An antibody or antigen binding fragment thereof that binds to a Fn14, wherein the antibody or antigen binding fragment thereof is an antagonist and non-agonist of Fn14.

Description

78 parts

›CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Stage Application under 35 U.S.C. § 371 of International Patent Application No. PCT/IB2019/061058, filed Dec. 19, 2019, which claims the benefit of U.S. Provisional Patent Application No. 62/782,912, filed Dec. 20, 2018, the disclosure of each of which is incorporated by reference herein in its entirety.

›SEQUENCE LISTING · 1 of 77

This application incorporates by reference a Sequence Listing submitted with this application as a text format, entitled 14233-010-228_SEQ_LISTING.txt, created on Dec. 4, 2019 having a size of 185,980 bytes.

1. FIELD

Provided herein are anti-Fn14 antibodies and pharmaceutical compositions, methods, and uses thereof.

2. BACKGROUND

Fn14 is a 15 kDa cell surface receptor that is a member of the TNF Receptor Superfamily (TNFRSF12A) and was initially identified as a protein with increased expression in cells stimulated with Fibroblast growth factor I or II (see Meighan-Mantha, R. L., et al., 1999, J. Biol. Chem. 274(46):33166-76; Feng, S.L., et al., 2000, Am. J. Pathol. 156(4):1253-61; Wiley, S. R., et al., 2001 Immunity 15(5):837-46). It was later discovered that TWEAK (TNFSF12) was a ligand for this receptor (Wiley, S. R., et al., 2001 Immunity 15(5):837-46) and is the only known ligand to date. TWEAK is able to induce multiple effects on cells expressing Fn14, including apoptosis (Wiley, S. R., et al., 1995 Immunity 3(6):673-82; Chicheportiche, Y., et al., 1997, J. Biol. Chem. 272(51):32401-10), angiogenesis (Lynch, C. N., et al., 1999, J. Biol. Chem. 274(13):8455-9; Ho, D. H., et al., 2004 Cancer Res. 64(24):8968-72), proliferation (Chen, H. N., et al., 2012, Mol. Biol. Rep. 39(8):8231-41), inflammatory mediator release (reviewed in Campbell, S., et al., 2004, Front Biosci. 9:2273-84) and upregulation of fibrotic mediators (Chen, H. N., et al., 2012, Mol. Biol. Rep. 39(8):8231-41; Son, A., et al., 2013 Mucosal Immunol. 6(6):1131-42; Zheng, L., et al., 2017, Pediatr. Surg. Int. 33(5):593-599).

In normal tissues Fn14 is expressed at very low to negligible levels, however, upon tissue injury, Fn14 is upregulated. Fn14 expression can be induced in multiple cell types including epithelial cells, endothelial cells, myofibroblasts, keratinocytes, chondrocytes, adipocytes, mesangial cells, mesenchymal stem cells and stellate cells. TWEAK is expressed by a variety of cell types including macrophages and dendritic cells and can be present both in a soluble or membrane-bound form (Nakayama, M., et al., 2002, J. Immunol. 168(2):734-43). The normal function of the TWEAK-Fn14 interaction is to facilitate tissue and wound repair, however, in situations where constitutive inflammation or tissue injury occurs, the pathway may become dysregulated, resulting in increased inflammation and development of fibrosis.

In vivo studies using mouse models of inflammation or fibrosis have identified a role for the Fn14-TWEAK pathway including kidney function in lupus nephritis (Xia, Y., et al., 2015, J. Am. Soc. Nephrol. 26(5):1053-70), chronic kidney disease (Gomez, I. G., et al., 2016, J. Am. Soc. Nephrol. 27(12):3639-3652), inflammatory bowel disease (Dohi, T., et al., 2009, Gastroenterology 136(3):912-23), chronic liver fibrosis (Wilhelm, A., et al., 2016, J. Pathol. 239(1):109-21), cancer-induced cachexia (Johnston, A. J., et al., 2015, Cell 162(6):1365-78), and muscle atrophy (Dogra, C., et al., 2016, J. Biol. Chem. 281(15):10327-36; Dogra, C., et al., 2007, FASEB J. 21(8):1857-69; Mittal, A., et al., 2010, Am. J. Pathol. 177(4):1732-42; Yadava, R. S., et al., 2015, Hum. Mol. Genet. 24(7):2035-48; Yadava, R. S., et al., 2016, PLoS One, 11(2):e0150192).

In a nephrotoxic serum nephritis model of kidney disease, Fn14 knockout (KO) mice and wild-type (WT) mice treated with a neutralizing anti-TWEAK mAb (clone P5G9) had significantly reduced proteinuria and renal histopathology compared to isotype control treated WT mice (Xia, Y., et al., 2012, Clin. Immunol. 145(2):108-21). There have also been several reports demonstrating that TWEAK and Fn14 are increased in models of unilateral ureteral obstruction (UUO). TWEAK KO mice had reduced renal fibrosis in this model and overexpression of TWEAK in mice with no underlying kidney disease induced kidney inflammation and fibrosis (Sanchez-Nino, M. D., et al., 2013, Biochim. Biophys. Acta 1832(12):2232-43). Fn14 KO mice were protected from kidney fibrosis, inflammation and vascular instability as compared to WT mice in a UUO model (Gomez, I. G., et al., 2016, J. Am. Soc. Nephrol. 27(12):3639-3652). Additionally, delivery of neutralizing anti-TWEAK mAbs to mice prone to chronic kidney disease (Alport's mice) blocked progression of kidney disease and organ dysfunction compared to isotype control treated mice (Gomez, I. G., et al., 2016, J. Am. Soc. Nephrol. 27(12):3639-3652). Taken together, these results indicate a role for TWEAK-Fn14 in both acute and chronic kidney diseases.

This pathway is also reported to be important in a variety of autoimmune mouse models. In a model of chronic graft-versus-host disease modeling Lupus erythematosus, Fn14 KO mice or WT mice treated with neutralizing anti-TWEAK mAbs, had significantly less kidney disease, kidney IgG deposition, inflammatory mediators and inflammatory cell infiltration into the kidney versus untreated WT mice (Zhao, Z., et al., 2007, J. Immunol. 179(11):7949-58). In a collagen-induced arthritis (CIA) model of rheumatoid arthritis, neutralizing anti-TWEAK mAbs significantly ameliorated paw swelling, synovial hyperplasia and infiltration of inflammatory cell and pro-inflammatory cytokine induction (Perper, S. J., et al., 2006, J. Immunol. 177(4):2610-20). Fn14-Fc was able to reduce clinical and histological scores of arthritis in a spontaneous model of autoimmune arthritis (Park, J.S., et al., 2017, Histol. Histopathol. 32(5):481-490). Fn14 KO mice had significantly attenuated skin disease versus WT mice in an MRL/lpr spontaneous lupus model (Doerner, J. L., et al., 2015, J. Invest. Dermatol. 135(8):1986-95).

Additionally, there is evidence for involvement of the TWEAK-Fn14 pathway in numerous human diseases. Many instances of this are in the area of autoimmune diseases, and examples include positive staining for both Fn14 and TWEAK in synovial tissues of RA patients (van Kuijk, A. W., et al., 2010, Ann. Rheum. Dis. 69(1):301-4), high expression of TWEAK and Fn14 in dermal vessel walls of skin lesions of urticarial vasculitis patients (Li, M., et al., 2013, J. Dermatol. 40(11):891-5) and lesions of patients with discoid cutaneous lupus (Liu, Y., et al., 2017, Front Immunol. 8:651) versus non-lesioned or healthy donor skin biopsies. The TWEAK-Fn14 pathway is also involved in various fibrotic kidney diseases including IgA nephropathy (Sasaki, Y., et al., 2015, BMC Nephrol. 16:27) and proteinuric kidney disease (Sanchez-Nino, M. D., et al., 2013, Biochim. Biophys. Acta, 1832(12):2232-43) and muscle wasting diseases including myotonic dystrophy 1(Sidler D., et al., 2017, Nature Communications 8: 15395; Claus M., et al., 2018, Am. J. Transplant 18: 1636; Yadava, R. S., et al., 2015, Hum. Mol. Genet. 24(7):2035-48; Yadava, R.S., et al., 2016, PLoS One 11(2):e0150192; Sydow, J. F., et al., 2014, PLoS One, 9(6): el 00736).

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Thus, there is a need in the art of an anti-Fn14 mAb with strong antagonist activity and no or minimal agonist activity, which would be beneficial in reducing inflammation and fibrosis in diseases where the TWEAK-Fn14 pathway is activated.

3. SUMMARY

In one aspect, provided herein is an antibody or antigen binding fragment thereof that binds to Fn14, wherein the antibody or antigen binding fragment thereof is an antagonist of Fn14, and wherein

(a) the antibody or antigen binding fragment thereof is not an agonist of Fn14; (b) the antibody or antigen binding fragment thereof binds human, cynomolgus macaque, rat and mouse Fn14; and/or (c) the antibody or antigen binding fragment thereof binds subdomain 1 comprising amino acid 30-50 of human Fn14 having an amino acid sequence of SEQ ID NO: 2.

In some embodiments, the antibody or antigen binding fragment thereof attenuates TWEAK induced signaling pathway and/or attenuates the binding of TWEAK to Fn14.

In some embodiments, the antibody or antigen binding fragment thereof attenuates TWEAK induced chemokine expression, wherein the chemokine is optionally selected from a group consisting IL-8, CCL2, IL-1(3, TGF(3, CCL21, TNFα, IL-6, CXCL1, CCL3, CCL4, CXCL12, CCLS, CXCL10, and CXCL16.

In some embodiments, the antibody or antigen binding fragment thereof reduces TWEAK induced IL-8 secretion.

In some embodiments, the antibody or antigen binding fragment thereof attenuates TWEAK induced ICAM-1 expression. In some embodiments, the antibody or antigen binding fragment thereof attenuates TWEAK induced apoptosis.

In some embodiments, the antibody or antigen binding fragment thereof is not an agonist of Fn14.

In some embodiments, the antibody or antigen binding fragment thereof does not induce IL-8 secretion in the absence of TWEAK.

In some embodiments, the antibody or antigen binding fragment thereof binds human, cynomolgus macaque, rat and mouse Fn14.

In some embodiments, the antibody or antigen binding fragment thereof binds subdomain 1 comprising amino acid 30-50 of human Fn14 having an amino acid sequence of SEQ ID NO: 2.

In some embodiments, the antibody or antigen binding fragment thereof interacts with one or more amino acid residues in the amino acid sequence of APGTAPCSRGSSWSADLDKCM (SEQ ID NO: 182).

In some embodiments, the antibody or antigen binding fragment thereof interacts with one or more amino acid residues of human Fn14 protein selected from a group consisting of Gly32, Thr33, Ala34, Pro35, Trp42, Ala44, Asp45, Leu46, Asp47, Lys48, Cys49, or a combination thereof. In a specific embodiment, the antibody or antigen binding fragment thereof interacts with all the amino acid residues Gly32, Thr33, Ala34, Pro35, Trp42, Ala44, Asp45, Leu46, Asp47, Lys48, and Cys49 of human Fn14 protein.

In some embodiments, the antibody or antigen binding fragment binds human Fn14 with a K D of less than 100 nM as determined by a surface plasmon resonance method, wherein the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 100 nM as determined by a surface plasmon resonance method, wherein the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 100 nM as determined by a surface plasmon resonance method, and wherein the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 100 nM as determined by a surface plasmon resonance method.

In some embodiments, the antibody or antigen binding fragment binds human Fn14 with a K D of less than 10 nM as determined by a surface plasmon resonance method, wherein the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 10 nM as determined by a surface plasmon resonance method, wherein the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 10 nM as determined by a surface plasmon resonance method, and wherein the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 10 nM as determined by a surface plasmon resonance method.

In some embodiments, the antibody or antigen binding fragment binds human Fn14 with a K D of less than 1 nM as determined by a surface plasmon resonance method, wherein the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 1 nM as determined by a surface plasmon resonance method, wherein the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 1 nM as determined by a surface plasmon resonance method, and wherein the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 1 nM as determined by a surface plasmon resonance method.

In some embodiments, the antigen binding fragment is selected from a group consisting of a Fab, a Fab′, a F(ab′)2, a Fv, a scFv, a dsFv, a diabody, a triabody, a tetrabody, and a multispecific antibody formed from antibody fragments.

In some embodiments, the antibody is a mouse antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a fully human antibody or antigen binding fragment thereof.

In some embodiments, the antibody or antigen binding fragment is a humanized antibody or antigen binding fragment thereof.

In some embodiments, the antibody or antigen binding fragment thereof is recombinantly produced.

In some embodiments, the antibody or antigen binding fragment thereof is produced by a hybridoma.

