PBS) for one hour on ice. Cells were washed three times with PBS and incubated with Alexa Fluo 488 conjugated Goat anti-Human IgG (JacksonImmune, code: 109-546-098; lot: 108427) 1:400 dilution in antibody dilution buffer, incubate on ice for 45 minutes. Cells were washed three times with PBS and mounted with mounting media with DAPI. Pictures were taken by fluorescent microscopy. As shown in FIG. 2B , affinity matured anti-PDGF-BB mAb showed positive staining on HUVEC cells while the staining of parental anti-PDGF-BB mAb on HUVEC cells is not evident ( FIG. 2B ). Anti-VEGF/anti-PDGF DVD-Ig (PR-1610561) built with affinity-matured anti-PDGF-BB mAb showed positive staining on HUVEC cells but control anti-tetanus toxoid DVD-Ig molecule also showed some weak staining which may be due to the background issue.
Example 13.6
Inhibition of Sprouting in HUVEC/MSC Co-culture Sprouting Assay by Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules
As described in Example 1.28, in early therapeutic treatment mode, Cytodex-3 beads (Sigma-Aldrich, cat# C3275) were coated with HUVEC cells (Lonza) overnight, and then embedded (100 beads/well) with human mesenchymal stem cells (Lonza, 20,000 cells/well) in fibrin gel in 24-well tissue culture plates. A 1:1 mixture of fresh EGM-2 complete media (Lonza) and fibroblast (Lonza) conditioned EGM-2 media were added on top of the fibrin gel along with 2 ng/mL of recombinant human HGF. Medium was replaced every 2-3 days till the end of the experiment. After EC sprouts and pericyte coverings were formed, usually on day 4, anti-VEGF-A (4G8.4), anti-PDGFBB (9E8.) or anti-PDGFBB/VEGF-A DVD-Ig were added to the culture medium at 10 nM. 10 days later cells were fixed in 4% PFA overnight at 4° C. Endothelial cells were stained with anti-PECAM (Abcam, ab32457), followed by fluorescence-conjugated secondary antibody, and pericytes were labeled with anti-aSMA-Cy3 (Sigma, C6198). Cells were then viewed by an inverted fluorescence microscope and 5× images were captured ( FIG. 3 ). As seen in the pictures, DVD-Ig molecules as well as the combination of anti-VEGF and anti-PDGF mAbs are able to prevent sprouting formation greater than that of anti-VEGF mAb alone. Neither anti-PDGF mAb or anti-PDGF aptamer alone appear to have any significant inhibition of sprouting formation ( FIG. 3 ). Similar experiments were also conducted in prophylactic and later therapeutic treatment modes and the results clearly demonstrated that anti-VEGF/anti-PDGF DVD-Ig (PR-1610561) strongly inhibited sprouting formation in this 3D co-culture assay.
Example 13.7
Characterization of FcRn and FcγRs Binding
Anti-VEGF/anti-PDGF DVD-Ig molecules, including 4G8.3-GS-9E8.4, 4G8.3-SL-9E8.4, 4G8.3-GS-9E8.4(g), 4G8.3-SL-9E8.4(g), 9E10.1GS_CL-33675, are human IgG1/κ isotype with L234A, L235A mutations to attenuate FcγRs binding and H435A mutation to eliminate FcRn binding. The binding of DVD-Ig molecules to FcRn from various species and the binding of DVD-Ig molecules to various FcγRs were characterized by Biacore using the method described in Example 1.2. The data is summarized in Tables 70 and 71 below.





TABLE 70



Binding of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules

to FcRn from Different Species, Measured by Biacore






Steady State
1:1 Binding fit









huFcRn
cynoFcRn
rabbitFcRn
ratFcRn
muFcRn













K D
K D
K D
ka
kd
K D
ka
kd
K D

Immobilized
(M)
(M)
(M)
(1/Ms)
(1/s)
(M)
(1/Ms)
(1/s)
(M)



4G8.3-GS-9E8.4(g)
NSB
NSB
NSB
n/a
n/a
NSB
n/a
n/a
NSB

PR-1572102

4G8.3-SL-9E8.4(g)
NSB
NSB
NSB
n/a
n/a
NSB
n/a
n/a
NSB

PR-1572105

9E10.1_GS_C
NSB
NSB
NSB
n/a
n/a
NSB
n/a
n/a
NSB

L-33675 PR-1610561

4G8.3-GS-9E8.4
NSB
NSB
NSB
n/a
n/a
NSB
n/a
n/a
NSB

PR-1569574

4G8.3-SL-9E8.4
NSB
NSB
NSB
n/a
n/a
NSB
n/a
n/a
NSB

PR-1569579



* NSB = No significant binding at the concentration tested;

n/a = not available













































TABLE 71



Binding of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules to Various Human FcγRs, Measured by Biacore











huFcRIIa
huFcRIIa
huFcRIIIa
huFcRIIIa



huFcRIIb
131H
131R
158F
158V












K D
K D
K D
K D
ka
kd
K D


Sample
(M)
(M)
(M)
(M)
(1/Ms)
(1/s)
(M)
Fit



4G8.3-GS-9E8.4(g)
NSB
NSB
NSB
NSB
n/a
n/a
7.40E−06
steady state

PR-1572102

4G8.3-SL-9E8.4(g)
NSB
NSB
NSB
NSB
n/a
n/a
6.20E−06
steady state

PR-1572105

9E10.1_GS_CL-33675
NSB
NSB
NSB
NSB
n/a
n/a
1.1E−05*
steady state

PR-1610561

4G8.3-GS-9E8.4
NSB
NSB
NSB
NSB
n/a
n/a
1.6E−05*
steady state

PR-1569574

4G8.3-SL-9E8.4
NSB
NSB
NSB
NSB
n/a
n/a
1.2E−05*
steady state

PR-1569579



*NSB = No significant binding at the concentration tested;

n/a = not available




































Example 14
Physicochemical Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules
Example 14.1
Assessment of Physicochemical Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules
Twenty one DVD-Ig molecules were selected for a screen of their solubility and stability profiles. Samples were prepped and evaluated according to Example 2.4. The DVD-Ig proteins were prepared in a formulation buffer and stored at 40° C. and 5° C. for up to 21 days. Samples were pulled and analyzed by SEC to determine changes in aggregation (Table 72). The molecules were evaluated at the listed concentrations. SEC was used to quantitate the aggregation percentage.





TABLE 72



Aggregation and Solubility Screening Of Selected DVD-Ig

Molecules Stored At 40° C. and 5° C. for 21 Days

in a Formulation Buffer







% Aggregation


Concentration
Change from T0






DVD-Ig Molecule
(mg/ml)
T21 d 5° C.
T21 d 40° C.








4G8.3-GS-9E8.4
100
0.24
*

4G8.3-SL-9E8.4
100
0.27
*

CL-34565_GS_CL-33675
48.7
0.20
0.25

CL-34565_GS_9E8.4
4.3
−0.30
0.05

CL-34565_GS_3E2.1
10.9
−1.12
−0.89

4G8.5_GS_CL-33675
50
−0.09
*

4G8.5_GS_9E8.4
50
−0.09
12.50

4G8.5_GS_3E2.1
50
0.53
14.63

9E10.1_GS_CL-33675
50
−2.08
−3.09

9E10.1_GS_9E8.4
50.7
2.95
−0.39

9E10.1_GS_3E2.1
43.2
−6.16
−9.05

9E10.6_GS_CL-33675
50
3.17
1.87

9E10.6_GS_3E2.1
34.9
−0.63
−0.65

1B10.1_GS_CL-33675
50
0.72
1.10

1E3.4_GS_3E2.1
50
0.17
*

CL-33675_GS_4G8.5
38.7
0.15
2.34

3E2.1_GS_4G8.5
50
16.15
*

3E2.1_GS_9E10.1
30.4
*
*

3E2.1_GS_9E10.6
50
0.17
5.55

3E2.1_GS_1B10.1
38.6
−6.33
*

3E2.1_GS_1E3.4
50
10.12
*



* Samples were too degraded or compromised to evaluate with SEC (e.g. gelled, precipitated).


















































Example 14.2
Further Assessment of Physicochemical Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules (Stability During Storage at 40° C., 25° C., and 5° C.)
Based on the physicochemical screen discussed above (Example 14.1), three anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules (4G8.3-GS-9E8.4, 4G8.3-SL-9E8.4, and 9E10.1-GS-33675) were selected for further characterization. Sample prep and analysis was performed according to Example 2.4.
Briefly, the molecules were prepared in a formulation buffer at 100±10 mg/ml and stored at 40° C., 25° C., and 5° C. for 84 days. Samples were periodically pulled for characterization (Tables 73-75 below).
As mentioned in Example 2.4, both 25° C. (room temperature) and 5° C. (storage temperature) are typical temperatures at which the samples would be subjected either during preparation and storage for manufacture or as part of the final drug product presentation. Also, storage at 40° C. is considered an accelerated stability condition which provides an indication of long-term stability prospects.





TABLE 73



Stability of 4G8.3-GS-9E8.4 During Storage. Aggregate, Monomer,

And Fragment Percentages Were Quantitated By SEC











Area Under SEC


%
%
%
Chromatogram Signal


Aggregate
Monomer
Fragment
Relative to T0










T0
1.8
97.3
0.9
1.00

T7 d 40° C.
*
*
*
*

T7 d 25° C.
2.2
97.0
0.9
0.91

T7 d 5° C.
1.9
97.2
0.9
0.92

T21 d 40° C.
*
*
*
*

T21 d 25° C.
3.0
96.4
0.6
0.84

T21 d 5° C.
1.8
97.8
0.5
0.90

T42 d 40° C.
*
*
*
*

T42 d 25° C.
3.4
95.6
1.0
0.88

T42 d 5° C.
2.0
97.3
0.7
1.00

T63 d 40° C.
*
*
*
*

T63 d 25° C.
4.2
94.7
1.0
0.85

T63 d 5° C.
2.1
97.4
0.5
0.92

T84 d 40° C.
*
*
*
*

T84 d 25° C.
5.0
93.7
1.3
0.79

T84 d 5° C.
2.2
97.3
0.6
0.85



* Samples were too degraded or compromised to evaluate with SEC (e.g. gelled, precipitated).














































TABLE 74



Stability of 4G8.3-SL-9E8.4 During Storage. Aggregate, Monomer,

And Fragment Percentages Were Quantitated by SEC











Area Under SEC


%
%
%
Chromatogram Signal


Aggregate
Monomer
Fragment
Relative to T0










T0
4.2
94.7
1.1
1.00

T7 d 40° C.
*
*
*
*

T7 d 25° C.
6.6
92.2
1.3
0.86

T7 d 5° C.
4.3
94.7
1.0
0.82

T21 d 40° C.
*
*
*
*

T21 d 25° C.
8.5
90.5
1.1
0.77

T21 d 5° C.
3.9
95.3
0.8
0.87

T42 d 40° C.
*
*
*
*

T42 d 25° C.
13.2
85.6
1.3
0.80

T42 d 5° C.
4.5
94.4
1.1
0.97

T63 d 40° C.
*
*
*
*

T63 d 25° C.
13.2
85.3
1.5
0.73

T63 d 5° C.
4.3
95.0
0.7
0.87

T84 d 40° C.
*
*
*
*

T84 d 25° C.
10.3
88.1
1.6
0.62

T84 d 5° C.
4.5
94.7
0.7
0.80



* Samples were too degraded or compromised to evaluate with SEC (e.g. gelled, precipitated).














































TABLE 75



Stability of 9E10.1-GS-33675 During Storage. Aggregate, Monomer,

And Fragment Percentages Were Quantitated by SEC.











Area Under SEC


%
%
%
Chromatogram Signal


Aggregate
Monomer
Fragment
Relative to T0










T0
0.8
98.4
0.7
1.00

T7 d 40° C.
5.3
93.8
0.8
0.84

T7 d 25° C.
4.8
94.6
0.6
0.89

T7 d 5° C.
3.7
95.5
0.8
0.92

T21 d 40° C.
6.1
92.5
1.4
0.77

T21 d 25° C.
4.4
95.0
0.6
0.82

T21 d 5° C.
6.7
92.8
0.5
0.89

T42 d 40° C.
13.8
83.9
2.3
0.76

T42 d 25° C.
4.7
94.6
0.8
0.85

T42 d 5° C.
7.7
91.7
0.5
0.92

T63 d 40° C.
19.8
77.0
3.2
0.77

T63 d 25° C.
4.8
94.4
0.8
0.84

T63 d 5° C.
8.4
91.2
0.4
0.94

T84 d 40° C.
22.8
73.2
4.0
0.68

T84 d 25° C.
5.3
93.7
1.0
0.80

T84 d 5° C.
8.1
91.5
0.4
0.88










































Both 4G8.3-GS-9E8.4 and 4G8.3-SL-9E8.4 formed a white precipitate when stored at 40° C. after 7 days and thus could not be analyzed by SEC. The samples are assumed to be completely aggregated. At 25° C., there was an observable increase in aggregation for both molecules. The aggregation was less rapid for 4G8.3-GS-9E8.4 than for 4G8.3-SL-9E8.4. Aggregation of the former increased from 1.8% to 5.0% after 84 days while that of the latter started at 4.2% and reached as high as 13.2% over the course of 84 days. At 5° C., there is no noticeable aggregate increase for the two molecules.
For 9E10.1-GS-33675, aggregation at 5° C. increased from 0.8% to 6.7% by 21 days and levelled off at ˜8% from 42 to 84 days. At 25° C., aggregation increased from 0.8% to 4.7% by 7 days and levelled off at that value up to 84 days. Finally, aggregation at 40° C. increased from 0.8% to 22.8% in an apparently linear fashion over the course of 84 days. The aggregation at 40° C. for 9E10.1-GS-33675 is much less that that observed for the other two DVD-Ig molecules. This may be the result of the universal formulation buffer used.
There was no apparent change in fragmentation for all three DVD-Ig molecules at 25° C. or 5° C. At 40° C., an apparent and expected increase in fragmentation was observed for 9E10.1-GS-33675 after 21 days.
Example 14.3
Further Assessment of Physicochemical Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules (Stability to Freeze-Thaw Stress)
Based on the earlier physicochemical screen (Example 14.1), three anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules (4G8.3-GS-9E8.4, 4G8.3-SL-9E8.4, and 9E10.1-GS-33675) were selected for further characterization. Sample prep, stress, and analysis were performed according to Example 2.5. Briefly, the molecules were prepared in a formulation buffer at concentrations of 100±10 mg/ml or 1 mg/ml and subjected to four cycles of freezing (˜80° C.) and thawing (30° C.). Samples were characterized after the second and fourth thaw (Tables 76-81 below).
As mentioned in Example 2.5, protein samples are typically frozen at −80° C. for long term storage as well as shipping to remote manufacturing sites. The samples are then thawed in order to complete the drug product manufacturing process.





TABLE 76



Stability of 4G8.3-GS-9E8.4 at 100 ± 10 mg/ml When Subjected

To Freeze-Thaw Stress (−80° C./30° C.). Aggregate,

Monomer, And Fragment Percentages Were Quantitated by SEC.











Area Under SEC


%
%
%
Chromatogram Signal


Aggregate
Monomer
Fragment
Relative to T0










F/T 0
1.8
97.3
0.9
1.00

F/T 2
1.8
97.4
0.8
0.90

F/T 4
2.2
96.9
0.9
0.92



































TABLE 77



Stability of 4G8.3-SL-9E8.4 at 100 ± 10 mg/ml

When Subjected To Freeze-Thaw stress (−80°

C./30° C.). Aggregate, Monomer, And Fragment

Percentages Were Quantitated by SEC











Area Under SEC


%
%
%
Chromatogram Signal


Aggregate
Monomer
Fragment
Relative to T0










F/T 0
4.2
94.7
1.1
1.00

F/T 2
4.1
95.2
0.7
0.83

F/T 4
4.3
94.4
1.3
0.82




































TABLE 78



Stability of 9E10.1-GS-33675 at 100 ± 10 mg/ml

when Subjected To Freeze-Thaw Stress (−80°

C./30° C.). Aggregate, Monomer, And Fragment

Percentages Were Quantitated by SEC.











Area Under SEC


%
%
%
Chromatogram Signal


Aggregate
Monomer
Fragment
Relative to T0










F/T 0
0.8
98.4
0.7
1.00

F/T 2
1.1
98.5
0.4
0.91

F/T 4
1.8
97.6
0.6
0.88




































TABLE 79



Stability of 4G8.3-GS-9E8.4 at 1 mg/ml When

Subjected To Freeze-Thaw Stress (−80°

C./30° C.). Aggregate, Monomer, And Fragment

Percentages Were Quantitated by SEC.











Area Under SEC


%
%
%
Chromatogram Signal


Aggregate
Monomer
Fragment
Relative to T0










F/T 0
1.8
97.3
0.9
1.00

F/T 2
1.9
97.5
0.6
0.95

F/T 4
2.0
97.1
0.9
0.96




































TABLE 80



Stability of 4G8.3-SL-9E8.4 at 1 mg/When Subjected To

Freeze-Thaw Stress (−80° C./30° C.). Aggregate,

Monomer, And Fragment Percentages Were Quantitated by SEC.











Area Under SEC


%
%
%
Chromatogram Signal


Aggregate
Monomer
Fragment
Relative to T0










F/T 0
4.2
94.7
1.1
1.00

F/T 2
3.9
95.4
0.7
0.94

F/T 4
4.1
94.9
1.0
0.94



































TABLE 81



Stability of 9E10.1-GS-33675 at 1 mg/ml When Subjected

To Freeze-Thaw Stress (−80° C./30° C.). Aggregate,

Monomer, And Fragment Percentages Were Quantitated by SEC.











Area Under SEC


%
%
%
Chromatogram Signal


Aggregate
Monomer
Fragment
Relative to T0










F/T 0
0.8
98.4
0.7
1.00

F/T 2
1.0
98.6
0.5
0.98

F/T 4
1.2
98.2
0.6
0.98






























For all three DVD-Igs, at either 100±10 mg/ml or 1 mg/ml, no apparent increase in aggregation was observed due to freeze-thaw stress after two cycles.
Example 14.4
Further Assessment of Physicochemical Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules (Viscosity Determination)
Based on the earlier physicochemical screen (Example 14.1), three anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules (4G8.3-GS-9E8.4, 4G8.3-SL-9E8.4, and 9E10.1-GS-33675) were selected for further characterization. The molecules were prepared in a formulation buffer at 100±10 mg/ml and the viscosities were measured at room temperature (Example 2.6). The viscosities were 5.1, 7.2, and 7.2 centipoise, respectively. The values are within the range that enables ease of administration via a small diameter needle attached to a syringe.
Example 14.5
Further Assessment of Physicochemical Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules (Thermal Stability Assessment)
Based on the earlier physicochemical screen (Example 14.1), three anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules (4G8.3-GS-9E8.4, 4G8.3-SL-9E8.4, and 9E10.1-GS-33675) were selected for further characterization. The molecules were prepared in a formulation buffer at 1 mg/ml according to Example 2.3 and the thermal stabilities were determined according to Example 2.2. The midpoint temperatures of the first transition of unfolding are 52° C., 51° C., and 62° C., respectively. The temperatures at which the first transitions began to appear are 44° C., 42° C., and 62° C., respectively. The data indicate that 9E10.1-GS-33675 has a significantly greater thermal stability than the other two DVD-Ig molecules.
Example 14.6
Physicochemical Properties of an Anti-VEGF/anti-PDGF DVD-Ig Molecule (PR-1610561)
Testing of PR-1610561 revealed high thermostability (T onset =62° C.), solubility at least at 76 mg/ml, and a viscosity at 100 mg/ml at room temperature of 7.2 centipoise, which is within the range that enables ease of administration via a small diameter needle attached to a syringe. PR-1610561 has appropriate storage stability in a universal buffer and freeze-thaw stability.
Example 14.76
Intact and Reduced Molecular Weight Determination
Q-TOF LC-MS can detect mass differences between proteins that can result from mis-sense mutations, post-translational modifications, truncations, and other covalent changes that affect protein molecular weight. Table 82 shows the intact molecular weight and deglycosylated intact molecular weight of all three DVD-Ig molecules. Table 83 shows the molecular weights of light chain, heavy chain and deglycosylated heavy chain. The observed molecular weights of the three DVD-Ig molecules match well with the theoretical values with difference of less than 3 Dalton, which is well within the expected range of the error for the instrument.





TABLE 82



Intact molecular weight






Intact MW
Deglycosylated Intact MW








Theoretical
Observed
Theoretical
Observed










PR-1572102
203220
203219
200330
200330

PR-1572105
204350
204348
201460
201460

PR-1610561
202452
202450
199562
199562



































TABLE 83



Reduced molecular weight







Light Chain
Heavy Chain
Deglycosylated


MW
MW
HC MW










Theo-
Ob-
Theo-
Ob-
Theo-
Ob-


retical
served
retical
served
retical
served












PR-1572102
36080
36080
65533
65533
64088
64091

PR-1572105
36735
36734
65444
65444
63999
64002

PR-1610561
36006
36005
65224
65224
63779
63780
































Example 14.8
Oligosaccharide Profiles by Fc Molecular Weight
DVD-Ig molecules contain N-linked oligosaccharides in the Fc region of the heavy chain Fc molecular weight measurement can provide a semi-quantitative analysis of the oligosaccharide profiles. Table 84 shows the results of oligosaccharide profiles by Fc molecular weight. The oligosaccharide profiles of all three DVD-Ig molecules were similar to what is normally observed for mAbs, with 70-73% Gal 0F and 21-24% Gal 1F. The level of high mannose species was very low in all three samples. No significant level of aglycosylated species was detected.





TABLE 84



Oligosaccharide Profiles By Fc Molecular Weight






Species
PR-1572102
PR-1572105
PR-1610561








Man 5
1.0
1.1
0.4

Gal 0F-GlcNAc
0.5
0.4
0.0

Gal 0
0.5
0.2
0.7

Gal 0F
73.4
73.4
70.8

Lys-1
0.8
0.3
0.8

Gal 1F
21.0
21.2
23.8

Gal 2F
2.8
3.3
3.6






























Example 14.9
Charge Heterogeneity by Weak Cation Exchange Chromatography and Imaged Isoelectric Focusing
Weak cation exchange (WCX) chromatography separates molecules on the basis of the differences in their net surface charge. Variation in the extent of C terminal processing and certain post-translational modifications can lead to different species of an antibody with different charge distributions. Molecules that vary in their charge properties will exhibit different degrees of interaction with ion exchange resins, thus different elution profiles. Each chromatogram is characterized by a predominant peak (“main”) and species eluting before (“acidic”) or after (“basic”). The relative abundances of these species types are shown in Table 85.





TABLE 85



Results of Weak Cation Exchange Chromatography Analysis







Acidic (%)
Main (%)
Basic (%)











PR-1572102
9.2
63.9
26.9


PR-1572105
14.9
52.4
32.7


PR-1610561
17.7
56.5
25.8



























Imaged capillary isoelectric focusing (icIEF) is a technique that separates proteins on the basis of their isoelectric points or pI values. Different proteins have different pI and peak profiles, which makes icIEF an ideal identity assay. In icIEF, proteins with different pI values focus into distinctive bands in a linear pH gradient formed by ampholytes after applying high voltage. Table 86 shows the theoretical pI (calculated based on amino acid sequence) and the observed pI values measured by imaged icIEF. Also shown in Table 86 are the relative abundances of different charge species detected by imaged icIEF.





TABLE 86



Results of Imaged Isoelectric Focusing










pI by





Thoe. pI
icIEF
Acidic (%)
Main (%)
Basic (%)











PR- 1572102
6.13
6.78
14.3
71.6
14.1

PR-1572105
6.13
6.74
25.3
60.2
14.4

PR-1610561
6.67
7.27
27.2
63.2
9.6



























Example 15
Pharmacokinetic Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules
Example 15.1
Pharmacokinetic Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules Intravenously Administered in huFcRN Transgenic Mice
Studies were conducted in accordance with the AbbVie IACUC guidelines. Anti-VEGF/anti-PDGF DVD-Ig molecules PR-1572102 (lot 2211502), PR-1572105 (lot 2211597), or PR-1610561 (lot 2213329) were administered to huFcRn B6.Cg transgenic mice (5/group) at 5 mg/kg by slow intravenous bolus dose injection. Blood samples were collected from each mouse at 1, 24 and 96 hours and 7, 10, 14 and 21 days post dose. All samples were stored at −80° C. until analysis. DVD-Ig serum concentrations were measured using a Meso Scale Discovery (MSD) electrochemiluminescence (ECL) Ligand Binding Assay. Biotinylated VEGF ligand was coated onto streptavidin MSD plates for capture of anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules from blood samples, and detection was achieved with a sulfo-tag goat anti-human IgG antibody. Concentrations were calculated by four-parameter logistic fit using XLfit4. Pharmacokinetic parameters were calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie).
All three anti-VEGF/PDGF DVD-Ig molecules carrying the H435A substitution had serum concentrations rapidly clear, with measurable concentrations only to 24 hours. These results are in agreement with the rapid clearance observed with other H435A modified antibody and DVD-Ig molecules in human FcRn transgenic mice.
Example 15.2
Pharmacokinetic Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules Intravitreously Administered in Rabbit
Studies were conducted in accordance with the Abbott IACUC guidelines. Female New Zealand White rabbits were used for the ocular pharmacokinetic characterization of Anti-VEGF-A/anti-PDGF-BB DVD-Igs: PR-1572102, PR-1572105 and PR-1610561. Animals (4 animals) were split into two cohorts of two for determination of ocular pharmacokinetics. Samples of aqueous humour were taken at 4, 24, 48, 72, 120, 168, 336 and 504 hours post dosing. With cohort 1 providing samples at 4, 48, 120 and 168 hours, and cohort 2 providing samples at 24, 72, 336 and 504 hours, post dosing. Drug levels in the eye were determined from concentrations in aqueous humour as a surrogate for the vitreous concentrations. Vitreous was harvested from each animal as a terminal sample after their last aqueous humour sample. The proportion of aqueous to vitreous concentration was determined from these terminal time points. Blood samples for the harvest of serum used to estimate systemic exposure after vitreous dosing were also collected at 4, 24, 48, 72, 120, and 168 hours post dosing from all animals, and at 336 and 504 hours from the animals in cohort 2. Test articles were dosed into the vitreous compartment at a range of 0.25 to 0.50 mg per eye with a dose volume of no more than 0.050 mL. Only the right eye of each animal was dosed. Prior to dosing, animals were anesthetized with xylazine/ketamine. The eye was prepared by first applying topical analgesic drops (procaine HCl Ophthalmic solution, 0.5%), then the injections site was swabbed with a saturated povidone-iodine swabstick (10% solution equivalent to 1% available iodine) prior to injection. The intravitreal dose was administered with a 26 gauge needle. The point of entry for the injection was 1-2 mm from the limbus through the sclera. After injection, a sterile cotton eye spear was placed on the injection site and held for 30 seconds to prevent leakage Animals were anesthetized for aqueous fluid collection. At the selected time points after dosing, the aqueous fluid was collected using a 30 gauge needle inserted through the cornea. The needle was advanced just past the bevel and fluid was collected. The samples provided approximately 0.05-0.1 mL of aqueous humour per sampling period. At the selected time points after dosing, blood samples were obtained from an ear vein or artery. Hemostasis following collection was achieved by the application of manual pressure and topical clotting factor or tissue glue as needed. The samples were from 0.5-1 ml in volume, and were allowed to clot for harvest of serum. Aqueous, vitreous and serum samples were stored at −80° C., and submitted for drug level determinations.
All DVD-Ig serum concentrations were measured using a GYROS method employing biotinylated VEGF ligand for capture, and Alexa Flour 647 goat anti-human IgG detection. Concentrations were calculated by four-parameter logistic fit using XLfit4. Pharmacokinetic parameters were calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie).





TABLE 87



Ocular Half Lives in Rabbit from Analysis of Aqueous Humor






Experiment
Test Article
Corporate ID
Half life (hours)



#1
9E10.1_GS_CL-33675
PR-1610561
111

#2
9E10.1_GS_CL-33675
PR-1610561
Pending






















Example 15.3
Pharmacokinetic Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules Intravenously Administered in Cynomolgus Monkey
Studies are conducted in accordance with the AbbVie IACUC guidelines. Female cynomolgus are used for the systemic pharmacokinetic characterization of Anti-VEGF-A/anti-PDGF-BB DVD-Igs, including PR-1572102, PR-1572105 and PR-1610561 after intravenous dosing. Monkeys are dosed intravenously at 5 mg/kg by slow bolus into the saphenous vein over approximately 2 minutes with a volume of 0.5 mL/kg. Samples are taken for determination of the pharmacokinetics of the test compounds at 0, 0.08, 4, 8, 24, 72, 168, 240, 336, 504 and 672 hours post dosing. At the selected time points after dosing, blood samples are obtained from a femoral vein. Hemostasis following collection is achieved by the application of manual pressure and topical clotting factor or tissue glue as needed. The samples may be approximately 1 ml in volume, and are allowed to clot for harvest of serum. Serum samples are stored at −80° C., and submitted for drug level determinations.
DVD-Ig serum concentrations are measured using either a GYROS or a MSD method. GYROS employs biotinylated VEGF ligand for capture, and Alexa Flour 647 goat anti-human IgG detection. MSD employs biotinylated VEGF ligand for capture, and Sulfo-tag goat anti-human IgG or sulfo-tag VEGF for detection. Concentrations are calculated by four-parameter logistic fit using XLfit4. Pharmacokinetic parameters are calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie).
Example 15.4
Pharmacokinetic Properties of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules Intravitreously Administered in Cynomolgus Monkey
Studies are conducted in accordance with the AbbVie IACUC guidelines. Female cynomolgus are used for the ocular pharmacokinetic characterization of Anti-VEGF-A/anti-PDGF-BB DVD-Igs, including PR-1572102, PR-1572105 and PR-1610561. Animals (4 animals) are split into two cohorts of two for determination of ocular pharmacokinetics. Samples of aqueous humour are taken at 4, 24, 48, 72, 120, 168, 336 and 504 hours post dosing. With cohort 1 providing samples at 4, 48, 120 and 168 hours, and cohort 2 providing samples at 24, 72, 336 and 504 hours, post dosing. Drug levels in the eye are determined from concentrations in aqueous humour as a surrogate for the vitreous concentrations. Blood samples for the harvest of serum used to estimate systemic exposure after vitreous dosing are also collected at 4, 24, 48, 72, 120, and 168 hours post dosing from all animals, and at 336 and 504 hours from the animals in cohort 2. Test articles are dosed into the vitreous compartment at a range of 0.25 to 0.50 mg per eye with a dose volume of no more than 0.050 mL. Only the right eye of each animal is dosed. Prior to dosing, animals are anesthetized with xylazine/ketamine. The eye is prepared by first applying topical analgesic drops (procaine HCl Ophthalmic solution, 0.5%), then the injections site is swabbed with a saturated povidone-iodine swabstick (10% solution equivalent to 1% available iodine) prior to injection. The intravitreal dose is administered with a 26 gauge needle. The point of entry for the injection is 1-2 mm from the limbus through the sclera. After injection, a sterile cotton eye spear is placed on the injection site and held for 30 seconds to prevent leakage. Animals are anesthetized for aqueous fluid collection. At the selected time points after dosing, the aqueous fluid is collected using a 30 gauge needle inserted through the cornea. The needle is advanced just past the bevel and fluid was collected. The samples provide approximately 0.05-0.1 mL of aqueous humour per sampling period. At the selected time points after dosing, blood samples are obtained from an ear vein or artery. Hemostasis following collection is achieved by the application of manual pressure and topical clotting factor or tissue glue as needed. The samples are approximately 1 ml in volume, and are allowed to clot for harvest of serum. Aqueous, vitreous and serum samples are stored at −80° C., and submitted for drug level determinations.
DVD-Ig serum concentrations are measured using either a GYROS or a MSD method. GYROS employs biotinylated VEGF ligand for capture, and Alexa Flour 647 goat anti-human IgG detection. MSD employs biotinylated VEGF ligand for capture, and Sulfo-tag goat anti-human IgG or sulfo-tag VEGF for detection. Concentrations are calculated by four-parameter logistic fit using XLfit4. Pharmacokinetic parameters are calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie).
Example 16
Efficacy of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules Human VEGF Transgenic Mice
Example 16.1
Efficacy of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules to Inhibit Subretinal Neovascularization in Rho/huVEGF Transgenic Mice
Transgenic mice in which the rhodopsin promoter drives expression of human VEGF 165 in photoreceptors (Rho-VEGF mice) have onset of VEGF expression at P7 and starting at P10, develop sprouts of NV from the deep capillary bed of the retina that grow through the photoreceptor layer and form an extensive network of new vessels in the subretinal space. Since the new vessels originate from retinal capillaries and not choroidal vessels, it is technically a model of retinal angiomatous proliferation (RAP) which occurs in roughly 30% of patients with neovascular AMD, but in general it mimics critical features of wet AMD. At P14, hemizygous Rho-VEGF mice were given an intraocular injection of test reagents. At P21, the mice were euthanized, and eyes were fixed in 10% phosphate-buffered formalin for 2 hours. Retinas were dissected, blocked with 5% normal swine serum in PBS for 1 hour, stained with FITC-conjugated GSA, a vascular stain, for 2 hours to stain vascular cells, flat mounted with the photoreceptor side up, and examined by fluorescence microscopy. The area of subretinal NV was measured with image analysis by an investigator blinded with respect to treatment group. The other eye will provide information regarding systemic effect of an intraocular injection.
In the study below, nine treatment groups were evaluated: DVD-Ig Control (DVD 889), Eylea, Anti VEGF mAb, Anti PDGF mAb, Anti VEGF+Anti PDGF (combination Ab treatment), Anti-VEGF/anti-PDGF DVD-Ig. Only eye measurements in the experimental eye were analyzed and reported here using one way ANOVA analysis. Posthoc comparison of treatment vs the DVD control groups was analysed by Dunnett's test. Results are shown in See FIG. 4 and in Table 88 below. Further, differences in PDGF neutralization potencies and the molecular size of the DVD-Ig versus IgG did not have an effect in this model.
An overall ANOVA F-test for significance was used and the data was shown to be significant (p<0.0001). Comparison of the test groups to the DVD-Ig control group shows that the difference from all the groups was significant (Dunnet test p<0.0001). PR-1610561 was significantly more effective at inhibiting subretinal neovascularization in Rho/huVEGF transgenic mice than Eylea (Tukey HSD test pvalue=0.0031). PR-1610561 was more effective, but not significantly different from, the anti-VEGF and anti-PDGF (potency matched mAbs) combination group.