In some embodiments, the antibody or antigen binding fragment thereof comprises:

(a) a heavy chain variable region (VH) comprising (i) VH complementarity determining region 1 (CDR H1) comprising an amino acid sequence of GYX 1 FX 2 DYNMEI (SEQ ID NO: 184), wherein X 1 is T, I or R, and X 2 is T or Q; (ii) VH complementarity determining region 2 (CDR H2) comprising an amino acid sequence of X 3 INPX 4 NX 5 X 6 TNYNX 9 KFXioG (SEQ ID NO: 257), wherein X 3 is Y or S, X 4 is N or R, X 5 is A or G, X 6 is G or W, X 9 is Q or D, and X 10 is K, G, H, or D; and (iii) VH complementarity determining region 3 (CDR H3) comprising an amino acid sequence of SGWFTY (SEQ ID NO: 121); and (b) a light chain variable region (VL) comprising (i) VL complementarity determining region 1 (CDR L1) comprising an amino acid sequence of KSSQSLLNSAGKTYLN (SEQ ID NO: 127); (ii) VL complementarity determining region 2 (CDR L2) comprising an amino acid sequence of LVX 11 Xi2LDX 13 (SEQ ID NO: 258), wherein X 11 is S or A, X 12 is Q or E, and X 13 is S or D; and (iii) VL complementarity determining region 3 (CDR L3) comprising an amino acid sequence of WQGTX 7 X 8 PWT (SEQ ID NO: 186), wherein X 7 is H or F, and X 8 is F or Y.

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In some embodiments, the antibody or antigen binding fragment thereof comprises:

(a) a heavy chain variable region (VH) comprising (i) VH complementarity determining region 1 (CDR H1) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 119 and SEQ ID NO: 122; (ii) VH complementarity determining region 2 (CDR H2) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 120, SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 149; SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, and SEQ ID NO: 250; and (iii) VH complementarity determining region 3 (CDR H3) comprising an amino acid sequence of SEQ ID NO: 121, and (b) a light chain variable region (VL) comprising (i) VL complementarity determining region 1 (CDR L1) comprising an amino acid sequence of SEQ ID NO: 127; (ii) VL complementarity determining region 2 (CDR L2) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 128, SEQ ID NO: 254, SEQ ID NO: 255, and SEQ ID NO: 256; and (iii) VL complementarity determining region 3 (CDR L3) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 129, SEQ ID NO: 130, and SEQ ID NO: 131.

In some embodiments, the antibody or antigen binding fragment thereof comprises:

(a) a heavy chain variable region (VH) comprising (i) VH complementarity determining region 1 (CDR H1) comprising an amino acid sequence of GYX 1 FX 2 DYNIVIII (SEQ ID NO: 184), wherein X 1 is T, I or R, and X 2 is T or Q; (ii) VH complementarity determining region 2 (CDR H2) comprising an amino acid sequence of X 3 INPX 4 NX 5 X 6 TNYNQKFKG (SEQ ID NO: 185), wherein X 3 is Y or S, X 4 is N or R; X 5 is A or G, and X 6 is G or W; and (iii) VH complementarity determining region 3 (CDR H3) comprising an amino acid sequence of SGWFTY (SEQ ID NO: 121); and (b) a light chain variable region (VL) comprising (i) VL complementarity determining region 1 (CDR L1) comprising an amino acid sequence of KSSQSLLNSAGKTYLN (SEQ ID NO: 127); (ii) VL complementarity determining region 2 (CDR L2) comprising an amino acid sequence of LVSQLDS (SEQ ID NO: 128); and (iii) VL complementarity determining region 3 (CDR L3) comprising an amino acid sequence of WQGTX 7 X 8 PWT (SEQ ID NO: 186), wherein X 7 is H or F, and X 8 is F or Y.

In some embodiments, the antibody or antigen binding fragment thereof comprises:

(a) a heavy chain variable region (VH) comprising (i) VH complementarity determining region 1 (CDR H1) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 119 and SEQ ID NO: 122; (ii) VH complementarity determining region 2 (CDR H2) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 120, SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, and SEQ ID NO: 149; and (iii) VH complementarity determining region 3 (CDR H3) comprising an amino acid sequence of SEQ ID NO: 121, and (b) a light chain variable region (VL) comprising (i) VL complementarity determining region 1 (CDR L1) comprising an amino acid sequence of SEQ ID NO: 127; (ii) VL complementarity determining region 2 (CDR L2) comprising an amino acid sequence of SEQ ID NO: 128; and (iii) VL complementarity determining region 3 (CDR L3) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 129, SEQ ID NO: 130, and SEQ ID NO: 131.

In some embodiments, the antibody or antigen binding fragment thereof comprises a CDR H1 of SEQ ID NO: 119, a CDR H2 of SEQ ID NO: 120, a CDR H3 of SEQ ID NO: 121, a CDR L1 of SEQ ID NO: 127, a CDR L2 of SEQ ID NO: 128, and a CDR L3 of SEQ ID NO: 129.

In some embodiments, the antibody or antigen binding fragment thereof comprises a CDR H1 of SEQ ID NO: 119, a CDR H2 of SEQ ID NO: 123, a CDR H3 of SEQ ID NO: 121, a CDR L1 of SEQ ID NO: 127, a CDR L2 of SEQ ID NO: 128, and a CDR L3 of SEQ ID NO: 129.

In some embodiments, the antibody or antigen binding fragment thereof comprises a CDR H1 of SEQ ID NO: 119, a CDR H2 of SEQ ID NO: 124, a CDR H3 of SEQ ID NO: 121, a CDR L1 of SEQ ID NO: 127, a CDR L2 of SEQ ID NO: 128, and a CDR L3 of SEQ ID NO: 129.

In some embodiments, the antibody or antigen binding fragment thereof comprises a CDR H1 of SEQ ID NO: 119, a CDR H2 of SEQ ID NO: 125, a CDR H3 of SEQ ID NO: 121, a CDR L1 of SEQ ID NO: 127, a CDR L2 of SEQ ID NO: 128, and a CDR L3 of SEQ ID NO: 129.

In some embodiments, the antibody or antigen binding fragment thereof comprises a CDR H1 of SEQ ID NO: 119, a CDR H2 of SEQ ID NO: 126, a CDR H3 of SEQ ID NO: 121, a CDR L1 of SEQ ID NO: 127, a CDR L2 of SEQ ID NO: 128, and a CDR L3 of SEQ ID NO: 129.

In some embodiments, the antibody or antigen binding fragment thereof comprises a CDR H1 of SEQ ID NO: 119, a CDR H2 of SEQ ID NO: 149, a CDR H3 of SEQ ID NO: 121, a CDR L1 of SEQ ID NO: 127, a CDR L2 of SEQ ID NO: 128, and a CDR L3 of SEQ ID NO: 129.

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In some embodiments, the antibody or antigen binding fragment thereof comprises a CDR H1 of SEQ ID NO: 122, a CDR H2 of SEQ ID NO: 120, a CDR H3 of SEQ ID NO: 121, a CDR L1 of SEQ ID NO: 127, a CDR L2 of SEQ ID NO: 128, and a CDR L3 of SEQ ID NO: 129.

In some embodiments, the antibody or antigen binding fragment thereof comprises a CDR H1 of SEQ ID NO: 122, a CDR H2 of SEQ ID NO: 123, a CDR H3 of SEQ ID NO: 121, a CDR L1 of SEQ ID NO: 127, a CDR L2 of SEQ ID NO: 128, and a CDR L3 of SEQ ID NO: 129.

In some embodiments, the antibody or antigen binding fragment thereof comprises a CDR H1 of SEQ ID NO: 122, a CDR H2 of SEQ ID NO: 124, a CDR H3 of SEQ ID NO: 121, a CDR L1 of SEQ ID NO: 127, a CDR L2 of SEQ ID NO: 128, and a CDR L3 of SEQ ID NO: 129.

In some embodiments, the antibody or antigen binding fragment thereof comprises a CDR H1 of SEQ ID NO: 122, a CDR H2 of SEQ ID NO: 125, a CDR H3 of SEQ ID NO: 121, a CDR L1 of SEQ ID NO: 127, a CDR L2 of SEQ ID NO: 128, and a CDR L3 of SEQ ID NO: 129.

In some embodiments, the antibody or antigen binding fragment thereof comprises a CDR H1 of SEQ ID NO: 122, a CDR H2 of SEQ ID NO: 126, a CDR H3 of SEQ ID NO: 121, a CDR L1 of SEQ ID NO: 127, a CDR L2 of SEQ ID NO: 128, and a CDR L3 of SEQ ID NO: 129.

In some embodiments, the antibody or antigen binding fragment thereof comprises a CDR H1 of SEQ ID NO: 122, a CDR H2 of SEQ ID NO: 149, a CDR H3 of SEQ ID NO: 121, a CDR L1 of SEQ ID NO: 127, a CDR L2 of SEQ ID NO: 128, and a CDR L3 of SEQ ID NO: 129.

In some embodiments, the antibody or antigen binding fragment thereof comprises a CDR H1 of SEQ ID NO: 122, a CDR H2 of SEQ ID NO: 249, a CDR H3 of SEQ ID NO: 121, a CDR L1 of SEQ ID NO: 127, a CDR L2 of SEQ ID NO: 128, and a CDR L3 of SEQ ID NO: 130.

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In some embodiments, the antibody or antigen binding fragment thereof comprises:

(a) a heavy chain variable region (VH) comprising (i) VH complementarity determining region 1 (CDR H1) comprising an amino acid sequence of GYIFQDYNMH (SEQ ID NO: 122); (ii) VH complementarity determining region 2 (CDR H2) comprising an amino acid sequence of X 3 INPRNX 5 X 6 TNYNX 9 KFXioG (SEQ ID NO: 259), wherein X 3 is Y or S, X 5 is A or G; X 6 is G or W, X 9 is Q or D, and X 10 is K, G, H, or D; and (iii) VH complementarity determining region 3 (CDR H3) comprising an amino acid sequence of SGWFTY (SEQ ID NO: 121); and (b) a light chain variable region (VL) comprising (i) VL complementarity determining region 1 (CDR L1) comprising an amino acid sequence of KSSQSLLNSAGKTYLN (SEQ ID NO: 127); (ii) VL complementarity determining region 2 (CDR L2) comprising an amino acid sequence of LVXiiXi2LDXi3 (SEQ ID NO: 258), wherein X 11 is S or A, X 12 is Q or E, and X 13 is S or D; and (iii) VL complementarity determining region 3 (CDR L3) comprising an amino acid sequence of WQGTX 7 YPWT (SEQ ID NO: 188), wherein X 7 is H or F.

In some embodiments, the antibody or antigen binding fragment thereof comprises:

(a) a heavy chain variable region (VH) comprising (i) VH complementarity determining region 1 (CDR H1) comprising an amino acid sequence of SEQ ID NO: 122; (ii) VH complementarity determining region 2 (CDR H2) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 126, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, SEQ ID NO: 250; and (iii) VH complementarity determining region 3 (CDR H3) comprising an amino acid sequence of SEQ ID NO: 121; and (b) a light chain variable region (VL) comprising (i) VL complementarity determining region 1 (CDR L1) comprising an amino acid sequence of SEQ ID NO: 127; (ii) VL complementarity determining region 2 (CDR L2) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 128, SEQ ID NO: 254, SEQ ID NO: 255, and SEQ ID NO: 256; and (iii) VL complementarity determining region 3 (CDR L3) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 130 and SEQ ID NO: 131.

In some embodiments, the antibody or antigen binding fragment thereof comprises:

(a) a heavy chain variable region (VH) comprising (i) VH complementarity determining region 1 (CDR H1) comprising an amino acid sequence of GYIFQDYNMH (SEQ ID NO: 122); (ii) VH complementarity determining region 2 (CDR H2) comprising an amino acid sequence of X 3 INPRNX 5 X 6 TNYNQKFKG (SEQ ID NO: 187), wherein X 3 is Y or S, X 5 is A or G; and X 6 is G or W; and (iii) VH complementarity determining region 3 (CDR H3) comprising an amino acid sequence of SGWFTY (SEQ ID NO: 121); and (b) a light chain variable region (VL) comprising (i) VL complementarity determining region 1 (CDR L1) comprising an amino acid sequence of KSSQSLLNSAGKTYLN (SEQ ID NO: 127); (ii) VL complementarity determining region 2 (CDR L2) comprising an amino acid sequence of LVSQLDS (SEQ ID NO: 128); and (iii) VL complementarity determining region 3 (CDR L3) comprising an amino acid sequence of WQGTX 7 YPWT (SEQ ID NO: 188), wherein X 7 is H or F.

In some embodiments, the antibody or antigen binding fragment thereof comprises:

(a) a heavy chain variable region (VH) comprising (i) VH complementarity determining region 1 (CDR H1) comprising an amino acid sequence of SEQ ID NO: 122; (ii) VH complementarity determining region 2 (CDR H2) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 123, SEQ ID NO: 124, and SEQ ID NO: 126; and (iii) VH complementarity determining region 3 (CDR H3) comprising an amino acid sequence of SEQ ID NO: 121, and (b) a light chain variable region (VL) comprising (i) VL complementarity determining region 1 (CDR L1) comprising an amino acid sequence of SEQ ID NO: 127; (ii) VL complementarity determining region 2 (CDR L2) comprising an amino acid sequence of SEQ ID NO: 128; and (iii) VL complementarity determining region 3 (CDR L3) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 130 and SEQ ID NO: 131.