TABLE 88



Inhibition Efficacy of Anti-VEGF-A, Anti-PDGF-

BB, Anti-VEGF-A + Anti-PDGF-BB, and Anti-

VEGF-A/Anti-PDGF-BB DVD-Ig Molecules to Subretinal

Neovascularization in Rho/huVEGF Transgenic Mice










Cor-
N (# of






porate
ani-

Std
Std
CV

Groups
ID#
mals)
Mean
Dev
Err
(%)











DVD negative
PR-
8
0.0892
0.0665
0.0235
74

control
1250499

Eylea
—
19
0.0198
0.0224
0.0051
113

Anti VEGF
—
7
0.0164
0.0088
0.0033
54

Anti PDGF
—
16
0.0297
0.0265
0.0066
89

Anti VEGF +
—
10
0.0119
0.0182
0.0058
153

Anti PDGF

Anti-VEGF/
PR-
9
0.0033
0.0038
0.0013
115

anti-PDGF
1610561

DVD-Ig






































Example 16.2
Efficacy of Anti-VEGF-A/Anti-PDGF-BB DVD-Ig Molecules in Tet-Opsin-Human VEGF 165 Double-Transgenic Mice
When given injections of doxycycline, Tet-opsin-VEGF double-transgenic mice with Dox-inducible expression of VEGF express 10-fold higher levels of human VEGF 165 than Rho-VEGF-transgenic mice and develop severe NV and exudative retinal detachments within 3 to 5 days. Tet-opsin-VEGF mice provide a severe model where mice develop exudative retinal detachments and only the most effective agents have a significant impact. Double-hemizygous Tet-opsin-VEGF mice were given intraocular injections of test reagent in the right eyes. For the next 3 days, the mice were also administered a daily subcutaneous injection of 50 mg/kg doxycycline. At the 4th day, mice were euthanized and fundus photographs taken with Micron III retinal imaging microscope (Phoenix Research Laboratories, Pleasanton, Calif.). Also, OCT images were taken by Bioptigen Image-guided OCT (Envisu R4110, Bioptigen Inc. Morrisville, N.C.). Then eyes were frozen in optimal cutting temperature embedding solution. Ten-micron ocular serial sections were cut through the entire eye, stained with H&E stain and examined by light microscopy. After that mean length of the retinal detachment per section was measured with image analysis by an investigator blinded with respect to treatment group. The percentage of the detached retina was computed. Retinal detachment was graded as no detachment (0); partial retinal detachment (1); or total retinal detachment (2).
Anti-VEGF-A, anti-PDGF-BB, and the combination of anti-VEGF-A and anti-PDGF-BB were tested for their ability to suppress retinal detachment (RD) in tet-opsin-VEGF double transgenic mice. Results showed differences among the 3 test groups (P=0.01, Kruskal-Wallis test). Based on the RD number, the combination of anti-VEGF-A and anti-PDGF-BB (7 NRD, 1 PRD, 0 TRD), and the anti-VEGF-A alone (5 NRD, 0 PRD, 0 TRD) groups were more effective than anti-PDGF-BB alone (2 NRD, 2 PRD, 2 TRD) in preventing RD in Tet-opsin-VEGF double transgenic mice.
The differences in efficacy between PR-1610561, Eylea, and control IgG were compared next in tet-opsin-VEGF mice. Differences were also found among the 3 groups (P=0.01, Kruskal-Wallis test). PR-1610561 (10 NRD, 0 PRD, 1 TRD) and Eylea (4 NRD, 3 PRD, 1 TRD) were more effective than IgG control (2 NRD, 2 PRD, 2 TRD) in preventing RD in Tet-opsin-VEGF double transgenic mice. The data is summarized in Table 89 below.





TABLE 89



The efficacy of test articles in tet-

opsin-VEGF double transgenic mice











Anti-
Anti-
Anti-




IgG
VEGF
PDGF
VEGF +
PR-

Grade
control
mAb
mAb
Anti-PDGF
1610561
Eylea











0
2
5
2
7
10
4

(NRD)

1
1
0
2
1
0
3

(PRD)

2
6
0
3
0
1
1

(TRD)







Total
9
5
7
8
11
8

eyes


































The effects of PR-1610561 in a tet/opsin/huVEGF double transgenic mouse retinal detachment model were also analyzed by another grading system (Table 89A). 1 μl of reagent was injected into one eye, followed by subcutaneous injection of doxycycline at 500 mg/kg once a day for three days, and then fundus images and OCTs were done at day 4. Retinal detachment was graded as no detachment (0); no retinal detachment but at least one sign selected from dilated retinal vessels, retinal edema, or hemorrhage (1); one or less than one quadrant of retinal detachment (2); two or three quandrants of retinal detachment or shallow pan retinal detachment (3); or severe bullous retinal detachment (4).





TABLE 89A



Efficacy of Anti-VEGF, Anti-PDGF, Anti-VEGF + Anti-PDGF, and Anti-

VEGF/Anti-PDGF DVD-Ig Molecules in Tet/Opsin/huVEGF Double Transgenic Mice









Grade
DVD889
Anti-VEGF
Anti-PDGF
Combo
PR-1610561
Aflibercept











0
1
4
1
4
3
1

1
1
1
1
2
7
3

2
1
0
2
0
0
1

3
0
0
0
1
1
1

4
6
0
3
0
0
1

Total eyes
9
5
7
8
11
7

evaluated































The results in the tables above show that PR-1610561 has similar efficacy to a combination of anti-VEGF-A and anti-PDGF-BB, and is superior to Aflibercept alone in suppressing subretinal neovascularization in Rho/huVEGF transgenic mice. PR-1610561 is also superior to the combination of Aflibercept and anti-PDGF-BB in the prevention of vascular leakage in Rho/huVEGF transgenic mice.
Example 16.3
Effects of Anti-VEGF/Anti-PDGF on Ocular Neovascularization and Vascular Permeability/Perfusion
This study compared the effects of intraocular injections of anti-VEGF/anti-PDGF DVD-Ig molecules, anti-VEGF mAb alone, anti-PDGF alone, and a combination of antibodies.
DVD-Ig molecules and DVD-Ig Fab fragments were selected for evaluation, first in Rho/VEGF mice and then in Tet/opsin/VEGF double transgenic mice.
Studies used rho/VEGF and Tet/opsin/VEGF mouse models as described in Example 16.1. The compounds evaluated are shown in Table 90 below. About 20 mice were included per experiment, where one eye was injected with agent and the other eye was not injected.





TABLE 90



Study Agents









4G8.3-GS-9E8.4 (PR-1572102; DVD-Ig-1)


4G8.3-LS-9E8.4 (PR-PR-1575573; DVD-Ig-2)


4G8.3-SL-9E8.4 (PR-1572105; DVD-Ig-3)


DVD 889(IgG control)


Anti-VEGF IgG 4G83


Anti-PDGF-BB IgG 9E8.4


Anti-VEGF IgG 24 μg + Anti-PDGF-BB IgG


Avastin 24 μg


Anti-PDGF-BB aptamer E10030.1


Avastin 24 μg + Anti-PDGF-BB aptamer































Transgenic mice in which the rhodopsin promoter drives expression of VEGF in photoreceptors (rho/VEGF mice) develop retinal angiomatous proliferation (RAP) which originates from the deep capillary bed of the retina and grows through the photoreceptor layer to reach the subretinal spaces. The transgenic mice were utilized to determine the effects of DVD-Ig molecules on subretinal neovascularization. The rho/VEGF mice have an onset of VEGF expression at P7 and, starting at P10, develop sprouts of NV from the deep capillary bed of the retina that grow through the photoreceptor layer and form an extensive network of new vessels in the subretinal space. At P14, hemizygous Rho-VEGF mice were given an intraocular injection of test reagents. At P21, the mice were euthanized, and eyes were fixed in 10% phosphate-buffered formalin for 2 hours. Retinas were dissected, blocked with 5% normal swine serum in PBS for 1 hour, stained with FITC-conjugated GSA for 2 hours to stain vascular cells, flat mounted with the photoreceptor side up, and examined by fluorescence microscopy. The area of subretinal NV was measured with image analysis by an investigator blinded with respect to treatment group.
Compared with the control DVD-Ig molecule, DVD-Ig-1 and DVD-Ig-3 significantly decreased choroidal neovascularization (CNV) (p=0.02, 0.04), whereas DVD-Ig-2 did not show much effect. Compared with the IgG control, the combined administration of anti-VEGF IgG and anti-PDGF-BB IgG significantly decreased CNV (p=0.045), while administration of anti-VEGF IgG or anti-PDGF IgG alone did not significantly reduce subretinal NV. No other difference was observed in eyes injected with Avastin, anti-PDGF-BB aptamer, or a mixture of Avastin and anti-PDGF-BB aptamer. Significantly decreased subretinal NV was found after administration of DVD-Ig-1 and DVD-Ig-3, when compared to the mixture of Avastin and the anti-PDGF-BB aptamer. No other difference was found between DVD-Ig reagents and the combined administration of anti-VEGF-IgG and anti-PDGF IgG. FIG. 5 .
No difference was found in the untreated eyes of mice injected with anti-VEGF/anti-PDGF DVD-Ig molecules, control DVD-Ig, anti-VEGF mAb alone, anti-PDGF alone, and a combination of antibodies (ANOVA, P>0.05), indicating there was no clear systemic effect of intraocular injection. FIG. 6 .
Tet/opsin/VEGF mice express higher levels of VEGF in photoreceptors than rho/VEGF mice, resulting in severe NV and vascular leakage with exudative retinal detachment. The efficacy of intraocular injections of anti-VEGF/anti-PDGF DVD-Ig molecules in this transgenic mouse was also evaluated. Mice were given intraocular injections of test reagent in the right eye. For the next 3 days, the mice were also administered a daily subcutaneous injection of 50 mg/kg doxycycline. At the 4th days, mice were euthanized and fundus photographs were taken with Micron III retinal imaging microscope (Phoenix Research Laboratories, Pleasanton, Calif.). OCT images were taken by Bioptigen Image-guided OCT (Envisu R4110, Bioptigen Inc. Morrisville, N.C.). Then eyes were frozen in optimal cutting temperature embedding solution. Ten-micron ocular serial sections were cut through the entire eye, stained with H&E stain and examined by light microscopy. Mean length of the retinal detachment per section was measured with image analysis by an investigator blinded with respect to treatment group. The percentage of the retina that was detached was computed.
Five mice in each test group were injected with DVD-Ig reagents separately. In DVD-Ig-1 injected eyes, two were not detached and three were partially detached, while three eyes were totally detached and two partially detached in the uninjected eye. In DVD-Ig-3 injected eyes, one was not detached, two were partially detached, and two were totally detached, while all the uninjected eyes were totally detached. In the DVD-Ig-2 injected eyes, one was not detached and four were totally detached, while one eye was partially detached and four eyes were totally detached in the uninjected eye. In the IgG control group, one injected eye was not detached, one eye was partially detached, and three eyes were totally detached, while all eyes were totally detached in the uninjected eye. FIG. 7 .
Thus, DVD-Ig-1 and DVD-Ig-3 appeared to perform at least as well as a combination of anti-VEGF mAb and anti-PDGF mAb for the measured parameters, while requiring the administration of only one compound.
Example 17
Generation and Identification of Various Molecular Formats Optimal for Applications in Ocular Diseases
Several attributes were considered in the design of a therapeutic biologic for the treatment of wet AMD:
PK, Efficacy and Frequency of Administration:
Longer ocular duration may support less frequent intravitreous injection. The size of the administered molecule may play a role in determining ocular half-life. This is supported by consistently longer ocular half-life for the current anti-VEGF agents with larger molecular size in humans and in experimental animals. Bevacizumab, which has a larger molecular size (150 kDa) than ranibizumab (49 kDa), also seems to have more robust duration of efficacy in both Rho/huVEGF and tet/huVEGF transgenic mice, the two models used for preclinical efficacy.
FcRn and FcγR Binding and Safety:
Fc neonatal receptor (FcRn), which plays a role for long circulating half-life of IgG molecules in serum, may or may not play an important role in determining ocular half-life. The molecules with wild type FcRn binding, however, will have long systemic half-life and may increase safety risk due to unnecessary systemic exposure of intravitreously injected molecules. FcRn is also perceived to play a role in active efflux of IgGs across blood-retina barrier. This may lead to shortened ocular retention time for the intravitreously inject molecules. Effector functions are not needed for the efficacy of anti-wet AMD agents. But both VEGF-A and PDGF-BB may be associated with extracellular matrix when they are initially synthesized and secreted. The ECM-associated VEGF-A and PDGF-BB therefore may potentially mediate effector functions.
Affinity, Valency and Potency:
Both VEGF-A and PDGF-BB are homodimeric molecules. If a monovalent molecular format similar to that of ranibizumab (Fab) is used for bispecific molecules targeting VEGF and PDGF for the treatment of wet AMD, high affinity may be needed to maintain binding and potent neutralization of both VEGF-A and PDGF-BB.
Manufacturability:
Any viable format needs to have acceptable expression, purification, formulation properties to accommodate DS and DP manufacturing.
Various binding protein formats disclosed herein may satisfy these characteristics:
(1) Full length DVD-Ig [L234A, L235A] (200 kDa, lacks binding to FcgRs)

(2) Full length DVD-Ig [L234A, L235A, H435A] (200 kDa, lacks binding to FcgRs and FcRn)

(3) Half DVD-Ig (100 kDa, lacks binding to FcgRs and FcRn)

(4) DVD-Fab (75 kDa, no Fc)

Example 17.1
Generation of Various Molecular Formats Including DVD-Ig [L234A, L235A], DVD-Ig [L234A, L235A and H435A], DVD-Ig [L234A, L235A and H435R], Half DVD-Ig and DVD-Fab
This example evaluates the impact of Fc mutations on the PK properties of DVD-Ig binding proteins. DVD-038 was used a tool molecule to study various DVD-Ig formats, including a half-DVD-Ig (DVD038 [L234A, L235A] Half-DVD), full DVD-Ig binding proteins having three constant domain mutations (DVD038 [L234A, L235A and H435A] and DVD038 [L234A, L235A and H435R]), and a full DVD-Ig binding protein having two constant domain mutations (DVD038 [L234A, L235A]). The data below was used to evaluate options for producing a VEGF/PDGF binding protein structure with good drug-like properties and exhibiting high ocular duration but low systemic circulation. DVD038 is a dual variable domain binding protein that binds HER2 and VEGF.
To prepare mutants of DVD038, overlapping PCR was used with primers designed to include the desired mutations. PCR products were digested and ligated into the cloning vector. Bacterial transformation was performed to identify positive clones and constructs were harvested and purified for use in mammalian transfection using standard protocols known in the art.
All variants were transiently transfected into 10 L of HEK 293 6E suspension cell cultures in a Wave-bag with a ratio of 60% to 40% light to heavy chain construct. 0.5 mg/mL PEI was used to transfect the cells. Supernatants were harvested after 11 days by centrifugation at 16000 g for 20 minutes followed by filtration using Pall Serum Capsule and Pall AcroPak 1000. All except DVD-Fab were purified on MabSelectSuRe resin (GE Healthcare, 17-5438-04). Following equilibration with PBS pH 7.4, the supernatant was loaded on the resin and washed with PBS pH 7.4. DVD-Ig protein was eluted with 50 mM Glycine, 50 mM NaCl pH 3.5. DVD-Fab was purified using Protein G Sepharose 4 FF resin (GE Healthcare, 17-0618-04). Elution was performed with Immunopure IgG elution buffer (Pierce, 185 1520). Fractions containing DVD-Ig were pooled and dialyzed in 30 mM Histidine pH 6, 8% sucrose overnight at 4° C.
Example 17.2
Binding of Various Formats to FcRns from Different Species
As described in Example 1.2, all variants of DVD038, except for DVD038 Fab which does not have an Fc region, were analyzed for their binding to FcRns from different species. The data is summarized in Table 91 below.