In some embodiments, the antibody or antigen binding fragment thereof comprises: a VH comprising CDR H1, CDR H2 and CDR H3 comprising amino acid sequences of the CDR H1, CDR H2 and CDR H3 contained in a VH amino acid sequence selected from a group consisting of SEQ ID NO: 179, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 106, SEQ ID NO: 108, SEQ ID NO: 110, SEQ ID NO: 203, SEQ ID NO: 205, SEQ ID NO: 207, SEQ ID NO: 209, SEQ ID NO: 211, SEQ ID NO: 213, SEQ ID NO: 215, SEQ ID NO: 217, SEQ ID NO: 219, SEQ ID NO: 221, SEQ ID NO: 223, SEQ ID NO: 225, and SEQ ID NO: 227; and a VL comprising CDR L1, CDR L2 and CDR L3 comprising amino acid sequences of the CDR L1, CDR L2 and CDR L3 contained in a VL amino acid sequence selected from a group consisting of SEQ ID NO: 92, SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 98, SEQ ID NO: 100, SEQ ID NO: 102, SEQ ID NO: 104, SEQ ID NO: 112, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 233, SEQ ID NO: 235, and SEQ ID NO: 237.

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In some embodiments, the CDR H1, CDR H2, CDR H3, CDR L1, CDR L2, and CDR L3 are determined according to Kabat numbering, AbM numbering, Chothia numbering, Contact numbering, or IMGT numbering, or a combination thereof.

In some embodiments, the CDR H1, CDR H2, CDR H3, CDR L1, CDR L2, and CDR L3 are determined according to Kabat numbering and Chothia numbering.

In some embodiments, the CDR H1, CDR H2, CDR H3, CDR L1, CDR L2, and CDR L3 are determined according to Kabat numbering.

In some embodiments, the CDR H1, CDR H2, CDR H3, CDR L1, CDR L2, and CDR L3 are determined according to AbM numbering.

In some embodiments, the CDR H1, CDR H2, CDR H3, CDR L1, CDR L2, and CDR L3 are determined according to Chothia numbering.

In some embodiments, the CDR H1, CDR H2, CDR H3, CDR L1, CDR L2, and CDR L3 are determined according to Contact numbering.

In some embodiments, the CDR H1, CDR H2, CDR H3, CDR L1, CDR L2, and CDR L3 are determined according to IMGT numbering.

In some embodiments, the antibody or antigen binding fragment thereof further comprises:

(i) VH framework 1 (FR1) comprising an amino acid sequence of SEQ ID NO: 132; (ii) VH framework 2 (FR2) comprising an amino acid sequence of SEQ ID NO: 138; (iii) VH framework 3 (FR3) comprising an amino acid sequence of SEQ ID NO: 145; (iv) VH framework 4 (FR4) comprising an amino acid sequence of SEQ ID NO: 158; (v) VL FR1 comprising an amino acid sequence of SEQ ID NO: 160; (vi) VL FR2 comprising an amino acid sequence of SEQ ID NO: 163; (vii) VL FR3 comprising an amino acid sequence of SEQ ID NO: 169; and (viii) VL FR4 comprising an amino acid sequence of SEQ ID NO: 171.

In some embodiments, the antibody or antigen binding fragment thereof further comprises:

(i) VH FR1 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 133, SEQ ID NO: 134, SEQ ID NO: 135, SEQ ID NO: 136, SEQ ID NO: 137, SEQ ID NO: 238, and SEQ ID NO: 239; (ii) VH FR2 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 141, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 144, SEQ ID NO: 173, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245 and SEQ ID NO: 246; (iii) VH FR3 comprising an amino acid sequence selected from a group consisting SEQ ID NO: 146, SEQ ID NO: 147, SEQ ID NO: 148, SEQ ID NO: 150, SEQ ID NO: 151, SEQ ID NO: 152, SEQ ID NO: 153, SEQ ID NO: 154, SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 157, SEQ ID NO: 174, and SEQ ID NO: 251; (iv) VH FR4 comprising an amino acid sequence of SEQ ID NO: 159; (v) VL FR1 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 161 and SEQ ID NO: 162; (vi) VL FR2 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 163, SEQ ID NO: 164, SEQ ID NO: 165, SEQ ID NO: 166, SEQ ID NO: 167, SEQ ID NO: 168, SEQ ID NO: 252, and SEQ ID NO: 253; (vii) VL FR3 comprising an amino acid sequence of SEQ ID NO: 170; and (viii) VL FR4 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 171 and SEQ ID NO: 172.

In some embodiments, the antibody or antigen binding fragment thereof comprises: a VH comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 35, SEQ ID NO: 50, SEQ ID NO: 54, SEQ ID NO: 60, SEQ ID NO: 56, and SEQ ID NO: 181; and a VL comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 40, SEQ ID NO: 52, and SEQ ID NO: 58.

In some embodiments, the antibody or antigen binding fragment thereof comprises: a VH comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 179, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 106, SEQ ID NO: 108, and SEQ ID NO: 110, SEQ ID NO: 203, SEQ ID NO: 205, SEQ ID NO: 207, SEQ ID NO: 209, SEQ ID NO: 211, SEQ ID NO: 213, SEQ ID NO: 215, SEQ ID NO: 217, SEQ ID NO: 219, SEQ ID NO: 221, SEQ ID NO: 223, SEQ ID NO: 225, and SEQ ID NO: 227; and a VL comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 92, SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 98, SEQ ID NO: 100, SEQ ID NO: 102, SEQ ID NO: 104, SEQ ID NO: 112, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 233, SEQ ID NO: 235, and SEQ ID NO: 237.

In some embodiments, the antibody or antigen binding fragment thereof is conjugated to an agent.

In some embodiments, the agent is selected from a group consisting of a cytotoxic agent, a radioisotope, a metal chelator, an enzyme, a fluorescent compound, a bioluminescent compound, a chemiluminescent compound, and a peptide.

In another aspect, provided herein is a pharmaceutical composition comprising the antibody or antigen binding fragment provided herein and a pharmaceutically acceptable excipient.

In yet another aspect, provided herein is a method of treating and/or preventing a disease or disorder comprising administering a therapeutically effective amount of the antibody or antigen binding fragment thereof provided herein to a subject.

In some embodiments, the disease or disorder is a disease or disorder mediated, induced and/or prolonged by Fn14 and/or TWEAK.

In some embodiments, the disease or disorder is selected from a group consisting of autoimmune and/or inflammatory diseases affecting joints, skin, kidney, liver, intestine, heart, lung, or muscle, wherein optionally the disease or disorder is selected from a group consisting of rheumatoid arthritis, bullous pemphigoid, discoid cutaneous lupus, urticarial vasculitis, Henoch-Schonlein Purpura, IgA nephrophathy, atopic dermatitis (atopic eczema), psoriasis (psoriasis vulgaris), seborrheic eczema, asthma, proteinuric kidney disease, liver disease, lupus nephritis, polymyositis, dermatomyositis, calcineurin inhibitor induced nephrotoxicity, myotonic dystrophy, cardiac dysfunction and failure, Alport syndrome, ulcerative colitis, Crohn's disease, cutaneous vasculitis, cachexia, and inflammatory bowel disease, and wherein optionally the disease or disorder is related to fibrosis and optionally selected from a group consisting tissue fibrosis, idiopathic pulmonary fibrosis, interstitial lung disease, scleroderma (systemic sclerosis), cancer, cancer-associated cachexia, muscle wasting, keloids, inclusion body myositis, and tissue remodeling.

›SEQUENCE LISTING · 7 of 77

In some embodiments, the subject is a human subject.

In another aspect, provided herein is a polynucleotide comprising nucleotide sequences encoding the antibody or antigen binding fragment thereof provided herein or a portion thereof.

In some embodiments, the polynucleotide comprises a polynucleotide sequence selected from a group consisting of the polynucleotide sequences listed in Table 36 and Table 37.

In another aspect, provided herein is a vector comprising the polynucleotide provided herein.

In another aspect, provided herein is a cell comprising the polynucleotide provided herein. In some embodiments, the cell provided herein comprises the vector provided herein.

In yet another aspect, provided herein is a method of making an antibody or antigen binding fragment thereof comprising culturing the cell provided herein to express the antibody or antigen binding fragment thereof.

4. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts binding of anti-Fn14 hybridoma supernatants to human and mouse Fn14 transfected cells. A series of histograms obtained by flow cytometry demonstrate the reactivity of hybridoma supernatants (KO41c, KO42d and KO43b) to 293F cells transfected with a human (dark gray lines) or mouse (black lines) Fn14 expression vector or empty vector (light gray lines). Hybridoma supernatant binding was detected using anti-mouse IgG PE.

FIGS. 2 A and 2 B depict binding of purified anti-Fn14 monoclonal antibodies to endogenously expressed Fn14. Å series of histograms obtained by flow cytometry demonstrate the reactivity of purified anti-Fn14 antibodies to HK2 cells ( FIG. 2 A ) and NRK-52E cells ( FIG. 2 B ). Primary antibodies were used at a concentration of 1 μg/mL and binding was detected using anti-mouse IgG PE.

FIGS. 3 A and 3 B depict that Fn14 antagonist monoclonal antibodies neutralize TWEAK-induced CCL2 expression. HK2 ( FIG. 3 A ) and NRK-52E ( FIG. 3 B ) cells were incubated with the indicated purified anti-Fn14 mAbs (10 μg/mL) and then rhTWEAK was added to the cells (30 ng/mL). After 6 hours, RNA was collected from the cells and CCL2 expression was quantified by real-time PCR. Gene expression was normalized to GAPDH. The graphs show relative CCL2 expression level of experimental samples compared to control samples.

FIGS. 4 A and 4 B depict that Fn14 antagonist monoclonal antibodies neutralize TWEAK-induced NEKB activity. NRK52E-A1 5/Luc cells (NFκB-Luciferase reporter) were stimulated with hTWEAK or hTNFα (0-100 ng/mL) ( FIG. 4 A ) or stimulated with hTWEAK (5 ng/mL) ( FIG. 4 B ) in the presence of purified anti-Fn14 mAbs or control mouse IgG1 antibody (0-50 ng/mL). NFκB-Luciferase activity is reported as Luc [cps].

FIG. 5 depicts sensorgrams of individual anti-Fn14 Fab binding to human or cynomolgus macaque Fn14 by Biacore.

FIG. 6 A depicts sensorgrams of individual anti-Fn14 Fab binding to mouse Fn14 by Biacore.

FIG. 6 B depicts sensorgrams of six humanized mAbs binding to human Fn14 by Biacore. Recombinant human Fn14 was injected with increasing concentrations in a single cycle, the surface not being regenerated between injections. Anti-human Fc specific antibodies were immobilized on a CMS sensor chip (cat# BR100012, GE Healthcare Life Sciences, Pittsburgh, Pennsylvania) by an amine coupling chemistry. Humanized anti-Fn14 antibodies were captured at approximately 200 RUs, followed by injections of increasing concentrations of recombinant human Fn14 protein. The association time was 120 seconds, and the final dissociation time was 900 seconds.

FIG. 7 depicts differential binding of anti-Fn14 monoclonal antibodies to subdomains of Fn14. All values were compared to a control sample (isotype antibodies, mIgG1 and mIgG2b).

FIG. 8 depicts crystal structure of Fn14-41c-His Fab complex. Part A shows cartoon representation of Fn14-41c-His Fab complex with transparent molecular surface for 41c Fab molecule. VH (variable region of heavy chain), CH (constant region of heavy chain), VL (variable region of light chain), CL (constant region of light chain), and N-terminal and C-terminal ends of heavy chain and light chain are also indicated. Fn14 molecule is shown in black cartoon and 41 c-His Fab as gray cartoon with transparent molecular surface. Part B shows representative 2Fo-Fc electron density map contoured at 1σ, for residues from Fn14 that are in contact with light chain loops L1 and L2 of 41c Fab molecule. Part C shows specific interacting residues in the interface between Fn14 (left side) and the loops of 41c-His Fab molecule heavy chain region (right side). Part D shows interaction of Fn14 (left side) with the light chain region of 41c-His Fab (right side). All interacting residues from both Fn14 and 41c-His Fab are shown as sticks and the hydrogen bonds are shown as black dashed lines. All figures were made in PyMOL.

FIG. 9 depicts crystal structure of Fn14-R35B9-His Fab complex. Part A shows superposition of Fn14-41c-His Fab (parental) complex with Fn14-R35B9-His Fab complex. The regions that show conformational change between parental and R35B9 version of Fab are highlighted. The N-terminal, C-terminal ends and variable and constant regions of both heavy chain and light chain are marked. Part B shows structural changes in the H1 loop region of Fab. The residues of H1 loop region of 41c-His Fab are shown as lines and are labeled with single-letter amino acid code, while the residues of R35B9-His Fab are shown as sticks and marked with three-letter amino acid code. Part C shows interactions between CDRs of heavy chain region of R35B9-His Fab (right) and Fn14 (left). Part D shows specific interactions between the CDR1 region of light chain R35B9-His Fab (right) and Fn14 (left). All interacting residues are shown as sticks with transparent cartoon and black dashed lines indicate hydrogen bonds.

FIG. 10 depicts that Fn14 mAb R35B9 potently antagonizes TWEAK-induced IL-8 secretion from HRMC. HRMC were incubated with 1.04 nM anti-Fn14 or isotype control mAbs for 30 minutes at 37° C. and then rhTWEAK was added to the wells at 250 ng/mL for 24 h. Supernatants were harvested and tested for IL-8 using an IL-8 ELISA kit. Data were analyzed using Student's t-test, comparing IL-8 reduction by R35B9 to that of 41c, ITEM-4 and CRCBT-06-002. 41c vs. R35B9 p<0.0001, ITEM-4 vs. R35B9 p<0.0001, CRCBT-06-002 vs. R35B9 p<0.0001.

›SEQUENCE LISTING · 8 of 77

FIGS. 11 A, 11 B and 11 C depict that Fn14 mAb R35B9 potently antagonizes TWEAK-induced IL-8 secretion from A375 cells. A375 cells were incubated with 16.7, 66.7, or 266.7 nM anti-Fn14 or isotype control mAbs for 30 minutes and then rhTWEAK was added to the wells at 300 ng/mL for 24 h. Supernatants were harvested and tested for IL-8 using an IL-8 ELISA kit. Data were analyzed using one-way ANOVA. The results for 16.7, 66.7, or 266.7 nM anti-Fn14 or isotype control mAbs are shown in FIG. 11 A , FIG. 11 B and FIG. 11 C , respectively. Statistical results for IL-8 reduction by R35B9 compared to that of 41c, ITEM-4 and CRCBT-06-002 are as follows: mAb concentration at 16.7 nM: 41c vs. R35B9 p<0.0001, ITEM-4 vs. R35B9 p<0.0001, CRCBT-06-002 vs. R35B9 p<0.0001 ( FIG. 11 A ); mAb concentration at 66.7 nM: 41c vs. R35B9 p<0.0001, ITEM-4 vs. R35B9 p<0.01, CRCBT-06-002 vs. R35B9 not significant (ns) ( FIG. 11 B ), mAb concentration at 266.7 nM: 41c vs. R35B9 p<0.0001, others are not significant (ns) in this assay.

FIG. 12 depicts that Fn14 mAb R35B9 optimized clones potently antagonize TWEAK-induced IL-8 secretion from HRMC. HRMC were incubated with 0.8325 nM anti-Fn14 or isotype control mAbs for 30 minutes and then rhTWEAK was added to the wells at 250 ng/mL for 24 h. Supernatants were harvested and tested for IL-8 using an IL-8 ELISA kit. Data were analyzed using Student's t-test, comparing IL-8 reduction (ITEM-4 vs. R35B9 p<0.01, ITEM-4 vs. A437/A290 p <0.05, ITEM-4 vs. A448/A290 p <0.05, ITEM-4 vs. A448/A439 p <0.05, CRCBT-06-002 vs. R35B9 p <0.001, CRCBT-06-002 vs A437/A290 p <0.01, CRCBT-06-002 vs A448/A290 p <0.01, CRCBT-06-002 vs A448/A439 p <0.01).

FIG. 13 depicts that humanized Fn14 mAbs potently antagonize TWEAK-induced IL-8 secretion from HRMC. HRMC were incubated with 0.833 nM humanized anti-Fn14 antibodies, mouse/human chimeric CRCBT-06-002 (mu/huCRCBT), ITEM-4 or isotype control mAbs for 30 minutes at 37° C. and then rhTWEAK was added to the wells at 250 ng/mL for 24 h. Supernatants were harvested and tested for IL-8 using an IL-8 ELISA kit. Each of the humanized anti-Fn14 clones was able to block TWEAK-induced IL-8 secretion significantly better than mu/huCRCBT-06-002 and ITEM-4. Data were analyzed using unpaired t test, comparing IL-8 reduction (ITEM-4 vs. A512/A468 p <0.001, ITEM-4 vs. A515/A518 p <0.01, ITEM-4 vs. A553/A472 p <0.01, mu/huCRCBT-06-002 vs A512/A468 p <0.01, mu/huCRCBT-06-002 vs A515/A518 p <0.01, mu/huCRCBT-06-002 vs A553/A472 p <0.05).

FIG. 14 depicts that Fn14 antagonist mAb R35B9 does not agonize Fn14. HRMC were incubated with 250 ng/mL rhTWEAK (positive control) or media alone (negative control) and anti-Fn14 or isotype control mAbs for 24 hours. Supernatants were harvested and tested for IL-8 using an IL-8 ELISA kit. Dotted lines represent average supernatant IL-8 levels from unstimulated cells (media alone) after 24 hours in culture (bottom line: 1,775 μg/mL) and cells stimulated with 250 ng/mL rhTWEAK for 24 hours (upper line: 12,271 μg/mL).

FIG. 15 depicts that Fn14 antagonist mAb R35B9 does not agonize Fn14. A375 cells were incubated with 300 ng/mL rhTWEAK, anti-Fn14 or isotype control mAbs for 24 h. Supernatants were harvested and tested for IL-8 using an IL-8 ELISA kit. Dotted line represents average supernatant IL-8 levels from cells stimulated with 300 ng/mL rhTWEAK for 24 hours (67,725 μg/mL).

FIGS. 16 A and 16 B depict that Fn14 antagonist mAb R35B9 optimized clones do not agonize Fn14. HRMC were incubated with 250 ng/mL rhTWEAK (positive control), media alone (negative control), anti-Fn14 or isotype control mAbs for 24 hours. Supernatants were harvested and tested for IL-8 using an IL-8 ELISA kit. Dotted line represents average supernatant IL-8 levels from unstimulated cells (media alone) after 24 hours in culture (A: 972.4 μg/mL) or (B: 494 μg/mL).

FIG. 17 depicts that humanized Fn14 antagonist mAbs do not agonize Fn14. HRMC were incubated with 250 ng/mL rhTWEAK (positive control) or media alone (negative control) and humanized anti-Fn14, mouse/human chimeric CRCBT-06-002 (mu/huCRCBT), ITEM-4 or isotype control mAbs for 24 h. Supernatants were harvested and tested for IL-8 using an IL-8 ELISA kit. Dotted lines represent average supernatant IL-8 levels from unstimulated cells (media alone) after 24 hours in culture (2,008 μg/mL) and cells stimulated with 250 ng/mL rhTWEAK for 24 hours (23,851 μg/mL).

FIG. 18 depicts that Fn14 mAb R35B9 potently antagonizes TWEAK-induced ICAM expression. HRMC were incubated with media alone or with anti-Fn14 or isotype control mAbs (0.1 ng/mL) for 30 minutes and then media with or without rhTWEAK (250 ng/mL) was added to the cells for 24 hours. Cells were dissociated with trypsin and stained for surface ICAM-1 expression. Intensity of surface ICAM-1 expression was measured using a flow cytometer (BD Biosciences Fortessa), gated on live cells. Data were analyzed using one-way ANOVA with multiple comparisons, statistical results for R35B9 vs. 41c, CRCBT-06-002 and ITEM-4 are shown (0.1 ng/mL mAb: R35B9 vs. 41c p≤0.0001, R35B9 vs. CRCBT-06-002 p≤0.0001, R35B9 vs. ITEM-4 p≤0.0001).

FIG. 19 depicts that anti-Fn14 mAb R35B9 optimized clones potently antagonize TWEAK-induced ICAM-1 expression. HRMC were incubated with media alone or with anti-Fn14 or isotype control mAbs at various concentrations for 30 minutes and then media with or without rhTWEAK (250 ng/mL) was added to the cells for 24 h. Cells were dissociated with trypsin and stained for surface ICAM-1 expression. Mean Fluorescence Intensity (MFI) of surface ICAM-1 expression was measured using a flow cytometer (BD Biosciences Fortessa), gated on live cells. Dotted lines represent the MFI of ICAM-1 on unstimulated cells (media alone) after 24 hours in culture (MFI 4,013) and cells stimulated with 250 ng/mL rhTWEAK for 24 hours (MFI 35,608).

FIG. 20 depicts VH and VL amino acid sequences of exemplary mouse Fn14 antagonist monoclonal antibodies.

FIG. 21 depicts VL amino acid sequences broken down into FR and CDR sequences of exemplary mouse and humanized antibodies provided herein.

›SEQUENCE LISTING · 9 of 77

FIG. 22 depicts VH amino acid sequences broken down into FR and CDR sequences of exemplary mouse and humanized antibodies provided herein.

FIG. 23 depicts CDRs of exemplary humanized R35B9 series antibodies.

FIG. 24 depicts the VH and VL amino acid sequences of exemplary humanized antibodies provided herein.

FIG. 25 depicts that humanized anti-Fn14 antibodies blocked TWEAK binding to Fn14 expressed on cells. HRMC were incubated with individual antibodies at various concentrations for 30 minutes followed by incubation with recombinant human TWEAK (250 ng/mL) for 45 minutes. Binding of TWEAK to HRMC cells was detected with biotinylated goat-anti-human TWEAK followed by streptavidin-PE. Stained cells were acquired on a Fortessa. % TWEAK blocking was calculated using the following formula: 100-(Geometric mean fluorescence intensity of sample—Geometric mean fluorescence intensity of cells without TWEAK)/(Geometric mean fluorescence intensity-TWEAK alone with no antibody—Geometric mean fluorescence intensity of cells without TWEAK)*100.

FIGS. 26 A, 26 B and 26 C depict the results showing further engineered humanized Fn14 mAbs antagonize TWEAK-induced IL-8 secretion from HRMC. HRMC were incubated with anti-Fn14 or isotype control mAbs at various concentrations ranging from 6.67 to 0.2085 nM for 30 minutes at 37° C. and then TWEAK was added to the wells at 250 ng/mL for 24 hours. Supernatants were harvested and tested for IL-8 using an IL-8 ELISA kit. Data was plotted in Prism. A512/A468 is the original humanized antibody, and the rest are further engineered clones from A512/A468. Anti-DNP huIgG4 null is the isotype control for Fn14 mAbs. Top dotted line: IL-8 production from TWEAK stimulated cells. Bottom dotted line: IL-8 production from unstimulated cells.

FIGS. 27 A and 27 B depict the results showing that further engineered humanized Fn14 mAbs are more potent antagonists of TWEAK-induced IL-8 secretion from HRMC than the CRCBT-06-002 Fn14 mAb. HRMC were incubated with various concentrations of anti-Fn14 antibodies, mouse/human chimeric CRCBT-06-002 (mu/huCRCBT), or isotype control mAb for 30 minutes at 37° C. and then TWEAK was added to the wells at 250 ng/mL for 24 hours. Supernatants were harvested and tested for IL-8 using an IL-8 ELISA kit. FIG. 27 A shows data at the antibody concentration of 1.67 nM (0.25 μg/mL). FIG. 27 B shows each of the anti-Fn14 clones was able to block TWEAK-induced IL-8 secretion more potently than mu/huCRCBT with lower IC50. Top dotted line: IL-8 production from TWEAK stimulated cells. Bottom dotted line: IL-8 production from unstimulated cells. Data were analyzed using unpaired t test, comparing IL-8 levels between individual anti-Fn14 mAb treated and mu/huCRCBT treated wells. ***: p <0.001, **: p <0.01. A512/A468: original humanized anti-Fn14 mAb, and the rest are further engineered clones of A512/A468. Anti-DNP huIgG4 null: isotype control.

FIGS. 28 A, 28 B and 28 C show that further engineered humanized mAbs do not agonize Fn14. HRMC were incubated with anti-Fn14 or isotype control mAbs at various concentrations ranging from 266.67 to 0.26 nM for 24 hours. Supernatants were harvested and tested for IL-8 using an IL-8 ELISA kit. Dotted line represents average supernatant IL-8 levels from unstimulated cells (media alone) after 24 hours. Anti-DNP huIgG4 null is the isotype control for Fn14 mAbs. ITEM-4 is a commercial mAb that exhibits agonist activity and used as a positive control. mIgG2b is the isotype control antibody for ITEM 4. Dotted line: IL-8 production from unstimulated cells.