TABLE 91



Binding of Various Formats to FcRns from Different Species










Hu
Cyno
Rabbit



Corporate
FcRn
FcRn
FcRn
Rat FcRn










Test Articles
ID
KD (M)
KD (M)
KD (M)
ka (1/Ms)
kd (1/s)
KD (M)



DVD038 (L234A,
PR-1578399
6.26E−06
3.13E−06
6.76E−07
3.06E+04
2.57E−02
8.40E−07

L235A) Half DVD-Ig

DVD038 (L234A,
PR-1564681
7.96E−06
2.57E−06
3.98E−07
5.15E+04
5.53E−02
1.07E−06

L235A, H435R)

DVD038 (L234A,
PR-1565009
4.90E−06
1.74E−06
2.75E−07
3.66E+04
1.94E−02
5.31E−07

L235A)








DVD038 (L234A,
PR-1565689
NSB
NSB
NSB
NSB

L235A, H435A)










HERCEPTIN
—
4.53E−06
2.62E−06
4.69E−07
3.27E+04
1.81E−02
5.55E−07



* NSB = no significant binding







































Example 17.3
Pharmacokinetic Properties of Different Formats in huFcRn Transgenic Mice Administered Intravenously
Studies were conducted in accordance with the Abbott IACUC guidelines. DVD038 (L234A, L235A) (PR-1565009), DVD038 (L234A, L235A, H435R) (PR-1564681), and DVD038 (L234A, L235A, H435A) (PR-1565689) were administered to huFcRn transgenic mice (5/group) at 6.7 mg/kg by slow intravenous bolus dose injection. Blood samples were collected from each mouse at 1, 24 and 96 hours and 7, 10, 14 and 21 days post dose. All samples were stored at −80° C. until analysis. DVD-Ig serum concentrations were measured using a Meso Scale Discovery (MSD) electrochemiluminescence (ECL) Ligand Binding Assay. Biotinylated VEGF ligand was coated onto streptavidin MSD plates for capture of anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules from blood samples, and detection was achieved with a sulfo-tag goat anti-human IgG antibody. Concentrations were calculated by four-parameter logistic fit using XLfit4.
Pharmacokinetic parameters were calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie).





TABLE 92



PK in huFcRn Transgenic Mice









CL

Test Articles
Corporate ID
T½ (d)
(mL/h/kg)



DVD038 (L234A, L235A)
PR-1565009
2.8
0.81

DVD038 (L234A, L235A, H435R)
PR-1564681
1.8
1.25

DVD038 (L234A, L235A, H435A)
PR-1565689
0.6
1.58
























The results demonstrate a trend for increased clearance and shorter half-life for DVD constructs with reduced or lack of Fc binding in huFcRn transgenic mice.
Example 17.4
Pharmacokinetic Properties of Different Formats in CD-1 Mice Administered Intravenously
Studies were conducted in accordance with the Abbott IACUC guidelines. DVD038 (L234A, L235A) (PR-1565009), DVD038 (L234A, L235A, H435R) (PR-1564681), DVD038 (L234A, L235A, H435A) (PR-1565689), DVD038 half DVD-Ig (L234A, L235A) (PR-1578399) and DVD-Fab (PR-1574215) were administered to CD-1 mice (5/group) at 6.7 mg/kg by slow intravenous bolus dose injection. Blood samples were collected from each mouse at 1, 24 and 96 hours and 7, 10, 14 and 21 days post dose. All samples were stored at −80° C. until analysis. DVD-Ig serum concentrations were measured using a Meso Scale Discovery (MSD) electrochemiluminescence (ECL) Ligand Binding Assay. Biotinylated VEGF ligand was coated onto streptavidin MSD plates for capture of anti-VEGF-A/anti-PDGF-BB DVD-Ig molecules from blood samples, and detection was achieved with a sulfo-tag goat anti-human IgG antibody. Concentrations were calculated by four-parameter logistic fit using XLfit4. Pharmacokinetic parameters were calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie).





TABLE 93



PK in CD-1 Mice









CL

Test Articles
Corporate ID
T½ (d)
(mL/h/kg)








DVD038 (L234A, L235A)
PR-1565009
7.6
0.46

DVD038 (L234A, L235A, H435R)
PR-1564681
6.4
0.29

DVD038 (L234A, L235A, H435A)
PR-1565689
2.7
0.73

DVD038 Half DVD-Ig (L234A,
PR-1578399
0.4
8.86

L235A)

DVD038 DVD-Fab
PR-1574215
0.2
20.76






























Results demonstrate a trend for increased clearance and shorter half-life for DVD constructs with reduced or lack of Fc binding in CD-1 mice. Molecules composed of a fragment of immunoglobulin structure are cleared fastest.
Example 17.5
Pharmacokinetic Properties of Different Formats in Rabbits Administered Intravitreously
Studies were conducted in accordance with the AbbVie IACUC guidelines. Female New Zealand White rabbits were used for the ocular pharmacokinetic characterization of formats DVD038 (PR-1565009, lot 2131983), DVD038 H435A (PR-1565689, lot 2131481), DVD038 Dhab (PR-1578399, lot 2149586) and DVDFab (PR-1574215, lot 2143755). Animals (4 animals) were split into two cohorts of two for determination of ocular pharmacokinetics. Samples of aqueous humour were taken at 48, 168, 336 and 504 hours post dosing. With cohort 1 providing samples at 48 and 168 hours, and cohort 2 providing samples at 336 and 504 hours, post dosing. Drug levels in the eye were determined from concentrations in aqueous humour. Blood samples for the harvest of serum used to estimate systemic exposure after vitreous dosing were also collected at 4, 24, 48, 72, 120, 168 hours post dosing from all animals, and at 336 and 504 hours from the animals in cohort 2. Test articles were dosed into the vitreous compartment at 0.50 mg per eye with a volume of no more than 0.050 mL. Only the right eye of each animal was dosed. Prior to dosing, animals were anesthetized with xylazine/ketamine. The eye was prepared by first applying topical analgesic drops (procaine HCl Ophthalmic solution, 0.5%), then the injections site was swabbed with a saturated povidone-iodine swab stick (10% solution equivalent to 1% available iodine) prior to injection. The intravitreal dose was administered with a 26 gauge needle. The point of entry for the injection was 1-2 mm from the limbus through the sclera. After injection, a sterile cotton eye spear was placed on the injection site and held for 30 seconds to prevent leakage. Animals were anesthetized for aqueous fluid collection. At the selected time points after dosing, the aqueous fluid was collected using a 30 gauge needle inserted through the cornea. The needle was advanced just past the bevel and fluid was collected. The samples provided approximately 0.05-0.1 mL of aqueous humour per sampling period. At the selected time points after dosing, blood samples were obtained from an ear vein or artery. Hemostasis following collection was achieved by the application of manual pressure and topical clotting factor or tissue glue as needed. The samples were from 0.5-1 ml in volume, and were allowed to clot for harvest of serum. Aqueous, vitreous and serum samples were stored at −80° C., and submitted for drug level determinations.
The serum, and aqueous humour concentrations for these molecules were measured using either a GYROS or a MSD method. GYROS employs a biotinylated VEGF ligand for capture, and Alexa Flour 647 goat anti-human IgG detection. MSD employs biotinylated VEGF ligand for capture, and Sulfo-tag goat anti-human IgG or sulfo-tag VEGF for detection. Results were comparable between the two methods. Concentrations were calculated by four-parameter logistic fit using XLfit4. Pharmacokinetic parameters were calculated with Non-compartmental analysis using Pharmacokinetics Laboratory Automation Software for Management and Analysis (PLASMA) (Version 2.6.12, SParCS, AbbVie). Results from the experiment are shown in Table 94.





TABLE 94



Ocular Half Lives in Rabbit from Analysis of Aqueous Humor





Test Articles
Corporate ID
Half life







DVD038 (L234A, L235A)
PR-1565009
151

DVD038 (L234A, L235A, H435A)
PR-1565689
157

DVD038 Half DVD-Ig (L234A, L235A)
PR-1578399
90

DVD038 DVD-Fab
PR-1574215
110



























Population analysis of the pooled data sets was performed on the composite profile from multiple animals at each dose level. The analysis provided parameter estimates with reasonable variability (CV<30%). The larger molecular weight constructs show a weak trend towards a longer ocular half-life.





TABLE 95



Exemplary DVD-Ig Binding Proteins And Component Subunits







SEQ





ID NO
DVD-Ig
Outer VD name
Linker
Inner VD name









45
PR-1563988H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBDB-4G8.3 VH (VEGF)



(SEQ ID NO: 1)

(SEQ ID NO: 17)

46
PR-1563988L
hBDI-9E8.4 VL (PDGF)
GS-L10
hBDB-4G8.3 VL (VEGF)



(SEQ ID NO: 2)

(SEQ ID NO: 18)

47
PR-1563990H
hBDI-9E8.4 VH (PDGF)
HG-short
hBDB-4G8.3 VH (VEGF)



(SEQ ID NO: 1)

(SEQ ID NO: 17)

48
PR-1563990L
hBDI-9E8.4 VL (PDGF)
LK-short
hBDB-4G8.3 VL (VEGF)



(SEQ ID NO: 2)

(SEQ ID NO: 18)

49
PR-1563998H
hBDI-9E8.4 VH (PDGF)
HG-short
hBDB-4G8.3 VH (VEGF)



(SEQ ID NO: 1)

(SEQ ID NO: 17)

50
PR-1563998L
hBDI-9E8.4 VL (PDGF)
LK-long
hBDB-4G8.3 VL (VEGF)



(SEQ ID NO: 2)

(SEQ ID NO: 18)

51
PR-1564009H
hBDI-9E8.4 VH (PDGF)
HG-long
hBDB-4G8.3 VH (VEGF)



(SEQ ID NO: 1)

(SEQ ID NO: 17)

51
PR-1564009L
hBDI-9E8.4 VL (PDGF)
LK-short
hBDB-4G8.3 VL (VEGF)



(SEQ ID NO: 2)

(SEQ ID NO: 18)

53
PR-1564010H
hBDB-4G8.3 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 17)

(SEQ ID NO: 1)

54
PR-1564010L
hBDB-4G8.3 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 18)

(SEQ ID NO: 2)

55
PR-1564011H
hBDB-4G8.3 VH (VEGF)
HG-short
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 17)

(SEQ ID NO: 1)

56
PR-1564011L
hBDB-4G8.3 VL (VEGF)
LK-short
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 18)

(SEQ ID NO: 2)

57
PR-1564012H
hBDB-4G8.3 VH (VEGF)
HG-short
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 17)

(SEQ ID NO: 1)

58
PR-1564012L
hBDB-4G8.3 VL (VEGF)
LK-long
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 18)

(SEQ ID NO: 2)

59
PR-1564013H
hBDB-4G8.3 VH (VEGF)
HG-long
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 17)

(SEQ ID NO: 1)

60
PR-1564013L
hBDB-4G8.3 VL (VEGF)
LK-short
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 18)

(SEQ ID NO: 2)

61
PR-1564883H
hBDI-5H1.9 VH (PDGF)
HG-short
hBDB-4G8.13 VH (VEGF)


(DVD3896H)a
(SEQ ID NO: 3)

(SEQ ID NO: 19)

62
PR-1564883L
hBDI-5H1.9 VL (PDGF)
LK-long
hBDB-4G8.13 VL (VEGF)


(DVD3896L)a
(SEQ ID NO: 4)

(SEQ ID NO: 20)

63
PR-1564893H
hBDI-5H1.9 VH (PDGF)
HG-short
hBDB-4G8.14 VH (VEGF)


(DVD3897H)a
(SEQ ID NO: 3)

(SEQ ID NO: 21)

64
PR-1564893L
hBDI-5H1.9 VL (PDGF)
LK-long
hBDB-4G8.14 VL (VEGF)


(DVD3897L)a
(SEQ ID NO: 4)

(SEQ ID NO: 22)

209
PR-1564896H
hBDI-5H1.9 VH (PDGF)
HG-short
hBDB-4G8.15 VH (VEGF)


(DVD3898H)a
(SEQ ID NO: 3)

(SEQ ID NO: 23)

65
PR-1564896L
hBDI-5H1.9 VL (PDGF)
LK-long
hBDB-4G8.15 VL (VEGF)


(DVD3898L)a
(SEQ ID NO: 4)

(SEQ ID NO: 24)

66
PR-1564898H
hBDI-5H1.12 VH (PDGF)
HG-short
hBDB-4G8.14 VH (VEGF)


(DVD3899H)a
(SEQ ID NO: 211)

(SEQ ID NO: 21)

67
PR-1564898L
hBDI-5H1.12 VL (PDGF)
LK-long
hBDB-4G8.14 VL (VEGF)


(DVD3899L)a
(SEQ ID NO: 212)

(SEQ ID NO: 22)

68
PR-1564899H
hBDI-5H1.12 VH (PDGF)
HG-short
hBDB-4G8.15 VH (VEGF)


(DVD3900H)a
(SEQ ID NO: 211)

(SEQ ID NO: 23)

69
PR-1564899L
hBDI-5H1.12 VL (PDGF)
LK-long
hBDB-4G8.15 VL (VEGF)


(DVD3900L)a
(SEQ ID NO: 212)

(SEQ ID NO: 24)

70
PR-1565023H
hBDI-9E8.9 VH (PDGF)
HG-short
hBDB-4G8.13 VH (VEGF)


(DVD3901H)a
(SEQ ID NO: 7)

(SEQ ID NO: 19)

71
PR-1565023L
hBDI-9E8.9 VL (PDGF)
LK-long
hBDB-4G8.13 VL (VEGF)


(DVD3901L)a
(SEQ ID NO: 8)

(SEQ ID NO: 20)

72
PR-1565029H
hBDI-9E8.9 VH (PDGF)
HG-short
hBDB-4G8.14 VH (VEGF)


(DVD3902H)a
(SEQ ID NO: 7)

(SEQ ID NO: 21)

73
PR-1565029L
hBDI-9E8.9 VL (PDGF)
LK-long
hBDB-4G8.14 VL (VEGF)


(DVD3902L)a
(SEQ ID NO: 8)

(SEQ ID NO: 22)

74
PR-1565030H
hBDI-9E8.9 VH (PDGF)
HG-short
hBDB-4G8.15 VH (VEGF)


(DVD3903H)a
(SEQ ID NO: 7)

(SEQ ID NO: 23)

75
PR-1565030L
hBDI-9E8.9 VL (PDGF)
LK-long
hBDB-4G8.15 VL (VEGF)


(DVD3903L)a
(SEQ ID NO: 8)