FIG. 29 A shows that humanized Fn14 mAbs potently antagonize TWEAK-induced RANTES secretion from HaCaT cells. HaCaT cells were incubated with anti-Fn14 or isotype control mAbs at various concentrations ranging from 0.156 to 10 μg/mL for 30 minutes at 37° C. and then TWEAK was added to the wells at 100 ng/mL for 48 hours. Supernatants were harvested and tested for RANTES using a RANTES ELISA kit. Data was plotted in Prism. Anti-DNP huIgG4 null is the isotype control for Fn14 mAbs. Top dotted line: cells treated with TWEAK only with no antibody added. Bottom dotted line: cells not stimulated with TWEAK.

FIG. 29 B shows that humanized Fn14 mAbs potently antagonize TWEAK-induced RANTES secretion from human primary adult keratinocytes. Primary keratinocytes were incubated with anti-Fn14 or isotype control mAbs at various concentrations ranging from 0.156 to 10 μg/mL for 30 minutes at 37° C. and then TWEAK was added to the wells at 100 ng/mL for 48 hours. Supernatants were harvested and tested for RANTES using a RANTES ELISA kit. Data was plotted in Prism. Anti-DNP huIgG4 null is the isotype control for Fn14 mAbs. Top dotted line: cells treated with TWEAK only with no antibody added. RANTES levels from cells that were not stimulated with TWEAK were below the limit of detection (no OD values obtained).

FIG. 30 shows humanized Fn14 mAbs potently antagonize TWEAK-induced apoptosis of human primary neonatal epidermal keratinocytes. Human primary epidermal keratinocytes were incubated with anti-Fn14 or isotype control mAbs (1.5 μg/mL), TWEAK (100 ng/mL), TNFα (10 ng/mL) or the combination of TWEAK and TNFα for 72 hours. Cells were collected, stained with Annexin V and 7-AAD, and analyzed on an LSR Fortessa. Annexin V+/7-AAD+cells: late apoptotic cells, Annexin V+/7-AAD- cells: early apoptotic cells.

FIG. 31 A shows humanized Fn14 mAbs potently antagonize TWEAK-induced ICAM-1 upregulation on HaCaT cells. HaCaT cells were incubated with anti-Fn14 or isotype control mAbs at various concentrations ranging from 0.156 to 10 μg/mL for 30 minutes at 37° C. and then TWEAK was added to the wells at 100 ng/mL for 48 hours. Cells were collected, stained with anti-ICAM-1, and analyzed on an LSR Fortessa. Anti-DNP huIgG4 null is the isotype control for Fn14 mAbs. Top dotted line: cells treated with TWEAK only with no antibody added. Bottom dotted line: cells not treated with TWEAK.

FIG. 31 B shows humanized Fn14 mAb A512/A468 potently antagonizes TWEAK-induced ICAM-1 upregulation on human primary neonatal keratinocytes. Primary neonatal keratinocytes were incubated with anti-Fn14 or isotype control mAbs at 1 μg/mL for 30 minutes at 37° C. and then TWEAK was added to the wells at 100 ng/mL for 48 hours. Cells were collected, stained with anti-ICAM-1, and analyzed on an LSR Fortessa. Anti-DNP huIgG4 null is the isotype control for Fn14 mAbs.

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FIG. 32 shows humanized Fn14 mAbs potently antagonize TWEAK-induced IL-6 secretion from human primary dermal fibroblasts. Human primary dermal fibroblasts were incubated with anti-Fn14 or isotype control mAbs at various concentrations ranging from 0.156 to 10 μg/mL for 30 minutes at 37° C. and then TWEAK was added to the wells at 100 ng/mL for 48 hours. Supernatants were harvested and tested for IL-6 using an IL-6 ELISA kit. Data was plotted in Prism. Anti-DNP huIgG4 null is the isotype control for Fn14 mAbs. Top dotted line: cells treated with TWEAK only with no antibody added. Bottom dotted line: cells not stimulated with TWEAK.

5. DETAILED DESCRIPTION

The present disclosure provides novel Fn14 antibodies, pharmaceutical compositions comprising same, and uses thereof. More specifically, the present disclosure provides antibodies antagonizing Fn14, pharmaceutical compositions comprising these antibodies, and uses thereof.

Anti-Fn14 mAbs have been described (see, e.g., Johnston, A. J., et al., 2015 Cell 162(6):1365-78; Sanchez-Nino, M. D., et al., Biochim Biophys Acta, 2013, 1832(12):2232-43; Zhao, Z., et al., J Immunol, 2007, 179(11):7949-58). For example, Johnston et. al., generated several anti-Fn14 mAbs (001, 002 and 004) and characterized them both in vitro and in vivo (Johnston, A. J., et al., Cell, 2015, 162(6):1365-78; Johnston, A. J. et al., Curr Opin Clin Nutr Metab Care, 2016, 19(4):316-8). In vitro characterization of the monoclonal antibodies revealed that all three clones are antagonist/non-agonist in an NFκB reporter assay, but only 001 and 002 were able to block TWEAK-induced cell death in a cytotoxicity assay. However, 001 was shown to be an agonist, non-antagonist in an A375 cell—IL-8 secretion assay (US2013/0273036 A1). They identified that 001, 002 and 004 bind to an epitope termed Subdomain 2 (Fn14 AA 51-70) but not Subdomain 1 (Fn14 AA 31-50). Subdomains 1 and 2 comprise the majority of the extracellular domain of Fn14 (Johnston, A. J., et al., Cell, 2015, 162(6):1365-78).

Provided herein in certain embodiments are novel anti-Fn14 antagonist, non-agonist, monoclonal antibodies, which bind human, cynomolgus macaque, rat and mouse Fn14 with high affinities. As shown in Section 6 below, the antibodies provided herein robustly neutralize TWEAK-induced inflammatory and pro-fibrotic signaling through Fn14. This is demonstrated with in vitro functional assays utilizing an NF-κB reporter cell line, A375 melanoma cell line, a human kidney derived cell line and primary human renal mesangial cells to measure TWEAK binding, TWEAK-induced chemokine expression, IL-8 secretion and ICAM-1 expression. No agonist activity was induced by these antibodies in the absence of TWEAK in any of these assays. The binding epitope was mapped to Subdomain 1 of the extracellular region of Fn14 and further defined by co-crystallization studies of Fn14 with two anti-Fn14 Fabs.

The antibodies provided herein provide numerous advantages as demonstrated by the data shown in Section 6 below. For example, previously reported antagonist Fn14 antibody—clone ITEM-4 (Nakayama, M., et al., J lmmunol, 2003, 170(1):341-8) demonstrates agonist activity (Nakayama, M., et al., J Immunol, 2003, 170(1):341-8; Potrovita, I., et al., J Neurosci, 2004, 24(38):8237-44) as well as antagonist properties (Nakayama, M., et al., J lmmunol, 2003, 170(1):341-8; Potrovita, I., et al., J Neurosci, 2004, 24(38):8237-44; Justo, P., et al., Kidney Int, 2006, 70(10):1750-8).

5.1 Definitions

Techniques and procedures described or referenced herein include those that are generally well understood and/or commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual (3d ed. 2001); Current Protocols in Molecular Biology (Ausubel et al. eds., 2003); Therapeutic Monoclonal Antibodies: From Bench to Clinic (An ed. 2009); Monoclonal Antibodies: Methods and Protocols (Albitar ed. 2010); and Antibody Engineering Vols 1 and 2 (Kontermann and DUbel eds., 2d ed. 2010).

Unless otherwise defined herein, technical and scientific terms used in the present description have the meanings that are commonly understood by those of ordinary skill in the art. For purposes of interpreting this specification, the following description of terms will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event that any description of a term set forth conflicts with any document incorporated herein by reference, the description of the term set forth below shall control.

The term “antibody,” “immunoglobulin,” or “Ig” is used interchangeably herein, and is used in the broadest sense and specifically covers, for example, monoclonal antibodies (including agonist, antagonist, neutralizing antibodies, full length or intact monoclonal antibodies), antibody compositions with polyepitopic or monoepitopic specificity, polyclonal or monovalent antibodies, multivalent antibodies, multispecific antibodies (e.g., bispecific antibodies so long as they exhibit the desired biological activity), formed from at least two intact antibodies, single chain antibodies, and fragments thereof, as described below. An antibody can be human, humanized, chimeric and/or affinity matured, as well as an antibody from other species, for example, mouse and rabbit, etc. The term “antibody” is intended to include a polypeptide product of B cells within the immunoglobulin class of polypeptides that is able to bind to a specific molecular antigen and is composed of two identical pairs of polypeptide chains, wherein each pair has one heavy chain (about 50-70 kDa) and one light chain (about 25 kDa), each amino-terminal portion of each chain includes a variable region of about 100 to about 130 or more amino acids, and each carboxy-terminal portion of each chain includes a constant region. See, e.g., Antibody Engineering (Borrebaeck ed., 2d ed. 1995); and Kuby, Immunology (3d ed. 1997). In specific embodiments, the specific molecular antigen can be bound by an antibody provided herein, including a polypeptide or an epitope. Antibodies also include, but are not limited to, synthetic antibodies, recombinantly produced antibodies, camelized antibodies or their humanized variants, intrabodies, anti-idiotypic (anti-Id) antibodies, and functional fragments (e.g., antigen-binding fragments) of any of the above, which refers to a portion of an antibody heavy or light chain polypeptide that retains some or all of the binding activity of the antibody from which the fragment was derived. Non-limiting examples of functional fragments (e.g., antigen binding fragments) include single-chain Fvs (scFv) (e.g., including monospecific, bispecific, etc.), Fab fragments, F(ab′) fragments, F(ab)2 fragments, F(ab′)2 fragments, disulfide-linked Fvs (dsFv), Fd fragments, Fv fragments, diabody, triabody, tetrabody, and minibody. In particular, antibodies provided herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, for example, antigen-binding domains or molecules that contain an antigen-binding site that binds to an antigen (e.g., one or more CDRs of an antibody). Such antibody fragments can be found in, for example, Harlow and Lane, Antibodies: A Laboratory Manual (1989); Mol. Biology and Biotechnology: A Comprehensive Desk Reference (Myers ed., 1995); Huston et al., 1993, Cell Biophysics 22:189-224; Phickthun and Skerra, 1989, Meth. Enzymol. 178:497-515; and Day, Advanced Immunochemistry (2d ed. 1990). The antibodies provided herein can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) of immunoglobulin molecule. Antibodies may be agonistic antibodies or antagonistic antibodies.

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An “antigen” is a structure to which an antibody can selectively bind. A target antigen may be a polypeptide, carbohydrate, nucleic acid, lipid, hapten, or other naturally occurring or synthetic compound. In some embodiments, the target antigen is a polypeptide. In certain embodiments, an antigen is associated with a cell, for example, is present on or in a cell.

An “antagonist” antibody is one, which inhibits or reduces biological activity of the antigen it binds. For example, antagonist antibodies may substantially or completely inhibit the biological activity of the antigen. As used herein, an “antagonist” or “inhibitor” of Fn14 refers to a molecule that is capable of inhibiting or otherwise decreasing one or more of the biological activities of Fn14. For example, in some embodiments, an antagonist of Fn14 (e.g., an antagonistic antibody provided herein) may act by inhibiting or otherwise decreasing the activation and/or cell signaling pathways of the cell expressing Fn14, thereby inhibiting or limiting an Fn14 mediated biological activity of the cell relative to the Fn14-mediated biological activity in the absence of antagonist.

An antagonist antibody as used herein is in contrast with an “agonist” antibody, which is an antibody that triggers a response, e.g., one that mimics at least one of the functional activities of a polypeptide of interest (e.g., Fn14). An agonist antibody includes an antibody that is a ligand mimetic, for example, wherein a ligand binds to a cell surface receptor and the binding induces cell signaling or activities via an intercellular cell signaling pathway and wherein the antibody induces a similar cell signaling or activation. An agonist of Fn14 refers to a molecule that is capable of activating or otherwise increasing one or more of the biological activities of Fn14, such as on a cell that is responsive to TWEAK through its expression of an Fn14. In some embodiments, an agonist of Fn14 may, for example, act by increasing the activity of Fn14, leading to an increase in the activation and/or cell signaling pathways of a cell expressing Fn14, thereby increasing an Fn14-mediated biological activity of the cell relative to the Fn14-mediated biological activity in the absence of agonist.

An “intact” antibody is one comprising an antigen binding site as well as a CL and at least heavy chain constant regions, CH1, CH2 and CH3. The constant regions may include human constant regions or amino acid sequence variants thereof. In certain embodiments, an intact antibody has one or more effector functions.

The terms “antigen binding fragment,” “antigen binding domain,” “antigen binding region,” and similar terms refer to that portion of an antibody, which comprises the amino acid residues that interact with an antigen and confer on the binding agent its specificity and affinity for the antigen (e.g., the CDRs). “Antigen binding fragment” as used herein include “antibody fragment,” which comprise a portion of an intact antibody, such as the antigen binding or variable region of the intact antibody. Examples of antibody fragments include, without limitation, Fab, Fab′, F(ab′)2, and Fv fragments; diabodies and di-diabodies (see, e.g., Holliger et al., Proc Natl Acad Sci 1993, 90:6444-48; Lu et al., J Biol Chem, 2005, 280:19665-72; Hudson et al., Nat Med, 2003, 9:129-34; WO 93/11161; and U.S. Pat. Nos. 5,837,242 and 6,492,123); single-chain antibody molecules (see, e.g., U.S. Pat. Nos. 4,946,778; 5,260,203; 5,482,858; and 5,476,786); dual variable domain antibodies (see, e.g., U.S. Pat. No. 7,612,181); single variable domain antibodies (sdAbs) (see, e.g., Woolven et al., Immunogenetics, 1999, 50: 98-101; and Streltsov et al., Proc Natl Acad Sci USA. 2004, 101:12444-49); and multispecific antibodies formed from antibody fragments.

The terms “binds” or “binding” refer to an interaction between molecules including, for example, to form a complex. Interactions can be, for example, non-covalent interactions including hydrogen bonds, ionic bonds, hydrophobic interactions, and/or van der Waals interactions. A complex can also include the binding of two or more molecules held together by covalent or non-covalent bonds, interactions, or forces. The strength of the total non-covalent interactions between a single antigen-binding site on an antibody and a single epitope of a target molecule, such as an antigen, is the affinity of the antibody or functional fragment for that epitope. The ratio of dissociation rate (k off ) to association rate (k on ) of a binding molecule (e.g., an antibody) to a monovalent antigen (k off /k on ) is the dissociation constant K D , which is inversely related to affinity. The lower the K D value, the higher the affinity of the antibody. The value of K D varies for different complexes of antibody and antigen and depends on both k on and k off . The dissociation constant K D for an antibody provided herein can be determined using any method provided herein or any other method well known to those skilled in the art. The affinity at one binding site does not always reflect the true strength of the interaction between an antibody and an antigen. When complex antigens containing multiple, repeating antigenic determinants, such as a polyvalent antigen, come in contact with antibodies containing multiple binding sites, the interaction of antibody with antigen at one site will increase the probability of a reaction at a second site. The strength of such multiple interactions between a multivalent antibody and antigen is called the avidity.

In connection with the antibody or antigen binding fragment described herein, the terms such as “bind to,” “that specifically bind to,” and analogous terms are also used interchangeably herein and refer to antibodies of antigen binding domains that specifically bind to an antigen, such as a polypeptide. An antibody or antigen binding domain that binds to or specifically binds to an antigen may be cross-reactive with related antigens. In certain embodiments, an antibody or antigen binding domain that binds to or specifically binds to an antigen does not cross-react with other antigens. An antibody or antigen binding domain that binds to or specifically binds to an antigen can be identified, for example, by immunoassays, Octet®, Biacore®, or other techniques known to those of skill in the art. In some embodiments, an antibody or antigen binding domain binds to or specifically binds to an antigen when it binds to an antigen with higher affinity than to any cross-reactive antigen as determined using experimental techniques, such as radioimmunoassays (RIA) and enzyme linked immunosorbent assays (ELISAs). Typically a specific or selective reaction will be at least twice background signal or noise and may be more than 10 times background. See, e.g., Fundamental Immunology 332-36 (Paul ed., 2d ed. 1989) for a discussion regarding binding specificity. In certain embodiments, the extent of binding of an antibody or antigen binding domain to a “non-target” protein is less than about 10% of the binding of the antibody or antigen binding domain to its particular target antigen, for example, as determined by fluorescence activated cell sorting (FACS) analysis or RIA. With regard to terms such as “specific binding,” “specifically binds to,” or “is specific for” means binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target, for example, an excess of non-labeled target. In this case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by excess unlabeled target. An antibody or antigen binding domain that binds to an antigen includes one that is capable of binding the antigen with sufficient affinity such that the antibody or antigen binding fragment is useful, for example, as a diagnostic or therapeutic agent in targeting the antigen. In certain embodiments, an antibody or antigen binding domain that binds to an antigen has a dissociation constant (K D ) of less than or equal to 1000 nM, 800 nM, 500 nM, 250 nM, 100 nM, 50 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, or 0.1 nM. In certain embodiments, an antibody or antigen binding domain binds to an epitope of an antigen that is conserved among the antigen from different species (e.g., between human and cynomolgus macaque species).

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“Binding affinity” generally refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., a binding protein such as an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a binding molecule X for its binding partner Y can generally be represented by the dissociation constant (K D ). Affinity can be measured by common methods known in the art, including those described herein. Low-affinity antibodies generally bind antigen slowly and tend to dissociate readily, whereas high-affinity antibodies generally bind antigen faster and tend to remain bound longer. A variety of methods of measuring binding affinity are known in the art, any of which can be used for purposes of the present disclosure. Specific illustrative embodiments include the following. In one embodiment, the “K D ” or “K D value” may be measured by assays known in the art, for example by a binding assay. The K D may be measured in a RIA, for example, performed with the Fab version of an antibody of interest and its antigen (Chen et a.l., J. Mol Biol, 1999, 293:865-81). The K D or K D value may also be measured by using biolayer interferometry (BLI) or surface plasmon resonance (SPR) assays by Octet®, using, for example, an Octet®Red96 system, or by Biacore®, using, for example, a Biacore® 2000 or a Biacore® 3000. An “on-rate” or “rate of association” or “association rate” or “k on ,” may also be determined with the same biolayer interferometry (BLI) or surface plasmon resonance (SPR) techniques described above using, for example, the Octet®Red96, the Biacore® 2000, or the Biacore® 3000 system.

In certain embodiments, the antibodies or antigen binding fragments can comprise “chimeric” sequences in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (see U.S. Pat. No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81:6851-55).

In certain embodiments, the antibodies or antigen binding fragments can comprise portions of “humanized” forms of nonhuman (e.g., murine) antibodies that are chimeric antibodies that include human immunoglobulins (e.g., recipient antibody) in which the native CDR residues are replaced by residues from the corresponding CDR of a nonhuman species (e.g., donor antibody) such as mouse, rat, rabbit, or nonhuman primate having the desired specificity, affinity, and capacity. In some instances, one or more FR region residues of the human immunoglobulin are replaced by corresponding nonhuman residues. Furthermore, humanized antibodies can comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. A humanized antibody heavy or light chain can comprise substantially all of at least one or more variable regions, in which all or substantially all of the CDRs correspond to those of a nonhuman immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. In certain embodiments, the humanized antibody will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see, Jones et al., 1986, Nature 321:522-25; Riechmann et al., 1988, Nature 332:323-29; Presta, 1992, Curr. Op. Struct. Biol. 2:593-96; Carter et al., 1992, Proc. Natl. Acad. Sci. USA 89:4285-89; U.S. Pat. Nos. 6,800,738; 6,719,971; 6,639,055; 6,407,213; and 6,054,297.

In certain embodiments, the antibodies or antigen binding fragments can comprise portions of a “fully human antibody” or “human antibody,” wherein the terms are used interchangeably herein and refer to an antibody that comprises a human variable region and, for example, a human constant region. In specific embodiments, the terms refer to an antibody that comprises a variable region and constant region of human origin. “Fully human” antibodies, in certain embodiments, can also encompass antibodies which bind polypeptides and are encoded by nucleic acid sequences which are naturally occurring somatic variants of human germline immunoglobulin nucleic acid sequence. The term “fully human antibody” includes antibodies having variable and constant regions corresponding to human germline immunoglobulin sequences as described by Kabat et al. (See 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). A “human antibody” is one that possesses an amino acid sequence which corresponds to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage-display libraries (Hoogenboom and Winter, 1991, J. Mol. Biol. 227:381; Marks et al., 1991, J. Mol. Biol. 222:581) and yeast display libraries (Chao et al., 2006, Nature Protocols 1: 755-68). Also available for the preparation of human monoclonal antibodies are methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy 77 (1985); Boerner et al., 1991, J. Immunol. 147(1):86-95; and van Dijk and van de Winkel, 2001, Curr. Opin. Pharmacol. 5: 368-74. Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., mice (see, e.g., Jakobovits, 1995, Curr. Opin. Biotechnol. 6(5):561-66; Brtiggemann and Taussing, 1997, Curr. Opin. Biotechnol. 8(4):455-58; and U.S. Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE™ technology). See also, for example, Li et al., 2006, Proc. Natl. Acad. Sci. USA 103:3557-62 regarding human antibodies generated via a human B-cell hybridoma technology.

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In certain embodiments, the antibodies or antigen binding fragments can comprise portions of a “recombinant human antibody,” wherein the phrase includes human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell, antibodies isolated from a recombinant, combinatorial human antibody library, antibodies isolated from an animal (e.g., a mouse or cow) that is transgenic and/or transchromosomal for human immunoglobulin genes (see e.g., Taylor, L. D. et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies can have variable and constant regions derived from human germline immunoglobulin sequences (See Kabat, E. A. et al. (1991) Sequences of Proteins of Immunological Interest , Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242). In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.

In certain embodiments, the antibodies or antigen binding fragments can comprise a portion of a “monoclonal antibody,” wherein the term as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, e.g., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts, and each monoclonal antibody will typically recognize a single epitope on the antigen. In specific embodiments, a “monoclonal antibody,” as used herein, is an antibody produced by a single hybridoma or other cell. The term “monoclonal” is not limited to any particular method for making the antibody. For example, the monoclonal antibodies useful in the present disclosure may be prepared by the hybridoma methodology first described by Kohler et al., 1975, Nature 256:495, or may be made using recombinant DNA methods in bacterial or eukaryotic animal or plant cells (see, e.g., U.S. Pat. No. 4,816,567). The “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al., 1991, Nature 352:624-28 and Marks et al., 1991, J. Mol. Biol. 222:581-97, for example. Other methods for the preparation of clonal cell lines and of monoclonal antibodies expressed thereby are well known in the art. See, e.g., Short Protocols in Molecular Biology (Ausubel et al. eds., 5th ed. 2002).

A typical 4-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. In the case of IgGs, the 4-chain unit is generally about 150,000 daltons. Each L chain is linked to an H chain by one covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. Each H and L chain also has regularly spaced intrachain disulfide bridges. Each H chain has at the N-terminus, a variable domain (VH) followed by three constant domains (CH) for each of the a and y chains and four CH domains for p. and isotypes. Each L chain has at the N-terminus, a variable domain (VL) followed by a constant domain (CL) at its other end. The VL is aligned with the VH, and the CL is aligned with the first constant domain of the heavy chain (CH1). Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable domains. The pairing of a VH and VL together forms a single antigen-binding site. For the structure and properties of the different classes of antibodies, see, for example, Basic and Clinical Immunology 71 (Stites et al. eds., 8th ed. 1994); and Immunobiology (Janeway et al. eds., 5 th ed. 2001).

The term “Fab” or “Fab region” refers to an antibody region that binds to antigens. A conventional IgG usually comprises two Fab regions, each residing on one of the two arms of the Y-shaped IgG structure. Each Fab region is typically composed of one variable region and one constant region of each of the heavy and the light chain. More specifically, the variable region and the constant region of the heavy chain in a Fab region are VH and CH1 regions, and the variable region and the constant region of the light chain in a Fab region are VL and CL regions. The VH, CH1, VL, and CL in a Fab region can be arranged in various ways to confer an antigen binding capability according to the present disclosure. For example, VH and CH1 regions can be on one polypeptide, and VL and CL regions can be on a separate polypeptide, similarly to a Fab region of a conventional IgG. Alternatively, VH, CH1, VL and CL regions can all be on the same polypeptide and oriented in different orders as described in more detail the sections below.

The term “variable region,” “variable domain,” “V region,” or “V domain” refers to a portion of the light or heavy chains of an antibody that is generally located at the amino-terminal of the light or heavy chain and has a length of about 120 to 130 amino acids in the heavy chain and about 100 to 110 amino acids in the light chain, and are used in the binding and specificity of each particular antibody for its particular antigen. The variable region of the heavy chain may be referred to as “VH.” The variable region of the light chain may be referred to as “VL.” The term “variable” refers to the fact that certain segments of the variable regions differ extensively in sequence among antibodies. The V region mediates antigen binding and defines specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed across the 110-amino acid span of the variable regions. Instead, the V regions consist of less variable (e.g., relatively invariant) stretches called framework regions (FRs) of about 15-30 amino acids separated by shorter regions of greater variability (e.g., extreme variability) called “hypervariable regions” that are each about 9-12 amino acids long. The variable regions of heavy and light chains each comprise four FRs, largely adopting a f3 sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases form part of, the 0 sheet structure. The hypervariable regions in each chain are held together in close proximity by the FRs and, with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest (5th ed. 1991)). The constant regions are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC). The variable regions differ extensively in sequence between different antibodies. In specific embodiments, the variable region is a human variable region.