(SEQ ID NO: 24)

76
PR-1565031H
hBDI-9E8.12 VH (PDGF)
HG-short
hBDB-4G8.14 VH (VEGF)


(DVD3904H)a
(SEQ ID NO: 9)

(SEQ ID NO: 21)

77
PR-1565031L
hBDI-9E8.12 VL (PDGF)
LK-long
hBDB-4G8.14 VL (VEGF)


(DVD3904L)a
(SEQ ID NO: 10)

(SEQ ID NO: 22)

78
PR-1565032H
hBDI-9E8.12 VH (PDGF)
HG-short
hBDB-4G8.15 VH (VEGF)


(DVD3905H)a
(SEQ ID NO: 5)

(SEQ ID NO: 23)

79
PR-1565032L
hBDI-9E8.12 VL (PDGF)
LK-long
hBDB-4G8.15 VL (VEGF)


(DVD3905L)a
(SEQ ID NO: 6)

(SEQ ID NO: 24)

80
PR-1565035H
hBDI-5H1.10 VH (PDGF)
HG-short
hBDB-4G8.15 VH (VEGF)


(DVD3906H)a
(SEQ ID NO: 9)

(SEQ ID NO: 23)

81
PR-1565035L
hBDI-5H1.10 VL (PDGF)
LK-long
hBDB-4G8.15 VL (VEGF)


(DVD3906L)a
(SEQ ID NO: 10)

(SEQ ID NO: 24)

82
PR-1565033H
hBDI-9E8.10 VH (PDGF)
HG-short
hBDB-4G8.15 VH (VEGF)


(DVD3907H)a
(SEQ ID NO: 9)

(SEQ ID NO: 23)

83
PR-1565033L
hBDI-9E8.10 VL (PDGF)
LK-long
hBDB-4G8.15 VL (VEGF)


(DVD3907L)a
(SEQ ID NO: 10)

(SEQ ID NO: 24)

84
PR-1569574H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBDB-4G8.3 VH (VEGF)



(SEQ ID NO: 1)

(SEQ ID NO: 17)

85
PR-1569574L
hBDI-9E8.4 VL (PDGF)
GS-L10
hBDB-4G8.3 VL (VEGF)



(SEQ ID NO: 2)

(SEQ ID NO: 18)

86
PR-1569579H
hBDI-9E8.4 VH (PDGF)
HG-short
hBDB-4G8.3 VH (VEGF)



(SEQ ID NO: 1)

(SEQ ID NO: 17)

87
PR-1569579L
hBDI-9E8.4 VL (PDGF)
LK-long
hBDB-4G8.3 VL (VEGF)



(SEQ ID NO: 2)

(SEQ ID NO: 18)

88
PR-1572102H
hBDB-4G8.3 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 17)

(SEQ ID NO: 1)

89
PR-1572102L
hBDB-4G8.3 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 18)

(SEQ ID NO: 2)

90
PR-1572103H
hBDB-4G8.3 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 17)

(SEQ ID NO: 1)

91
PR-1572103L
hBDB-4G8.3 VL (VEGF)
GS-L11
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 18)

(SEQ ID NO: 2)

92
PR-1572104H
hBDB-4G8.3 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 17)

(SEQ ID NO: 1)

93
PR-1572104L
hBDB-4G8.3 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 18)

(SEQ ID NO: 2)

94
PR-1572105H
hBDB-4G8.3 VH (VEGF)
HG-short
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 17)

(SEQ ID NO: 1)

95
PR-1572105L
hBDB-4G8.3 VL (VEGF)
LK-long
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 18)

(SEQ ID NO: 2)

96
PR-1572106H
hBDB-4G8.3 VH (VEGF)
HG-long
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 17)

(SEQ ID NO: 1)

97
PR-1572106L
hBDB-4G8.3 VL (VEGF)
LK-short
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 18)

(SEQ ID NO: 2)

210
PR-1575573H
hBDI-9E8.4 VH (PDGF)
HG-long
hBDB-4G8.3 VH (VEGF)



(SEQ ID NO: 1)

(SEQ ID NO: 17)

98
PR-1575573L
hBDI-9E8.4 VL (PDGF)
LK-short
hBDB-4G8.3 VL (VEGF)



(SEQ ID NO: 2)

(SEQ ID NO: 18)

99
PR-1575832H
hBDB-4G8.3 VH (VEGF)
GS-H10
hBDI-9E8.4E VH (PDGF)



(SEQ ID NO: 17)

(SEQ ID NO: 11)

100
PR-1575832L
hBDB-4G8.3 VL (VEGF)
GS-L10
hBDI-9E8.4E VL (PDGF)



(SEQ ID NO: 18)

(SEQ ID NO: 12)

101
PR-1575834H
hBDB-4G8.3 VH (VEGF)
HG-short
hBDI-9E8.4E VH (PDGF)



(SEQ ID NO: 17)

(SEQ ID NO: 11)

102
PR-1575834L
hBDB-4G8.3 VL (VEGF)
LK-long
hBDI-9E8.4E VL (PDGF)



(SEQ ID NO: 18)

(SEQ ID NO: 12)

103
PR-1575835H
hBDB-4G8.3 VH (VEGF)
HG-long
hBDI-9E8.4E VH (PDGF)



(SEQ ID NO: 17)

(SEQ ID NO: 11)

104
PR-1575835L
hBDB-4G8.3 VL (VEGF)
LK-short
hBDI-9E8.4E VL (PDGF)



(SEQ ID NO: 18)

(SEQ ID NO: 12)

105
PR-1577165H
hBEW-9A8.12 VH (VEGF)
GS-H10
hBDI-9E8.4E VH (PDGF)



(SEQ ID NO: 25)

(SEQ ID NO: 11)

106
PR-1577165L
hBEW-9A8.12 VL (VEGF)
GS-L10
hBDI-9E8.4E VL (PDGF)



(SEQ ID NO: 26)

(SEQ ID NO: 12)

107
PR-1577166H
hBEW-9A8.12 VH (VEGF)
HG-short
hBDI-9E8.4E VH (PDGF)



(SEQ ID NO: 25)

(SEQ ID NO: 11)

108
PR-1577166L
hBEW-9A8.12 VL (VEGF)
LK-long
hBDI-9E8.4E VL (PDGF)



(SEQ ID NO: 26)

(SEQ ID NO: 12)

109
PR-1577547H
hBEW-9A8.12 VH (VEGF)
HG-long
hBDI-9E8.4E VH (PDGF)



(SEQ ID NO: 25)

(SEQ ID NO: 11)

110
PR-1577547L
hBEW-9A8.12 VL (VEGF)
LK-short
hBDI-9E8.4E VL (PDGF)



(SEQ ID NO: 26)

(SEQ ID NO: 12)

111
PR-1577548H
hBDI-9E8.4E VH (PDGF)
HG-short
hBEW-9A8.12 VH (VEGF)



(SEQ ID NO: 11)

(SEQ ID NO: 25)

112
PR-1577548L
hBDI-9E8.4E VL (PDGF)
LK-long
hBEW-9A8.12 VL (VEGF)



(SEQ ID NO: 12)

(SEQ ID NO: 26)

113
PR-1577550H
hBDI-9E8.4E VH (PDGF)
HG-long
hBEW-9A8.12 VH (VEGF)



(SEQ ID NO: 11)

(SEQ ID NO: 25)

114
PR-1577550L
hBDI-9E8.4E VL (PDGF)
LK-short
hBEW-9A8.12 VL (VEGF)



(SEQ ID NO: 12)

(SEQ ID NO: 26)

115
PR-1578137H
hBDI-9E8.4E VH (PDGF)
GS-H10
hBEW-9A8.12 VH (VEGF)



(SEQ ID NO: 11)

(SEQ ID NO: 25)

116
PR-1578137L
hBDI-9E8.4E VL (PDGF)
GS-L10
hBEW-9A8.12 VL (VEGF)



(SEQ ID NO: 12)

(SEQ ID NO: 26)

117
PR-1598261H
hBDB-4G8.2 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 27)

(SEQ ID NO: 1)

118
PR-1598261L
hBDB-4G8.2 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 28)

(SEQ ID NO: 2)

119
PR-1598262H
hBDB-4G8.4 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 29)

(SEQ ID NO: 1)

120
PR-1598262L
hBDB-4G8.4 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 30)

(SEQ ID NO: 2)

121
PR-1598263H
hBDB-4G8.5 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 31)

(SEQ ID NO: 1)

122
PR-1598263L
hBDB-4G8.5 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 32)

(SEQ ID NO: 2)

123
PR-1598264H
hBDB-4G8.12 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 33)

(SEQ ID NO: 1)

124
PR-1598264L
hBDB-4G8.12 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 34)

(SEQ ID NO: 2)

125
PR-1598265H
hBDB-4G8.13 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 19)

(SEQ ID NO: 1)

126
PR-1598265L
hBDB-4G8.13 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 20)

(SEQ ID NO: 2)

127
PR-1598266H
hBDB-4G8.14 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 21)

(SEQ ID NO: 1)

128
PR-1598266L
hBDB-4G8.14 VL (VEGF)
GS-L10
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 22)

(SEQ ID NO: 2)

129
PR-1610560H
hBDB-4G8.5 VH (VEGF)
GS-H10
hBFU-3E2.1 VH (PDGF)



(SEQ ID NO: 31)

(SEQ ID NO: 13)

130
PR-1610560L
hBDB-4G8.5 VL (VEGF)
GS-L10(dR)
hBFU-3E2.1 VL (PDGF)



(SEQ ID NO: 32)

(SEQ ID NO: 14)

131
PR-1610561H
hBEW-9E10.1 VH (VEGF)
GS-H10
CL-33675 VH (PDGF)



(SEQ ID NO: 35)

(SEQ ID NO: 15)

132
PR-1610561L
hBEW-9E10.1 VL (VEGF)
GS-L10(dR)
CL-33675 VL (PDGF)



(SEQ ID NO: 36)

(SEQ ID NO: 16)

133
PR-1610562H
hBEW-9E10.1 VH (VEGF)
GS-H10
hBFU-3E2.1 VH (PDGF)



(SEQ ID NO: 35)

(SEQ ID NO: 13)

134
PR-1610562L
hBEW-9E10.1 VL (VEGF)
GS-L10(dR)
hBFU-3E2.1 VL (PDGF)



(SEQ ID NO: 36)

(SEQ ID NO: 14)

135
PR-1610563H
hBEW-9E10.6 VH (VEGF)
GS-H10
hBFU-3E2.1 VH (PDGF)



(SEQ ID NO: 37)

(SEQ ID NO: 13)

136
PR-1610563L
hBEW-9E10.6 VL (VEGF)
GS-L10(dR)
hBFU-3E2.1 VL (PDGF)



(SEQ ID NO: 38)

(SEQ ID NO: 14)

137
PR-1610564H
hBEW-1B10.1 VH (VEGF)
GS-H10
hBFU-3E2.1 VH (PDGF)



(SEQ ID NO: 39)

(SEQ ID NO: 13)

138
PR-1610564L
hBEW-1B10.1 VL (VEGF)
GS-L10(dR)
hBFU-3E2.1 VL (PDGF)



(SEQ ID NO: 40)

(SEQ ID NO: 14)

139
PR-1611291H
hBDB-4G8.5 VH (VEGF)
GS-H10
CL-33675 VH (PDGF)



(SEQ ID NO: 31)

(SEQ ID NO: 15)

140
PR-1611291L
hBDB-4G8.5 VL (VEGF)
GS-L10(dR)
CL-33675 VL (PDGF)



(SEQ ID NO: 32)

(SEQ ID NO: 16)

141
PR-1611292H
hBEW-1B10.1 VH (VEGF)
GS-H10
CL-33675 VH (PDGF)



(SEQ ID NO: 39)

(SEQ ID NO: 15)

142
PR-1611292L
hBEW-1B10.1 VL (VEGF)
GS-L10(dR)
CL-33675 VL (PDGF)



(SEQ ID NO: 40)

(SEQ ID NO: 16)

143
PR-1611293H
hBEW-1E3.4 VH (VEGF)
GS-H10
CL-33675 VH (PDGF)



(SEQ ID NO: 41)

(SEQ ID NO: 15)

144
PR-1611293L
hBEW-1E3.4 VL (VEGF)
GS-L10(dR)
CL-33675 VL (PDGF)



(SEQ ID NO: 42)

(SEQ ID NO: 16)

145
PR-1611294H
hBEW-1E3.4 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 41)

(SEQ ID NO: 1)

146
PR-1611294L
hBEW-1E3.4 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 42)

(SEQ ID NO: 2)

147
PR-1611295H
CL-33675 VH (PDGF)
GS-H10
hBEW-9E10.1 VH (VEGF)



(SEQ ID NO: 15)

(SEQ ID NO: 35)

148
PR-1611295L
CL-33675 VL (PDGF)
GS-L10(dR)
hBEW-9E10.1 VL (VEGF)



(SEQ ID NO: 16)

(SEQ ID NO: 36)

149
PR-1611296H
CL-33675 VH (PDGF)
GS-H10
hBEW-9E10.6 VH (VEGF)



(SEQ ID NO: 15)

(SEQ ID NO: 37)

150
PR-1611296L
CL-33675 VL (PDGF)
GS-L10(dR)
hBEW-9E10.6 VL (VEGF)



(SEQ ID NO: 16)

(SEQ ID NO: 38)

151
PR-1611297H
CL-33675 VH (PDGF)
GS-H10
hBEW-1E3.4 VH (VEGF)



(SEQ ID NO: 15)

(SEQ ID NO: 41)

152
PR-1611297L
CL-33675 VL (PDGF)
GS-L10(dR)
hBEW-1E3.4 VL (VEGF)



(SEQ ID NO: 16)

(SEQ ID NO: 42)

153
PR-1611298H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBEW-9E10.1 VH (VEGF)



(SEQ ID NO: 1)

(SEQ ID NO: 35)

154
PR-1611298L
hBDI-9E8.4 VL (PDGF)
GS-L10(dR)
hBEW-9E10.1 VL (VEGF)



(SEQ ID NO: 2)

(SEQ ID NO: 36)

155
PR-1611299H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBEW-9E10.6 VH (VEGF)



(SEQ ID NO: 1)

(SEQ ID NO: 37)

156
PR-1611299L
hBDI-9E8.4 VL (PDGF)
GS-L10(dR)
hBEW-9E10.6 VL (VEGF)



(SEQ ID NO: 2)

(SEQ ID NO: 38)

157
PR-1611300H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBEW-1B10.1 VH (VEGF)



(SEQ ID NO: 1)

(SEQ ID NO: 39)

158
PR-1611300L
hBDI-9E8.4 VL (PDGF)
GS-L10(dR)
hBEW-1B10.1 VL (VEGF)



(SEQ ID NO: 2)

(SEQ ID NO: 40)

159
PR-1611301H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBEW-1E3.4 VH (VEGF)



(SEQ ID NO: 1)

(SEQ ID NO: 41)

160
PR-1611301L
hBDI-9E8.4 VL (PDGF)
GS-L10(dR)
hBEW-1E3.4 VH (VEGF)



(SEQ ID NO: 2)

(SEQ ID NO: 42)

161
PR-1612489H
hBDB-4G8.5 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 31)

(SEQ ID NO: 1)

162
PR-1612489L
hBDB-4G8.5 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 32)

(SEQ ID NO: 2)

163
PR-1612491H
hBEW-9E10.1 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 35)

(SEQ ID NO: 1)

164
PR-1612491L
hBEW-9E10.1 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 36)

(SEQ ID NO: 2)

165
PR-1612492H
hBEW-9E10.6 VH (VEGF)
GS-H10
CL-33675 VH (PDGF)



(SEQ ID NO: 37)

(SEQ ID NO: 15)

166
PR-1612492L
hBEW-9E10.6 VL (VEGF)
GS-L10(dR)
CL-33675 VL (PDGF)



(SEQ ID NO: 38)

(SEQ ID NO: 16)

167
PR-1612493H
hBEW-9E10.6 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 37)

(SEQ ID NO: 1)

168
PR-1612493L
hBEW-9E10.6 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 38)

(SEQ ID NO: 2)

169
PR-1612494H
hBEW-1B10.1 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 39)

(SEQ ID NO: 1)

170
PR-1612494L
BEW-1B10.1 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 40)

(SEQ ID NO: 2)