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The term “variable region residue numbering according to Kabat” or “amino acid position numbering as in Kabat”, and variations thereof, refer to the numbering system used for heavy chain variable regions or light chain variable regions of the compilation of antibodies in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, an FR or CDR of the variable domain. For example, a heavy chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 and three inserted residues (e.g., residues 82a, 82b, and 82c, etc. according to Kabat) after residue 82. The Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence. The Kabat numbering system is generally used when referring to a residue in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., supra). The “EU numbering system” or “EU index” is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra). The “EU index as in Kabat” refers to the residue numbering of the human IgG 1 EU antibody. Other numbering systems have been described, for example, by AbM, Chothia, Contact, IMGT, and AHon.

The term “heavy chain” when used in reference to an antibody refers to a polypeptide chain of about 50-70 kDa, wherein the amino-terminal portion includes a variable region of about 120 to 130 or more amino acids, and a carboxy-terminal portion includes a constant region. The constant region can be one of five distinct types, (e.g., isotypes) referred to as alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ), based on the amino acid sequence of the heavy chain constant region. The distinct heavy chains differ in size: α, δ, and γ contain approximately 450 amino acids, while μ and ε contain approximately 550 amino acids. When combined with a light chain, these distinct types of heavy chains give rise to five well known classes (e.g., isotypes) of antibodies, IgA, IgD, IgE, IgG, and IgM, respectively, including four subclasses of IgG, namely IgG1, IgG2, IgG3, and IgG4.

The term “light chain” when used in reference to an antibody refers to a polypeptide chain of about 25 kDa, wherein the amino-terminal portion includes a variable region of about 100 to about 110 or more amino acids, and a carboxy-terminal portion includes a constant region. The approximate length of a light chain is 211 to 217 amino acids. There are two distinct types, referred to as kappa (K) or lambda (X) based on the amino acid sequence of the constant domains.

As used herein, the terms “hypervariable region,” “HVR,” “Complementarity Determining Region,” and “CDR” are used interchangeably. A “CDR” refers to one of three hypervariable regions (H1, H2 or H3) within the non-framework region of the immunoglobulin (Ig or antibody) VH β-sheet framework, or one of three hypervariable regions (L1, L2 or L3) within the non-framework region of the antibody VL 0-sheet framework. Accordingly, CDRs are variable region sequences interspersed within the framework region sequences.

CDR regions are well known to those skilled in the art and have been defined by well-known numbering systems. For example, the Kabat Complementarity Determining Regions (CDRs) are based on sequence variability and are the most commonly used (see, e.g., Kabat et al., supra). Chothia refers instead to the location of the structural loops (see, e.g., Chothia and Lesk, 1987, J. Mol. Biol. 196:901-17). The end of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35 Å and H35B; if neither 35 Å nor 35B is present, the loop ends at 32; if only 35 Å is present, the loop ends at 33; if both 35 Å and 35B are present, the loop ends at 34). The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software (see, e.g., Antibody Engineering Vol. 2 (Kontermann and DUbel eds., 2d ed. 2010)). The “contact” hypervariable regions are based on an analysis of the available complex crystal structures. Another universal numbering system that has been developed and widely adopted is ImMunoGeneTics (IMGT) Information System® (Lafranc et al., 2003, Dev. Comp. Immunol. 27(1):55-77). IMGT is an integrated information system specializing in immunoglobulins (IG), T-cell receptors (TCR), and major histocompatibility complex (MHC) of human and other vertebrates. Herein, the CDRs are referred to in terms of both the amino acid sequence and the location within the light or heavy chain. As the “location” of the CDRs within the structure of the immunoglobulin variable domain is conserved between species and present in structures called loops, by using numbering systems that align variable domain sequences according to structural features, CDR and framework residues are readily identified. This information can be used in grafting and replacement of CDR residues from immunoglobulins of one species into an acceptor framework from, typically, a human antibody. An additional numbering system (AHon) has been developed by Honegger and Pluckthun, 2001, J. Mol. Biol. 309: 657-70. Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art (see, e.g., Kabat, supra; Chothia and Lesk, supra; Martin, supra; Lefranc et al., supra). The residues from each of these hypervariable regions or CDRs are noted below.

The boundaries of a given CDR may vary depending on the scheme used for identification. Thus, unless otherwise specified, the terms “CDR” and “complementary determining region” of a given antibody or region thereof, such as a variable region, as well as individual CDRs (e.g., CDR-H1, CDR-H2) of the antibody or region thereof, should be understood to encompass the complementary determining region as defined by any of the known schemes described herein above. In some instances, the scheme for identification of a particular CDR or CDRs is specified, such as the CDR as defined by the Kabat, Chothia, or Contact method. In other cases, the particular amino acid sequence of a CDR is given.

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Hypervariable regions may comprise “extended hypervariable regions” as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in the VL, and 26-35 or 26-35 Å (H1), 50-65 or 49-65 (H2), and 93-102, 94-102, or 95-102 (H3) in the VH.

The term “constant region” or “constant domain” refers to a carboxy terminal portion of the light and heavy chain which is not directly involved in binding of the antibody to antigen but exhibits various effector function, such as interaction with the Fc receptor. The term refers to the portion of an immunoglobulin molecule having a more conserved amino acid sequence relative to the other portion of the immunoglobulin, the variable region, which contains the antigen binding site. The constant region may contain the CH1, CH2, and CH3 regions of the heavy chain and the CL region of the light chain.

The term “framework” or “FR” refers to those variable region residues flanking the CDRs. FR residues are present, for example, in chimeric, humanized, human, domain antibodies, diabodies, linear antibodies, and bispecific antibodies. FR residues are those variable domain residues other than the hypervariable region residues or CDR residues. There are typically four FR regions in each of VH and VL regions. The FR regions in VH are VH FR1, VH FR2, VH FR3, and VH FR4 (or FR H1, FR H2, FR H3 and FR H4). The FR regions in VL are VL FR1, VL FR2, VL FR3 and VL FR4 (or FR L1, FR L2, FR L3 and FR L4).

The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain, including, for example, native sequence Fc regions, recombinant Fc regions, and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is often defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody. Accordingly, a composition of intact antibodies may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations having a mixture of antibodies with and without the K447 residue. A “functional Fc region” possesses an “effector function” of a native sequence Fc region. Exemplary “effector functions” include C1q binding; CDC; Fc receptor binding; ADCC; phagocytosis; downregulation of cell surface receptors (e.g., B cell receptor), etc. Such effector functions generally require the Fc region to be combined with a binding region or binding domain (e.g., an antibody variable region or domain) and can be assessed using various assays known to those skilled in the art. A “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification (e.g., substituting, addition, or deletion). In certain embodiments, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, for example, from about one to about ten amino acid substitutions, or from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of a parent polypeptide. The variant Fc region herein can possess at least about 80% homology with a native sequence Fc region and/or with an Fc region of a parent polypeptide, or at least about 90% homology therewith, for example, at least about 95% homology therewith.

The term “variant” when used in relation to an antigen or an antibody may refer to a peptide or polypeptide comprising one or more (such as, for example, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) amino acid sequence substitutions, deletions, and/or additions as compared to a native or unmodified sequence. For example, an Fn14 variant may result from one or more (such as, for example, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) changes to an amino acid sequence of a native Fn14. Also by way of example, a variant of an anti-Fn14 antibody may result from one or more (such as, for example, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) changes to an amino acid sequence of a native or previously unmodified anti-Fn14 antibody. Variants may be naturally occurring, such as allelic or splice variants, or may be artificially constructed. Polypeptide variants may be prepared from the corresponding nucleic acid molecules encoding the variants. In specific embodiments, the Fn14 variant or anti-Fn14 antibody variant at least retains Fn14 or anti-Fn14 antibody functional activity, respectively. In specific embodiments, an anti-Fn14 antibody variant binds Fn14 and/or is antagonistic to Fn14 activity. In certain embodiments, the variant is encoded by a single nucleotide polymorphism (SNP) variant of a nucleic acid molecule that encodes Fn14 or anti-Fn14 antibody VH or VL regions or subregions, such as one or more CDRs.

The term “identity” refers to a relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, as determined by aligning and comparing the sequences. “Percent (%) amino acid sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN (DNAStar, Inc.) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

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A “modification” of an amino acid residue/position refers to a change of a primary amino acid sequence as compared to a starting amino acid sequence, wherein the change results from a sequence alteration involving said amino acid residue/position. For example, typical modifications include substitution of the residue with another amino acid (e.g., a conservative or non-conservative substitution), insertion of one or more (e.g., generally fewer than 5, 4, or 3) amino acids adjacent to said residue/position, and/or deletion of said residue/position.

As used herein, an “epitope” is a term in the art and refers to a localized region of an antigen to which an antibody or antigen binding fragment can specifically bind. An epitope can be a linear epitope or a conformational, non-linear, or discontinuous epitope. In the case of a polypeptide antigen, for example, an epitope can be contiguous amino acids of the polypeptide (a “linear” epitope) or an epitope can comprise amino acids from two or more non-contiguous regions of the polypeptide (a “conformational,” “non-linear” or “discontinuous” epitope). It will be appreciated by one of skill in the art that, in general, a linear epitope may or may not be dependent on secondary, tertiary, or quaternary structure. For example, in some embodiments, an antibody binds to a group of amino acids regardless of whether they are folded in a natural three dimensional protein structure. In other embodiments, an antibody requires amino acid residues making up the epitope to exhibit a particular conformation (e.g., bend, twist, turn or fold) in order to recognize and bind the epitope.

The terms “polypeptide” and “peptide” and “protein” are used interchangeably herein and refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid, including but not limited to, unnatural amino acids, as well as other modifications known in the art. It is understood that, because the polypeptides of this disclosure may be based upon antibodies or other members of the immunoglobulin superfamily, in certain embodiments, a “polypeptide” can occur as a single chain or as two or more associated chains.

The term “vector” refers to a substance that is used to carry or include a nucleic acid sequence, including for example, a nucleic acid sequence encoding an antibody or antigen binding fragment as described herein, in order to introduce a nucleic acid sequence into a host cell. Vectors applicable for use include, for example, expression vectors, plasmids, phage vectors, viral vectors, episomes, and artificial chromosomes, which can include selection sequences or markers operable for stable integration into a host cell's chromosome. Additionally, the vectors can include one or more selectable marker genes and appropriate expression control sequences. Selectable marker genes that can be included, for example, provide resistance to antibiotics or toxins, complement auxotrophic deficiencies, or supply critical nutrients not in the culture media. Expression control sequences can include constitutive and inducible promoters, transcription enhancers, transcription terminators, and the like, which are well known in the art. When two or more nucleic acid molecules are to be co-expressed (e.g., both an antibody heavy and light chain or an antibody VH and VL), both nucleic acid molecules can be inserted, for example, into a single expression vector or in separate expression vectors. For single vector expression, the encoding nucleic acids can be operationally linked to one common expression control sequence or linked to different expression control sequences, such as one inducible promoter and one constitutive promoter. The introduction of nucleic acid molecules into a host cell can be confirmed using methods well known in the art. Such methods include, for example, nucleic acid analysis such as Northern blots or polymerase chain reaction (PCR) amplification of mRNA, immunoblotting for expression of gene products, or other suitable analytical methods to test the expression of an introduced nucleic acid sequence or its corresponding gene product. It is understood by those skilled in the art that the nucleic acid molecules are expressed in a sufficient amount to produce a desired product and it is further understood that expression levels can be optimized to obtain sufficient expression using methods well known in the art.

The term “host” as used herein refers to an animal, such as a mammal (e.g., a human).

The term “host cell” as used herein refers to a particular subject cell that may be transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell. Progeny of such a cell may not be identical to the parent cell transfected with the nucleic acid molecule due to mutations or environmental influences that may occur in succeeding generations or integration of the nucleic acid molecule into the host cell genome.

An “isolated nucleic acid” is a nucleic acid, for example, an RNA, DNA, or a mixed nucleic acids, which is substantially separated from other genome DNA sequences as well as proteins or complexes such as ribosomes and polymerases, which naturally accompany a native sequence. An “isolated” nucleic acid molecule is one which is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid molecule. Moreover, an “isolated” nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized. In a specific embodiment, one or more nucleic acid molecules encoding an antibody as described herein are isolated or purified. The term embraces nucleic acid sequences that have been removed from their naturally occurring environment, and includes recombinant or cloned DNA isolates and chemically synthesized analogues or analogues biologically synthesized by heterologous systems. A substantially pure molecule may include isolated forms of the molecule.