171
PR-1612495H
hBEW-1E3.4 VH (VEGF)
GS-H10
hBFU-3E2.1 VH (PDGF)



(SEQ ID NO: 41)

(SEQ ID NO: 13)

172
PR-1612495L
hBEW-1E3.4 VL (VEGF)
GS-L10(dR)
hBFU-3E2.1 VL (PDGF)



(SEQ ID NO: 42)

(SEQ ID NO: 14)

173
PR-1612496H
CL-33675 VH (PDGF)
GS-H10
hBDB-4G8.5 VH (VEGF)



(SEQ ID NO: 15)

(SEQ ID NO: 31)

174
PR-1612496L
CL-33675 VL (PDGF)
GS-L10(dR)
hBDB-4G8.5 VL (VEGF)



(SEQ ID NO: 16)

(SEQ ID NO: 32)

175
PR-1612498H
CL-33675 VH (PDGF)
GS-H10
hBEW-1B10.1 VH (VEGF)



(SEQ ID NO: 15)

(SEQ ID NO: 39)

176
PR-1612498L
CL-33675 VL (PDGF)
GS-L10(dR)
hBEW-1B10.1 VL (VEGF)



(SEQ ID NO: 16)

(SEQ ID NO: 40)

177
PR-1612499H
hBFU-3E2.1 VH (PDGF)
GS-H10
hBDB-4G8.5 VH (VEGF)



(SEQ ID NO: 13)

(SEQ ID NO: 31)

178
PR-1612499L
hBFU-3E2.1 VL (PDGF)
GS-L10(dR)
hBDB-4G8.5 VL (VEGF)



(SEQ ID NO: 14)

(SEQ ID NO: 32)

179
PR-1612500H
hBFU-3E2.1 VH (PDGF)
GS-H10
hBEW-9E10.1 VH (VEGF)



(SEQ ID NO: 13)

(SEQ ID NO: 35)

180
PR-1612500L
hBFU-3E2.1 VL (PDGF)
GS-L10(dR)
hBEW-9E10.1 VL (VEGF)



(SEQ ID NO: 14)

(SEQ ID NO: 36)

181
PR-1612501H
hBFU-3E2.1 VH (PDGF)
GS-H10
hBEW-9E10.6 VH (VEGF)



(SEQ ID NO: 13)

(SEQ ID NO: 37)

182
PR-1612501L
hBFU-3E2.1 VL (PDGF)
GS-L10(dR)
hBEW-9E10.6 VL (VEGF)



(SEQ ID NO: 14)

(SEQ ID NO: 38)

183
PR-1612502H
hBFU-3E2.1 VH (PDGF)
GS-H10
hBEW-1B10.1 VH (VEGF)



(SEQ ID NO: 13)

(SEQ ID NO: 39)

184
PR-1612502L
hBFU-3E2.1 VL (PDGF)
GS-L10(dR)
hBEW-1B10.1 VL (VEGF)



(SEQ ID NO: 14)

(SEQ ID NO: 40)

185
PR-1613183H
CL-34565 VH (VEGF)
GS-H10
CL-33675 VH (PDGF)



(SEQ ID NO: 43)

(SEQ ID NO: 15)

186
PR-1613183L
CL-34565 VL (VEGF)
GS-L10(dR)
CL-33675 VL (PDGF)



(SEQ ID NO: 44)

(SEQ ID NO: 16)

187
PR-1613184H
CL-34565 VH (VEGF)
GS-H10
hBDI-9E8.4 VH (PDGF)



(SEQ ID NO: 43)

(SEQ ID NO: 1)

188
PR-1613184L
CL-34565 VL (VEGF)
GS-L10(dR)
hBDI-9E8.4 VL (PDGF)



(SEQ ID NO: 44)

(SEQ ID NO: 2)

189
PR-1613185H
CL-34565 VH (VEGF)
GS-H10
hBFU-3E2.1 VH (PDGF)



(SEQ ID NO: 43)

(SEQ ID NO: 13)

190
PR-1613185L
CL-34565 VL (VEGF)
GS-L10(dR)
hBFU-3E2.1 VL (PDGF)



(SEQ ID NO: 44)

(SEQ ID NO: 14)

191
PR-1613186H
CL-33675 VH (PDGF)
GS-H10
CL-34565 VH (VEGF)



(SEQ ID NO: 15)

(SEQ ID NO: 43)

192
PR-1613186L
CL-33675 VL (PDGF)
GS-L10(dR)
CL-34565 VL (VEGF)



(SEQ ID NO: 16)

(SEQ ID NO: 44)

193
PR-1613187H
hBDI-9E8.4 VH (PDGF)
GS-H10
CL-34565 VH (VEGF)



(SEQ ID NO: 1)

(SEQ ID NO: 43)

194
PR-1613187L
hBDI-9E8.4 VL (PDGF)
GS-L10(dR)
CL-34565 VL (VEGF)



(SEQ ID NO: 2)

(SEQ ID NO: 44)

195
PR-1613188H
hBDI-9E8.4 VH (PDGF)
GS-H10
hBDB-4G8.5 VH (VEGF)



(SEQ ID NO: 1)

(SEQ ID NO: 31)

196
PR-1613188L
hBDI-9E8.4 VL (PDGF)
GS-L10(dR)
hBDB-4G8.5 VL (VEGF)



(SEQ ID NO: 2)

(SEQ ID NO: 32)

197
PR-1613189H
hBFU-3E2.1 VH (PDGF)
GS-H10
CL-34565 VH (VEGF)



(SEQ ID NO: 13)

(SEQ ID NO: 43)

198
PR-1613189L
hBFU-3E2.1 VL (PDGF)
GS-L10(dR)
CL-34565 VL (VEGF)



(SEQ ID NO: 14)

(SEQ ID NO: 44)

199
PR-1613190H
hBFU-3E2.1 VH (PDGF)
GS-H10
hBEW-1E3.4 VH (VEGF)



(SEQ ID NO: 13)

(SEQ ID NO: 41)

200
PR-1613190L
hBFU-3E2.1 VL (PDGF)
GS-L10(dR)
hBEW-1E3.4 VL (VEGF)



(SEQ ID NO: 14)

(SEQ ID NO: 42)

201
PR-1629646H
hBEW-9E10.1 VH (VEGF)
HG-short
CL-33675 VH (PDGF)



(SEQ ID NO: 35)

(SEQ ID NO: 15)

202
PR-1629646L
hBEW-9E10.1 VL (VEGF)
LK-long
CL-33675 VL (PDGF)



(SEQ ID NO: 36)

(SEQ ID NO: 16)

203
PR-1629647H
hBEW-1B10.1 VH (VEGF)
HG-short
CL-33675 VH (PDGF)



(SEQ ID NO: 39)

(SEQ ID NO: 15)

204
PR-1629647L
hBEW-1B10.1 VL (VEGF)
LK-long
CL-33675 VL (PDGF)



(SEQ ID NO: 40)

(SEQ ID NO: 16)

205
PR-1629648H
hBEW-9E10.1 VH (VEGF)
HG-long
CL-33675 VH (PDGF)



(SEQ ID NO: 35)

(SEQ ID NO: 15)

206
PR-1629648L
hBEW-9E10.1 VL (VEGF)
LK-short
CL-33675 VL (PDGF)



(SEQ ID NO: 36)

(SEQ ID NO: 16)

207
PR-1629649H
hBEW-1B10.1 VH (VEGF)
HG-long
CL-33675 VH (PDGF)



(SEQ ID NO: 39)

(SEQ ID NO: 15)

208
PR-1629649L
hBEW-1B10.1 VL (VEGF)
LK-short
CL-33675 VL (PDGF)



(SEQ ID NO: 40)

(SEQ ID NO: 16)









































































































































































































































































































































































TABLE 96



Sequences of Exemplary DVD-Ig Binding Proteins





SEQ



ID NO
DVD-Ig
Sequence







45
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1563988H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW



GQGTMVTVSSGGGGSGGGGSEVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMY



WVRQAPGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT



AVYYCARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAA



LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI



CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP



EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNHYTQKSLSLSPGK



46
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS


1563988L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGGSGGG



GSGDTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNL



ESGVPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



47
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1563990H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW



GQGTMVTVSSASTKGPEVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQ



APGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYY



CARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV



KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH



KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV



VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG



KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP



SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE



ALHNHYTQKSLSLSPGK



48
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS


1563990L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAPDT



VLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESGVP



ARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPSVFIF



PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS



LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



49
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1563998H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW



GQGTMVTVSSASTKGPEVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQ



APGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYY



CARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV



KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH



KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV



VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG



KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP



SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE



ALHNHYTQKSLSLSPGK



50
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS


1563998L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAPSV



FIFPPDTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASN



LESGVPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVA



APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS



KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



51
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1564009H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW



GQGTMVTVSSASTKGPSVFPLAPEVQLVQSGSELKKPGASVKVSCKASGYTFTNYG



MYWVRQAPGQGLEWMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAE



DTAVYYCARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGT



AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ



TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMIS



RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL



HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT



CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV



FSCSVMHEALHNHYTQKSLSLSPGK



51
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS


1564009L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAPDT



VLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESGVP



ARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPSVFIF



PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS



LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



53
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE


1564010H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD



YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM



GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP



VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL



GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC



NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE



VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNHYTQKSLSLSPGK



54
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG


1564010L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRGGSGGGG



SGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQR



PSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAP



SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD



STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



55
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE


1564011H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD



YWGQGTMVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI



RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT



YYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV



KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH



KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV



VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG



KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP



SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE



ALHNHYTQKSLSLSPGK



56
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG


1564011L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPEF



VLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPSGI



PDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAPSVFI



FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY



SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



57
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE


1564012H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD



YWGQGTMVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI



RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT



YYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV



KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH



KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV



VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG



KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP



SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE



ALHNHYTQKSLSLSPGK



58
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG


1564012L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPSVF



IFPPEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ



RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



59
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE


1564013H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD



YWGQGTMVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG



MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM



DPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA



ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT



YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR



TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH



QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC



LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS



CSVMHEALHNHYTQKSLSLSPGK



60
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG


1564013L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPEF



VLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPSGI



PDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAPSVFI



FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY



SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



61
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGVGWIRQPPGKALEWLANIWWDD


1564883H
DKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARISTGISSYYVMDAWG


(DVD3896H)a
QGTTVTVSSASTKGPEIQLVQSGTEVKKPGESLKISCKASGYTFTNYGMYWVKQMP



GKGLEYMGWINTETGKPTYADDFKGRFTFSLDKSFNTAFLQWSSLKASDTAMYFCA



RTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD



YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP



SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV



DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE



YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD



IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL



HNHYTQKSLSLSPGK



62
PR-
DFVLTQSPDSLAVSLGERATINCERSSGDIGDTYVSWYQQKPGQPPKNVIYGNDQRP


1564883L
SGVPDRFSGSGSGNSATLTISSLQAEDVAVYFCQSYDSDIDIVFGGGTKVEIKGTVAA


(DVD3896L)a
PSVFIFPPETVLTQSPATLSVSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYG



ASNLESGVPARFSGSGSGTDFTLTISSLQSEDFAVYFCQQSWNDPFTFGQGTRLEIKRT



VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ



DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



63
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGVGWIRQPPGKALEWLANIWWDD


1564893H
DKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARISTGISSYYVMDAWG


(DVD3897H)a
QGTTVTVSSASTKGPEIQLVQSGGGVVQPGGSLRLSCAASGYTFTNYGMYWVKQAP



GKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQLNSLRAEDTAVYFCA



RTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD



YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP



SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV



DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE



YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD



IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL



HNHYTQKSLSLSPGK



64
PR-
DFVLTQSPDSLAVSLGERATINCERSSGDIGDTYVSWYQQKPGQPPKNVIYGNDQRP


1564893L
SGVPDRFSGSGSGNSATLTISSLQAEDVAVYFCQSYDSDIDIVFGGGTKVEIKGTVAA


(DVD3897L)a
PSVFIFPPDTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIYGA



SNLESGVPSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTFGQGTKVEIKRTV



AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD



SKDSTYSLSSTLTLSKADYEK



209
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGVGWIRQPPGKALEWLANIWWDD


1564896H
DKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARISTGISSYYVMDAWG


(DVD3898H)a
QGTTVTVSSASTKGPEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQAP



GKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYFCA



RTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD



YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP



SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV



DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE



YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD



IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL



HNHYTQKSLSLSPGK



65
PR-
DFVLTQSPDSLAVSLGERATINCERSSGDIGDTYVSWYQQKPGQPPKNVIYGNDQRP


1564896L
SGVPDRFSGSGSGNSATLTISSLQAEDVAVYFCQSYDSDIDIVFGGGTKVEIKGTVAA


(DVD3898L)a
PSVFIFPPDTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKAPKLLIYG



ASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKVEIKRT



VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ



DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



66
PR-
EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTFGMGVGWIRQAPGKGLEWLANIWWD


1564898H
DDKYYNPSLKNRLTISKDTSKNQAYLQINSLRAEDTAVYYCARISTGISSYYVMDAW


(DVD3899H)a
GQGTLVTVSSASTKGPEIQLVQSGGGVVQPGGSLRLSCAASGYTFTNYGMYWVKQA



PGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQLNSLRAEDTAVYFC



ARTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK



DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK



PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV



VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK



EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS



DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA



LHNHYTQKSLSLSPGK



67
PR-
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVSWYQQKPGKAPKNVIYGNDQRP


1564898L
SGVPSRFSGSGSGNSATLTISSLQPEDFATYFCQSYDSDIDIVFGQGTKVEIKGTVAAP


(DVD3899L)a
SVFIFPPDTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIYGAS



NLESGVPSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTFGQGTKVEIKRTV



AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD



SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



68
PR-
EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTFGMGVGWIRQAPGKGLEWLANIWWD


1564899H
DDKYYNPSLKNRLTISKDTSKNQAYLQINSLRAEDTAVYYCARISTGISSYYVMDAW


(DVD3900H)a
GQGTLVTVSSASTKGPEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQ



APGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYF



CARTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV



KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH



KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV



VVDVSHEDPEVKTNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG



KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP



SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE



ALHNHYTQKSLSLSPGK



69
PR-
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVSWYQQKPGKAPKNVIYGNDQRP


1564899L
SGVPSRFSGSGSGNSATLTISSLQPEDFATYFCQSYDSDIDIVFGQGTKVEIKGTVAAP


(DVD3900L)a
SVFIFPPDTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKAPKLLIYGA



SNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKVEIKRTV



AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD



SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



70
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1565023H
DDKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYSFDYWG


(DVD3901H)a
QGTTVTVSSASTKGPEIQLVQSGTEVKKPGESLKISCKASGYTFTNYGMYWVKQMP



GKGLEYMGWINTETGKPTYADDFKGRFTFSLDKSFNTAFLQWSSLKASDTAMYFCA



RTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD



YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP



SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV



DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE



YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD



IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL



HNHYTQKSLSLSPGK



71
PR-
DFVLTQSPDSLAVSLGERATINCERSSGDIGDSYVSWYQQKPGQPPKNVIYADDQRP


1565023L
SGVPDRFSGSGSGNSASLTISSLQAEDVAVYFCQSYDINIDIVFGGGTKVEIKGTVAAP


(DVD3901L)a
SVFIFPPETVLTQSPATLSVSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGA



SNLESGVPARFSGSGSGTDFTLTISSLQSEDFAVYFCQQSWNDPFTFGQGTRLEIKRTV



AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD



SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



72
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1565029H
DDKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYSFDYWG


(DVD3902H)a
QGTTVTVSSASTKGPEIQLVQSGGGVVQPGGSLRLSCAASGYTFTNYGMYWVKQAP



GKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQLNSLRAEDTAVYFCA



RTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD



YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP



SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV



DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE



YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD



IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL



HNHYTQKSLSLSPGK



73
PR-
DFVLTQSPDSLAVSLGERATINCERSSGDIGDSYVSWYQQKPGQPPKNVIYADDQRP


1565029L
SGVPDRFSGSGSGNSASLTISSLQAEDVAVYFCQSYDINIDIVFGGGTKVEIKGTVAAP


(DVD3902L)a
SVFIFPPDTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIYGAS



NLESGVPSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTFGQGTKVEIKRTV



AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD



SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



74
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1565030H
DDKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYSFDYWG


(DVD3903H)a
QGTTVTVSSASTKGPEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQAP



GKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYFCA



RTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD



YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP



SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV



DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE



YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD



IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL



HNHYTQKSLSLSPGK



75
PR-
DFVLTQSPDSLAVSLGERATINCERSSGDIGDSYVSWYQQKPGQPPKNVIYADDQRP


1565030L
SGVPDRFSGSGSGNSASLTISSLQAEDVAVYFCQSYDINIDIVFGGGTKVEIKGTVAAP


(DVD3903L)a
SVFIFPPDTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKAPKLLIYGA



SNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKVEIKRTV



AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD



SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



76
PR-
EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTYGMGVGWIRQAPGKGLEWLANIWW


1565031H
DDDKYYNPSLKNRLTISKDTSKNQAYLQINSLRAEDTAVYYCARIESIGTTYSFDYW


(DVD3904H)a
GQGTLVTVSSASTKGPEIQLVQSGGGVVQPGGSLRLSCAASGYTFTNYGMYWVKQA



PGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQLNSLRAEDTAVYFC



ARTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK



DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK



PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV



VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK



EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS



DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA



LHNHYTQKSLSLSPGK



77
PR-
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQKPGKAPKNVIYADDQRPS


1565031L
GVPSRFSGSGSGNSASLTISSLQPEDFATYFCQSYDINIDIVFGQGTKVEIKGTVAAPSV


(DVD3904L)a
FIFPPDTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIYGASNL



ESGVPSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTFGQGTKVEIKRTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



78
PR-
EVQLVESGGGLVQPGGSLRLSCAFSGFSLSTYGMGVGWIRQAPGKGLEWLANIWW


1565032H
DDDKYYNPSLKNRLTISKDTSKNQAYLQINSLRAEDTAVYYCARIESIGTTYSFDYW


(DVD3905H)a
GQGTLVTVSSASTKGPEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQ



APGKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYF



CARTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV



KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH



KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV



VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG



KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP



SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE



ALHNHYTQKSLSLSPGK



79
PR-
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQKPGKAPKNVIYADDQRPS


1565032L
GVPSRFSGSGSGNSASLTISSLQPEDFATYFCQSYDINIDIVFGQGTKVEIKGTVAAPSV


(DVD3905L)a
FIFPPDTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKAPKLLIYGASN



LESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKVEIKRTVA



APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS



KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



80
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTFGMGVGWIRQPPGKALEWLANIWWDD


1565035H
DKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARISTGISSYYVMDAWG


(DVD3906H)a
QGTTVTVSSASTKGPEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQAP



GKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYFCA



RTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD



YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP



SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV



DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE



YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD



IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL



HNHYTQKSLSLSPGK



81
PR-
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDTYVSWYQQKPGKAPKNVIYGNDQRP


1565035L
SGVPSRFSGSGSGNSATLTISSLQPEDFATYFCQSYDSDIDIVFGQGTKVEIKGTVAAP


(DVD3906L)a
SVFIFPPDTQLTQSPSSLSASVGDRVTISCRASESVSTHMHWYQQKPGKAPKLLIYGA



SNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKVEIKRTV



AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD



SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



82
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1565033H
DDKYYNPSLKNRLTISKDTSKNQAVLTITNMDPVDTATYYCARIESIGTTYSFDYWG


(DVD3907H)a
QGTTVTVSSASTKGPEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMYWVKQAP



GKGLEYMGWINTETGKPTYADDFKGRFTFSLDTSKSTAYLQMNSLRAEDTAVYFCA



RTNYYYRSYIFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD



YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP



SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV



DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE



YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD



IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL



HNHYTQKSLSLSPGK



83
PR-
DFQLTQSPSSLSASVGDRVTITCERSSGDIGDSYVSWYQQKPGKAPKNVIYADDQRPS


1565033L
GVPSRFSGSGSGNSASLTISSLQPEDFATYFCQSYDINIDIVFGQGTKVEIKGTVAAPSV


(DVD3907L)a
FIFPPDTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIYGASNL



ESGVPSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTFGQGTKVEIKRTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



84
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE


1569574H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD



YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM



GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP



VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL



GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC



NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE



VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



85
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG


1569574L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRGGSGGGG



SGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQR



PSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAP



SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD



STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



86
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE


1569579H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD



YWGQGTMVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI



RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT



YYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV



KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH



KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV



VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG



KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP



SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE



ALHNAYTQKSLSLSPGK



87
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG


1569579L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPSVF



IFPPEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ



RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



88
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE


1572102H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD



YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM



GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP



VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL



GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC



NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE



VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



89
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG


1572102L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRGGSGGGG



SGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQR



PSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAP



SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD



STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



90
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE


1572103H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD



YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM



GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP



VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL



GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC



NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE



VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



91
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG


1572103L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRGGSGGGG



SGGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ



RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



92
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE


1572104H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD



YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM



GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP



VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL



GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC



NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE



VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



93
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG


1572104L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKGGSGGGGS



GGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ



RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



94
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE


1572105H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD



YWGQGTMVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI



RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT



YYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV



KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH



KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV



VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG



KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP



SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE



ALHNAYTQKSLSLSPGK



95
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG


1572105L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPSVF



IFPPEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ



RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



96
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE


1572106H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD



YWGQGTMVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG



MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM



DPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA



ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT



YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR



TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH



QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC



LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS



CSVMHEALHNAYTQKSLSLSPGK



97
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG


1572106L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPEF



VLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPSGI



PDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPSVFI



FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY



SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



210
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE


1575573H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD



YWGQGTMVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG



MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM



DPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA



ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT



YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR



TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH



QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC



LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS



CSVMHEALHNAYTQKSLSLSPGK



98
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG


1575573L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPEF



VLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPSGI



PDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGTVAAPSVFI



FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY



SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



99
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE


1575832H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD



YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM



GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP



VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL



GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC



NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE



VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



100
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG


1575832L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRGGSGGGG



SGEFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQR



PSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAP



SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD



STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



101
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE


1575834H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD



YWGQGTMVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI



RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT



YYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV



KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH



KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV



VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG



KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP



SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE



ALHNAYTQKSLSLSPGK



102
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG


1575834L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPSVF



IFPPEFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQ



RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



103
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE


1575835H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD



YWGQGTMVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG



MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM



DPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA



ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT



YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR



TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH



QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC



LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS



CSVMHEALHNAYTQKSLSLSPGK



104
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG


1575835L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRTVAAPEF



VLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQRPSGI



PDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPSVFI



FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY



SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



105
PR-
EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE


1577165H
TGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARVDYDGSFWFAY



WGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV



GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVD



TATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC



LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV



NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT



CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL



NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG



FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV



MHEALHNAYTQKSLSLSPGK



106
PR-
DTQLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIHGASNLESGV


1577165L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTFGQGTKLEIKRGGSGGGGS



GEFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQRP



SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS



VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS



TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



107
PR-
EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE


1577166H
TGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARVDYDGSFWFAY



WGQGTLVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIR



QPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATY



YCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK



DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK



PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV



VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK



EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS



DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA



LHNAYTQKSLSLSPGK



108
PR-
DTQLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIHGASNLESGV


1577166L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTFGQGTKLEIKRTVAAPSVFI



FPPEFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQ



RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



109
PR-
EVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE


1577547H
TGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARVDYDGSFWFAY



WGQGTLVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM



GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP



VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL



GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC



NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE



VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



110
PR-
DTQLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIHGASNLESGV


1577547L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTFGQGTKLEIKRTVAAPEFVL



TQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQRPSGIPD



RFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPSVFIFP



PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL



SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



111
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1577548H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW



GQGTMVTVSSASTKGPEVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMYWVRQ



APGQGLEWMGWINTETGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYY



CARVDYDGSFWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD



YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP



SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV



DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE



YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD



IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL



HNAYTQKSLSLSPGK



112
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQRPS


1577548L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPSV



FIFPPDTQLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIHGASNL



ESGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTFGQGTKLEIKRTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



113
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1577550H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW



GQGTMVTVSSASTKGPSVFPLAPEVQLVQSGAEVKKPGASVKVSCKASGYTFTNYG



MYWVRQAPGQGLEWMGWINTETGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRS



DDTAVYYCARVDYDGSFWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAA



LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI



CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP



EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



114
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQRPS


1577550L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPDT



QLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIHGASNLESGVPS



RFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTFGQGTKLEIKRTVAAPSVFIFP



PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL



SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



115
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1578137H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW



GQGTMVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMY



WVRQAPGQGLEWMGWINTETGKPIYADDFKGRVTMTTDTSTSTAYMELRSLRSDD



TAVYYCARVDYDGSFWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG



CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN



VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV



TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW



LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK



GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV



MHEALHNAYTQKSLSLSPGK



116
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGESYVSWYQQKPGQAPRLVIYADDQRPS


1578137L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRGGSGGG



GSGDTQLTQSPSSLSASVGDRVTITCRASESVSTVIHWYQQKPGKQPKLLIHGASNLE



SGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQHWNDPPTFGQGTKLEIKRTVAAPS



VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS



TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



117
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWINTE


1598261H
TGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRSYIFYFD



YWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM



GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP



VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL



GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC



NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE



VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNHYTQKSLSLSPGK



118
PR-
ATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLESGV


1598261L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKRGGSGGGGS



GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP



SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS



VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS



TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



119
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMGWINTET


1598262H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARTNYYYRSYIFYFDY



WGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG



VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV



DTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG



CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN



VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV



TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW



LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK



GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV



MHEALHNHYTQKSLSLSPGK



120
PR-
AIQLTQSPSSLSASVGDRVTITCRASESVSTHMHWYQQKPGKAPKLLIYGASNLESGV


1598262L
PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSWNDPFTFGQGTKLEIKRGGSGGGGS



GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP



SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS



VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS



TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



121
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMGWINTET


1598263H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARTNYYYRSYIFYFDY



WGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG



VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV



DTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG



CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN



VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV



TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW



LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK



GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV



MHEALHNHYTQKSLSLSPGK



122
PR-
ATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLESGV


1598263L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKRGGSGGGGS



GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP



SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS



VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS



TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



123
PR-
EIQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMGWINTET


1598264H
GKPTYADDFKGRFTFTLDTSTSTAYMELRSLRSDDTAVYFCARTNYYYRSYIFYFDY



WGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG



VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV



DTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG



CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN



VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV



TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW



LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK



GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV



MHEALHNHYTQKSLSLSPGK



124
PR-
DTVLTQSPATLSLSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG


1598264L
VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPFTFGQGTKLEIKRGGSGGGG



SGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQR



PSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAP



SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD



STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



125
PR-
EIQLVQSGTEVKKPGESLKISCKASGYTFTNYGMYWVKQMPGKGLEYMGWINTETG


1598265H
KPTYADDFKGRFTFSLDKSFNTAFLQWSSLKASDTAMYFCARTNYYYRSYIFYFDY



WGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG



VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV



DTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG



CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN



VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV



TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW



LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK



GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV



MHEALHNHYTQKSLSLSPGK



126
PR-
ETVLTQSPATLSVSPGERATLSCRASESVSTHMHWYQQKPGQAPRLLIYGASNLESG


1598265L
VPARFSGSGSGTDFTLTISSLQSEDFAVYFCQQSWNDPFTFGQGTRLEIKRGGSGGGG



SGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQR



PSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAP



SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD



STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



127
PR-
EIQLVQSGGGVVQPGGSLRLSCAASGYTFTNYGMYWVKQAPGKGLEYMGWINTET


1598266H
GKPTYADDFKGRFTFSLDTSKSTAYLQLNSLRAEDTAVYFCARTNYYYRSYIFYFDY



WGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV



GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVD



TATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC



LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV



NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT



CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL



NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG



FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV



MHEALHNHYTQKSLSLSPGK



128
PR-
DTVLTQSPSTLSASPGERATISCRASESVSTHMHWYQQKPGQAPKLLIYGASNLESGV


1598266L
PSRFSGSRSGTDFTLTISSLQPEDFAVYFCQQSWNDPFTFGQGTKVEIKRGGSGGGGS



GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP



SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS



VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS



TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



129
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMGWINTET


1610560H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARTNYYYRSYIFYFDY



WGQGTMVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYM



YWVKQAPGQGLELIGRIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRSEDT



AVYFCARFGARSYFYPMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALG



CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN



VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV



TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW



LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK



GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV



MHEALHNAYTQKSLSLSPGK



130
PR-
ATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLESGV


1610560L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKGGSGGGGSG



GETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESG



VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKRTVAAPSV



FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST



YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



131
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVKQAPGQGLEYMGWIDTET


1610561H
GRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWSGDTTGIRGPWFA



YWGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG



VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV



DTATYYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL



GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC



NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE



VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



132
PR-
DIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV


1610561L
PSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKGGSGGGGSG



GEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRA



SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAAP



SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD



STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



133
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVKQAPGQGLEYMGWIDTET


1610562H
GRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWSGDTTGIRGPWFA



YWGQGTLVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTESY



MYWVKQAPGQGLELIGRIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRSE



DTAVYFCARFGARSYFYPMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAAL



GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC



NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE



VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



134
PR-
DIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV


1610562L
PSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKGGSGGGGSG



GETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESG



VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKRTVAAPSV



FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST



YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



135
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWIDTE


1610563H
TGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDTAVYYCARWSGDTTGIRGPWF



AYWGQGTLVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTESY



MYWVKQAPGQGLELIGRIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRSE



DTAVYFCARFGARSYFYPMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAAL



GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC



NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE



VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



136
PR-
DIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV


1610563L
PSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKGGSGGGGSG



GETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESG



VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKRTVAAPSV



FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST



YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



137
PR-
EVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWFRQAPGKGLEWVASITTSGV


1610564H
GTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAVYYCARGYGAMDAWGQGT



TVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQ



APGQGLELIGRIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFC



ARFGARSYFYPMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD



YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP



SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV



DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE



YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD



IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL



HNAYTQKSLSLSPGK



138
PR-
DIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRLADG


1610564L
VPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKGGSGGGGS



GGETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLES



GVPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKRTVAAPS



VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS



TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



139
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMGWINTET


1611291H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARTNYYYRSYIFYFDY



WGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG



VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV



DTATYYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL



GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC



NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE



VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



140
PR-
ATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLESGV


1611291L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKGGSGGGGSG



GEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRA



SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAAP



SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD



STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



141
PR-
EVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWFRQAPGKGLEWVASITTSGV


1611292H
GTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAVYYCARGYGAMDAWGQGT



TVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQ



PPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYY



CARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD



YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP



SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV



DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE



YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD



IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL



HNAYTQKSLSLSPGK



142
PR-
DIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRLADG


1611292L
VPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKGGSGGGGS



GGEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQR



ASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



143
PR-
EIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMYWVKQAPGQGLEYMGWINTEA


1611293H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWGYISDNSYGWFDY



WGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV



GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVD



TATYYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG



CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN



VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV



TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW



LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK



GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV



MHEALHNAYTQKSLSLSPGK



144
PR-
ATQLTQSPSSLSASVGDRVTISCRASEGVYSYMHWYQQKPGKQPKLLIYKASNLASG


1611293L
VPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTFGQGTKLEIKGGSGGGGS



GGEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQR



ASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



145
PR-
EIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMYWVKQAPGQGLEYMGWINTEA


1611294H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWGYISDNSYGWFDY



WGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGV



GWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVD



TATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC



LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV



NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT



CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL



NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG



FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV



MHEALHNAYTQKSLSLSPGK



146
PR-
ATQLTQSPSSLSASVGDRVTISCRASEGVYSYMHWYQQKPGKQPKLLIYKASNLASG


1611294L
VPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTFGQGTKLEIKGGSGGGGS



GGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ



RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



147
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1611295H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESSGPKYSFDYW



GQGTMVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMY



WVKQAPGQGLEYMGWIDTETGRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT



AVYFCARWSGDTTGIRGPWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA



ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT



YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR



TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH



QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC



LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS



CSVMHEALHNAYTQKSLSLSPGK



148
PR-
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRAS


1611295L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKGGSGGGG



SGGDIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQ



NGVPSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAP



SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD



STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



149
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1611296H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESSGPKYSFDYW



GQGTMVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMY



WVRQAPGQGLEWMGWIDTETGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDT



AVYYCARWSGDTTGIRGPWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA



ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT



YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR



TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH



QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC



LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS



CSVMHEALHNAYTQKSLSLSPGK



150
PR-
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRAS


1611296L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKGGSGGGG



SGGDIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQ



NGVPSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAP



SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD



STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



151
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1611297H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESSGPKYSFDYW



GQGTMVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMY



WVKQAPGQGLEYMGWINTEAGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT



AVYFCARWGYISDNSYGWFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAA



LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI



CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP



EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



152
PR-
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRAS


1611297L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKGGSGGGG



SGGATQLTQSPSSLSASVGDRVTISCRASEGVYSYMHWYQQKPGKQPKLLIYKASNL



ASGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTFGQGTKLEIKRTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



153
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1611298H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW



GQGTMVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMY



WVKQAPGQGLEYMGWIDTETGRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT



AVYFCARWSGDTTGIRGPWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA



ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT



YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR



TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH



QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC



LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS



CSVMHEALHNAYTQKSLSLSPGK



154
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS


1611298L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGSGGGG



SGGDIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQ



NGVPSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAP



SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD



STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



155
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1611299H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW



GQGTMVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMY



WVRQAPGQGLEWMGWIDTETGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDT



AVYYCARWSGDTTGIRGPWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTA



ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT



YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR



TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH



QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC



LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS



CSVMHEALHNAYTQKSLSLSPGK



156
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS


1611299L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGSGGGG



SGGDIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQ



NGVPSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAP



SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD



STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



157
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1611300H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW



GQGTMVTVSSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMA



WFRQAPGKGLEWVASITTSGVGTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDT



AVYYCARGYGAMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK



DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK



PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV



VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK



EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS



DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA



LHNAYTQKSLSLSPGK



158
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS


1611300L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGSGGGG



SGGDIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRL



ADGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKRTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



159
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1611301H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW



GQGTMVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMY



WVKQAPGQGLEYMGWINTEAGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT



AVYFCARWGYISDNSYGWFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAA



LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI



CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP



EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



160
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS


1611301L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGSGGGG



SGGATQLTQSPSSLSASVGDRVTISCRASEGVYSYMHWYQQKPGKQPKLLIYKASNL



ASGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTFGQGTKLEIKRTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



161
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVRQAPGQGLEYMGWINTET


1612489H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARTNYYYRSYIFYFDY



WGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG



VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV



DTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG



CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN



VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV



TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW



LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK



GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV



MHEALHNAYTQKSLSLSPGK



162
PR-
ATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLESGV


1612489L
PSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKGGSGGGGSG



GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP



SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS



VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS



TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



163
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVKQAPGQGLEYMGWIDTET


1612491H
GRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWSGDTTGIRGPWFA



YWGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMG



VGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPV



DTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALG



CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN



VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV



TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW



LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK



GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV



MHEALHNAYTQKSLSLSPGK



164
PR-
DIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV


1612491L
PSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKGGSGGGGSG



GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP



SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS



VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS



TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



165
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWIDTE


1612492H
TGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDTAVYYCARWSGDTTGIRGPWF



AYWGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM



GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP



VDTATYYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAA



LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI



CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP



EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



166
PR-
DIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV


1612492L
PSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKGGSGGGGSG



GEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRA



SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAAP



SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD



STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



167
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMYWVRQAPGQGLEWMGWIDTE


1612493H
TGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDTAVYYCARWSGDTTGIRGPWF



AYWGQGTLVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGM



GVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDP



VDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL



GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC



NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE



VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



168
PR-
DIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV


1612493L
PSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKGGSGGGGSG



GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP



SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS



VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS



TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



169
PR-
EVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWFRQAPGKGLEWVASITTSGV


1612494H
GTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAVYYCARGYGAMDAWGQGT



TVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQ



PPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYY



CARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD



YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP



SNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVV



DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE



YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD



IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL



HNAYTQKSLSLSPGK



170
PR-
DIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRLADG


1612494L
VPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKGGSGGGGS



GGEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQ



RPSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



171
PR-
EIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMYWVKQAPGQGLEYMGWINTEA


1612495H
GKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWGYISDNSYGWFDY



WGQGTLVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYM



YWVKQAPGQGLELIGRIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRSEDT



AVYFCARFGARSYFYPMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALG



CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN



VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV



TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW



LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK



GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV



MHEALHNAYTQKSLSLSPGK



172
PR-
ATQLTQSPSSLSASVGDRVTISCRASEGVYSYMHWYQQKPGKQPKLLIYKASNLASG


1612495L
VPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTFGQGTKLEIKGGSGGGGS



GGETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLES



GVPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKRTVAAPS



VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS



TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



173
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1612496H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESSGPKYSFDYW



GQGTMVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMY



WVRQAPGQGLEYMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT



AVYFCARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL



GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC



NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE



VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



174
PR-
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRAS


1612496L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKGGSGGGG



SGGATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLE



SGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKRTVAAPS



VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS



TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



175
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1612498H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESSGPKYSFDYW



GQGTMVTVSSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMA



WFRQAPGKGLEWVASITTSGVGTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDT



AVYYCARGYGAMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK



DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK



PSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV



VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK



EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS



DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA



LHNAYTQKSLSLSPGK



176
PR-
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRAS


1612498L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKGGSGGGG



SGGDIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRL



ADGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKRTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



177
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIGRIDPEDG


1612499H
STDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPMDAWG



QGTTVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWV



RQAPGQGLEYMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVY



FCARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL



VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN



HKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTC



VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN



GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF



YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM



HEALHNAYTQKSLSLSPGK



178
PR-
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESGV


1612499L
PARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKGGSGGGGS



GGATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLES



GVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKRTVAAPSV



FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST



YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



179
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIGRIDPEDG


1612500H
STDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPMDAWG



QGTTVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWV



KQAPGQGLEYMGWIDTETGRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVY



FCARWSGDTTGIRGPWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC



LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV



NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT



CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL



NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG



FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV



MHEALHNAYTQKSLSLSPGK



180
PR-
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESGV


1612500L
PARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKGGSGGGGS



GGDIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLTYNANGLQN



GVPSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAPS



VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS



TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



181
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIGRIDPEDG


1612501H
STDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPMDAWG



QGTTVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMYW



VRQAPGQGLEWMGWIDTETGRPTYADDFKGRFTFTADKSTSTAYMELSSLRSEDTA



VYYCARWSGDTTGIRGPWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAA



LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI



CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP



EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



182
PR-
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESGV


1612501L
PARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKGGSGGGGS



GGDIRMTQSPSSLSASVGDRVTITCLASEDIYSDLAWYQQKPGKSPKLLTYNANGLQN



GVPSRFSGSGSGTDYTLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAPS



VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS



TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



183
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIGRIDPEDG


1612502H
STDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPMDAWG



QGTTVTVSSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWF



RQAPGKGLEWVASITTSGVGTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAV



YYCARGYGAMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF



PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN



TKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVD



VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY



KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI



AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH



NAYTQKSLSLSPGK



184
PR-
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESGV


1612502L
PARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKGGSGGGGS



GGDIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRLA



DGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKRTVAAP



SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD



STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



185
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGLEWMGWIDTE


1613183H
TGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRNYMFYF



DYWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG



MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM



DPVDTATYYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGT



AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ



TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMIS



RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL



HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT



CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV



FSCSVMHEALHNAYTQKSLSLSPGK



186
PR-
EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIYGASILESGV


1613183L
PARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIKGGSGGGGSG



GEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRA



SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAAP



SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD



STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



187
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGLEWMGWIDTE


1613184H
TGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRNYMFYF



DYWGQGTMVTVSSGGGGSGGGGSEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG



MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM



DPVDTATYYCARIESIGTTYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA



ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT



YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR



TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH



QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC



LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS



CSVMHEALHNAYTQKSLSLSPGK



188
PR-
EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIYGASILESGV


1613184L
PARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIKGGSGGGGSG



GEFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRP



SGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKRTVAAPS



VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS



TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



189
PR-
EVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYWVRQAPGQGLEWMGWIDTE


1613185H
TGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARTNYYYRNYMFYF



DYWGQGTMVTVSSGGGGSGGGGSEVQLVQSGAEVKKPGSSVKVSCKASGYTFTES



YMYWVKQAPGQGLELIGRIDPEDGSTDYVEKFKNKATLTADKSTSTAYMELSSLRS



EDTAVYFCARFGARSYFYPMDAWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAA



LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI



CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP



EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



190
PR-
EIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIYGASILESGV


1613185L
PARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIKGGSGGGGSG



GETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESG



VPARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKRTVAAPSV



FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST



YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



191
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1613186H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESSGPKYSFDYW



GQGTMVTVSSGGGGSGGGGSEVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMY



WVRQAPGQGLEWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT



AVYYCARTNYYYRNYMFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA



ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT



YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR



TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH



QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC



LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS



CSVMHEALHNAYTQKSLSLSPGK



192
PR-
EIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRAS


1613186L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKGGSGGGG



SGGEIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIYGASILE



SGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIKRTVAAPS



VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS



TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



193
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1613187H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW



GQGTMVTVSSGGGGSGGGGSEVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMY



WVRQAPGQGLEWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT



AVYYCARTNYYYRNYMFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTA



ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT



YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISR



TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH



QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC



LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS



CSVMHEALHNAYTQKSLSLSPGK



194
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS


1613187L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGSGGGG



SGGEIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIYGASILE



SGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIKRTVAAPS



VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS



TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



195
PR-
EVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWD


1613188H
DDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIESIGTTYSFDYW



GQGTMVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMY



WVRQAPGQGLEYMGWINTETGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDT



AVYFCARTNYYYRSYIFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAAL



GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC



NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPE



VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



196
PR-
EFVLTQSPGTLSLSPGERATLSCERSSGDIGDSYVSWYQQKPGQAPRLVIYADDQRPS


1613188L
GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYDINIDIVFGGGTKVEIKGGSGGGG



SGGATQLTQSPSLSASVGDRVTITCRASESVSTHMHWYQQKPGKQPKLLIYGASNLE



SGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQSWNDPFTFGQGTKLEIKRTVAAPS



VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS



TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



197
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIGRIDPEDG


1613189H
STDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPMDAWG



QGTTVTVSSGGGGSGGGGSEVQLVQSGSELKKPGASVKVSCKASGYTFTDYGMYW



VRQAPGQGLEWMGWIDTETGDPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTA



VYYCARTNYYYRNYMFYFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAA



LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI



CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP



EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD



WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV



KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS



VMHEALHNAYTQKSLSLSPGK



198
PR-
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESGV


1613189L
PARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKGGSGGGGS



GGEIVLTQSPATLSLSPGERATLFCRASQSVSNHMHWYQQKPGQAPRLLIYGASILES



GVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSWYDPITFGQGTKLEIKRTVAAPS



VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS



TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



199
PR-
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTESYMYWVKQAPGQGLELIGRIDPEDG


1613190H
STDYVEKFKNKATLTADKSTSTAYMELSSLRSEDTAVYFCARFGARSYFYPMDAWG



QGTTVTVSSGGGGSGGGGSEIQLVQSGSELKKPGASVKVSCKASGYPFTNSGMYWV



KQAPGQGLEYMGWINTEAGKPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAV



YFCARWGYISDNSYGWFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG



CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN



VNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV



TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW



LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK



GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV



MHEALHNAYTQKSLSLSPGK



200
PR-
ETVLTQSPATLSLSPGERATLSCRASESVSTLMHWYQQKPGQQPRLLIYGASNLESGV


1613190L
PARFSGSGSGTDFTLTISSLEPEDFAVYFCQQSWNDPWTFGGGTKVEIKGGSGGGGS



GGATQLTQSPSSLSASVGDRQVTISCRASEGVYSYMHWYQQKPGKQPKLLIYKASNLA



SGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCHQNWNDPLTFGQGTKLEIKRTVAAP



SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD



STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



201
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVKQAPGQGLEYMGWIDTET


1629646H
GRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWSGDTTGIRGPWFA



YWGQGTLVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI



RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT



YYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV



KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH



KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV



VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG



KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP



SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE



ALHNAYTQKSLSLSPGK



202
PR-
DIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV


1629646L
PSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAPSVFI



FPPEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQR



ASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAA



PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK



DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



203
PR-
EVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWFRQAPGKGLEWVASITTSGV


1629647H
GTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAVYYCARGYGAMDAWGQGT



TVTVSSASTKGPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKA



LEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIE



SSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP



VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK



VDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS



HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC



KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV



EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNA



YTQKSLSLSPGK



204
PR-
DIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRLADG


1629647L
VPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKRTVAAPSVF



IFPPEIVLTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQ



RASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVA



APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS



KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



205
PR-
EIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMYWVKQAPGQGLEYMGWIDTET


1629648H
GRPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARWSGDTTGIRGPWFA



YWGQGTLVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYG



MGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNM



DPVDTATYYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGT



AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ



TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMIS



RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL



HQDWLNGKEYKCKVSNKALPAPIEKTIMISKAKGQPREPQVYTLPPSREEMTKNQVSLT



CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV



FSCSVMHEALHNAYTQKSLSLSPGK



206
PR-
DIRMTQSPSSLSASVGDRVTIECLASEDIYSDLAWYQQKPGKSPKLLIYNANGLQNGV


1629648L
PSRFSGSGSGTDYSLTISSLQPEDVATYFCQQYNYFPGTFGQGTKLEIKRTVAAPEIVL



TQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRASGIPD



RFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAAPSVFIFP



PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL



SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC



207
PR-
EVQLVESGGGLVQPGGSLRLSCAASGFSFSKYDMAWFRQAPGKGLEWVASITTSGV


1629649H
GTYYRDSVKGRFTVSRDNAKSTLYLQMNSLRAEDTAVYYCARGYGAMDAWGQGT



TVTVSSASTKGPSVFPLAPEVTLRESGPALVKPTQTLTLTCTFSGFSLSTYGMGVGWI



RQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTAT



YYCARIESSGPKYSFDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV



KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH



KPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCV



VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG



KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP



SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE



ALHNAYTQKSLSLSPGK



208
PR-
DIQMTQSPSSLSASVGDRVTITCKASQDIDDYLSWYQQKPGKSPKLVIYAATRLADG


1629649L
VPSRFSGSGSGTDYTLTISSLQPEDFATYYCLQSSSTPWTFGGGTKVEIKRTVAAPEIV



LTQSPGTLSLSPGERATLSCRASSGSIWYSFVSWYQQKPGQAPRLLIYADDQRASGIP



DRFSGSGSGTDFTLTISRLEPEDFAVYYCQSYGINIDVVFGGGTKVEIKRTVAAPSVFI



FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY



SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































Example 18
PR-1610561 Cell Lines
Chimeric, humanized, and affinity matured antibodies, and DVD-Ig binding proteins were expressed using pHybE vectors. Transient expression of PR-1610561 in HEK cells was also achieved using a vector similar to pHybE-hCg1,z,non-a,mut(234,235) V2. See U.S. Pat. No. 8,187,836.
CHO cell lines producing PR-1610561 have been generated. The growth and productivity of the CHO cell lines were similar to those of other DVD-Ig molecules. All cell lines passed a screening for acceptable product quality by MS, SEC, and CIEX. CHO cell lines were produced using pBJ and pCD plasmid vectors encoding the amino acid sequences of PR-1610561. See US 2014/0295497.
Example 19
Epitope Binning
Antibodies and binding proteins disclosed herein are tested in a label-free cell-based competition assay in order to determine which antibodies and binding proteins are capable of binding to the same antigen (e.g., VEGF, PDGF, or one of their receptors) simultaneously. If antibodies or binding proteins are not able to bind simultaneously (therefore possibly competing for the same or similar epitope), those antibodies or binding proteins are assigned to the same “epitope bin.” If antibodies or binding proteins are capable of binding simultaneously and therefore do not compete for antigen binding, those antibodies or binding proteins are assigned to different epitope bins.
INCORPORATION BY REFERENCE
The contents of all cited references (including literature references, patents, patent applications, and websites) that maybe cited throughout this application are hereby expressly incorporated by reference in their entirety for any purpose, as are the references cited therein. To the extent those references contradict or are inconsistent with any statements in this application, the text of the application will control. The disclosure will employ, unless otherwise indicated, conventional techniques of immunology, molecular biology and cell biology, and pathology, which are well known in the art.
EQUIVALENTS
The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting of the inventions described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are therefore intended to be embraced herein.