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“Polynucleotide” or “nucleic acid,” as used interchangeably herein, refers to polymers of nucleotides of any length and includes DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. “Oligonucleotide,” as used herein, refers to short, generally single-stranded, synthetic polynucleotides that are generally, but not necessarily, fewer than about 200 nucleotides in length. The terms “oligonucleotide” and “polynucleotide” are not mutually exclusive. The description above for polynucleotides is equally and fully applicable to oligonucleotides. A cell that produces an antibody or antigen binding fragment of the present disclosure may include a parent hybridoma cell, as well as bacterial and eukaryotic host cells into which nucleic acids encoding the antibodies have been introduced. Unless specified otherwise, the left-hand end of any single-stranded polynucleotide sequence disclosed herein is the 5′ end; the left-hand direction of double-stranded polynucleotide sequences is referred to as the 5′ direction. The direction of 5′ to 3′ addition of nascent RNA transcripts is referred to as the transcription direction; sequence regions on the DNA strand having the same sequence as the RNA transcript that are 5′ to the 5′ end of the RNA transcript are referred to as “upstream sequences”; sequence regions on the DNA strand having the same sequence as the RNA transcript that are 3′ to the 3′ end of the RNA transcript are referred to as “downstream sequences.”

The term “pharmaceutically acceptable” as used herein means being approved by a regulatory agency of the Federal or a state government, or listed in United States Pharmacopeia, European Pharmacopeia, or other generally recognized Pharmacopeia for use in animals, and more particularly in humans.

“Excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof. The term “excipient” can also refer to a diluent, adjuvant (e.g., Freunds' adjuvant (complete or incomplete) or vehicle.

In some embodiments, excipients are pharmaceutically acceptable excipients. Examples of pharmaceutically acceptable excipients include buffers, such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid; low molecular weight (e.g., fewer than about 10 amino acid residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt-forming counterions, such as sodium; and/or nonionic surfactants, such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™ Other examples of pharmaceutically acceptable excipients are described in Remington and Gennaro, Remington's Pharmaceutical Sciences (18th ed. 1990).

In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009. In some embodiments, pharmaceutically acceptable excipients are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. In some embodiments, a pharmaceutically acceptable excipient is an aqueous pH buffered solution.

In some embodiments, excipients are sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is an exemplary excipient when a composition (e.g., a pharmaceutical composition) is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions. An excipient can also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations, and the like. Oral compositions, including formulations, can include standard excipients such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.

Compositions, including pharmaceutical compounds, may contain an antibody or antigen binding fragment, for example, in isolated or purified form, together with a suitable amount of excipients.

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The term “effective amount” or “therapeutically effective amount” as used herein refers to the amount of an antibody or antigen binding fragment or pharmaceutical composition provided herein which is sufficient to result in the desired outcome.

The terms “subject” and “patient” may be used interchangeably. As used herein, in certain embodiments, a subject is a mammal, such as a non-primate (e.g., cow, pig, horse, cat, dog, rat, etc.) or a primate (e.g., monkey and human). In specific embodiments, the subject is a human. In one embodiment, the subject is a mammal, e.g., a human, diagnosed with a condition or disorder. In another embodiment, the subject is a mammal, e.g., a human, at risk of developing a condition or disorder.

“Administer” or “administration” refers to the act of injecting or otherwise physically delivering a substance as it exists outside the body into a patient, such as by mucosal, intradermal, intravenous, intramuscular, subcutaneous delivery, and/or any other method of physical delivery described herein or known in the art.

As used herein, the terms “treat,” “treatment” and “treating” refer to the reduction or amelioration of the progression, severity, and/or duration of a disease or condition resulting from the administration of one or more therapies. Treating may be determined by assessing whether there has been a decrease, alleviation and/or mitigation of one or more symptoms associated with the underlying disorder such that an improvement is observed with the patient, despite that the patient may still be afflicted with the underlying disorder. The term “treating” includes both managing and ameliorating the disease. The terms “manage,” “managing,” and “management” refer to the beneficial effects that a subject derives from a therapy which does not necessarily result in a cure of the disease.

The terms “prevent,” “preventing,” and “prevention” refer to reducing the likelihood of the onset (or recurrence) of a disease, disorder, condition, or associated symptom(s).

The terms “about” and “approximately” mean within 20%, within 15%, within 10%, within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2%, within 1%, or less of a given value or range.

As used in the present disclosure and claims, the singular forms “a”, “an” and “the” include plural forms unless the context clearly dictates otherwise.

It is understood that wherever embodiments are described herein with the term “comprising” otherwise analogous embodiments described in terms of “consisting of” and/or “consisting essentially of” are also provided. It is also understood that wherever embodiments are described herein with the phrase “consisting essentially of” otherwise analogous embodiments described in terms of “consisting of” are also provided.

The term “between” as used in a phrase as such “between A and B” or “between A-B” refers to a range including both A and B.

The term “and/or” as used in a phrase such as “A and/or B” herein is intended to include both A and B; A or B; A (alone); and B (alone). Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

5.2 Anti-Fn14 Antibodies and Related Molecules

5.2.1 Anti-Fn14 Antibodies

The antibodies provided herein include, but are not limited to, synthetic antibodies, monoclonal antibodies, recombinantly produced antibodies, multispecific antibodies (including bi-specific antibodies), human antibodies, humanized antibodies, chimeric antibodies, intrabodies, single-chain Fvs (scFv) (e.g., including monospecific, bispecific, etc.), camelized antibodies, Fab fragments, F(ab′) fragments, disulfide-linked Fvs (sdFv), anti-idiotypic (anti-Id) antibodies, and epitope-binding fragments of any of the above.

In particular, the antibodies provided herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds to an Fn14 antigen. The immunoglobulin molecules provided herein 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 of immunoglobulin molecule. In a specific embodiment, an antibody provided herein is an IgG antibody, such as an IgG1 antibody, IgG2 antibody or IgG4 antibody (e.g., IgG4 nullbody and variants of IgG4 antibodies).

Variants and derivatives of antibodies include antibody fragments that retain the ability to specifically bind to an epitope. Exemplary fragments include Fab fragments (an antibody fragment that contains the antigen-binding domain and comprises a light chain and part of a heavy chain bridged by a disulfide bond); Fab′ (an antibody fragment containing a single anti-binding domain comprising an Fab and an additional portion of the heavy chain through the hinge region); F(ab′)2 (two Fab′ molecules joined by interchain disulfide bonds in the hinge regions of the heavy chains; the Fab′ molecules may be directed toward the same or different epitopes); a bispecific Fab (a Fab molecule having two antigen binding domains, each of which may be directed to a different epitope); a single chain Fab chain comprising a variable region, also known as, a scFv (the variable, antigen-binding determinative region of a single light and heavy chain of an antibody linked together by a chain of 10-25 amino acids); a disulfide-linked Fv, or dsFv (the variable, antigen-binding determinative region of a single light and heavy chain of an antibody linked together by a disulfide bond); a camelized VH (the variable, antigen-binding determinative region of a single heavy chain of an antibody in which some amino acids at the VH interface are those found in the heavy chain of naturally occurring camel antibodies); a bispecific scFv (a scFv or a dsFv molecule having two antigen-binding domains, each of which may be directed to a different epitope); a diabody (a dimerized scFv formed when the VH domain of a first scFv assembles with the VL domain of a second scFv and the VL domain of the first scFv assembles with the VH domain of the second scFv; the two antigen-binding regions of the diabody may be directed towards the same or different epitopes); a triabody (a trimerized scFv, formed in a manner similar to a diabody, but in which three antigen-binding domains are created in a single complex; the three antigen binding domains may be directed towards the same or different epitopes); and a tetrabody (a tetramerized scFv, formed in a manner similar to a diabody, but in which four antigen-binding domains are created in a single complex; the four antigen binding domains may be directed towards the same or different epitopes). Derivatives of antibodies also include one or more CDR sequences of an antibody combining site. The CDR sequences may be linked together on a scaffold when two or more CDR sequences are present. In certain embodiments, an antibody provided herein comprises a single-chain Fv (“scFv”). scFvs are antibody fragments comprising the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. Generally, the scFv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen binding. For a review of scFvs see Pluckthun in The Pharmacology of Monoclonal Antibodies , vol. 113, Rosenburg and Moore eds. Springer-Verlag, New York, pp. 269-315 (1994).

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The antibodies provided herein may be from any animal origin including birds and mammals (e.g., human, monkey, murine, donkey, sheep, rabbit, goat, guinea pig, camel, horse, or chicken). In certain embodiments, the antibodies provided herein are human or humanized monoclonal antibodies. As used herein, “human” antibodies include antibodies having the amino acid sequence of a human immunoglobulin and include antibodies isolated from human immunoglobulin libraries or from mice that express antibodies from human genes.

In certain embodiments, the antibodies are full mouse antibodies. In certain embodiments, the antibodies are mouse-human chimeric antibodies. In certain embodiments, the antibodies are humanized antibodies. In certain embodiments, the antibodies are fully human antibodies, such as fully human antibodies that immunospecifically bind an Fn14 polypeptide, an Fn14 polypeptide fragment, or an Fn14 epitope. In other embodiments, the antibodies provided herein are humanized antibodies (e.g., comprising human constant and framework regions) that bind Fn14, including an Fn14 polypeptide, an Fn14 polypeptide fragment, or an Fn14 epitope.

The antibodies provided herein may be monospecific, bispecific, trispecific or of greater multispecificity. For example, in certain embodiments, the bispecific antibodies have one specificity to one epitope of Fn14 polypeptide and a second specificity to a second epitope of the Fn14 polypeptide. In other embodiments, the bispecific antibodies have one specificity to an Fn14 polypeptide and a second specificity for a heterologous epitope, such as a heterologous polypeptide or solid support material.

In certain embodiments, the antibodies provided herein bind to human Fn14. In other embodiments, the antibodies provided herein bind to cynomolgus macaque Fn14. In yet other embodiments, the antibodies provided herein binds to rat Fn14. In yet other embodiments, the antibodies provided herein binds to mouse Fn14. In yet other embodiments, the antibodies provided herein binds to human, cynomolgus macaque, rat and mouse Fn14.

The terms “Fn14” and “Fn14 polypeptide” encompasses a polypeptide (“polypeptide” and “protein” are used interchangeably herein), including any native polypeptide, from any vertebrate source, including mammals such as primates (e.g., humans and cynomolgus monkeys (cynomolgus macaque)), dogs, and rodents (e.g., mice and rats), unless otherwise indicated. The term “Fn14” also encompasses “full-length,” unprocessed Fn14 as well as any form of Fn14 that results from processing in the cell or extracellularly. “Related Fn14 polypeptides” include allelic variants (e.g., SNP variants); splice variants; fragments; derivatives; substitution, deletion, and insertion variants; fusion polypeptides; interspecies homologs; and interspecies chimeras, which can retain Fn14 activity. As those skilled in the art will appreciate, an anti-Fn14 antibody provided herein can bind to an Fn14 polypeptide, an Fn14 polypeptide fragment, an Fn14 antigen, and/or an Fn14 epitope. An “epitope” may be part of a larger Fn14 antigen, which may be part of a larger Fn14 polypeptide fragment, which, in turn, may be part of a larger Fn14 polypeptide. Fn14 may exist in a native or denatured form. Fn14 polypeptides described herein may be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods. Orthologs to the Fn14 polypeptide are also well known in the art.

Table 13 in Example 1 lists exemplary human, cynomolgus macaque, rat and mouse Fn14 amino acid and nucleotide sequences. In some embodiments, the antibody provided herein binds a peptide of SEQ ID NO: 2 or a fragment thereof. In some embodiments, the antibody provided herein binds a peptide of SEQ ID NO: 4 or a fragment thereof. In other embodiments, the antibody provided herein binds a peptide of SEQ ID NO: 6 or a fragment thereof. In other embodiments, the antibody provided herein binds a peptide of SEQ ID NO: 8 or a fragment thereof. In yet other embodiments, the antibody provided herein binds a peptide of SEQ ID NO: 10 or a fragment thereof.

In some embodiments, the antibody or antigen binding fragment provided herein bind to amino acid residues 30-50 of human Fn14 having an amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibody or antigen binding fragment provided herein bind to the subdomain 1 comprises an amino acid sequence of APGTAPCSRGSSWSADLDKCM (SEQ ID NO: 182). In some embodiments, the antibody or antigen binding fragment provided herein interacts with one or more amino acid residues of human Fn14 protein selected from a group consisting of Gly32, Thr33, Ala34, Pro35, Trp42, Ala44, Asp45, Leu46, Asp47, Lys48, Cys49, or a combination thereof.

In some embodiments, the antibody or antigen binding fragment provided herein binds Fn14 with a K D of less than 1000 nM. In some embodiments, the antibody or antigen binding fragment provided herein binds Fn14 with a K D of less than 100 nM. In some embodiments, the antibody or antigen binding fragment provided herein binds Fn14 with a K D of less than 50 nM. In some embodiments, the antibody or antigen binding fragment provided herein binds Fn14 with a K D of less than 40 nM. In some embodiments, the antibody or antigen binding fragment provided herein binds Fn14 with a K D of less than 30 nM. In some embodiments, the antibody or antigen binding fragment provided herein binds Fn14 with a K D of less than 20 nM. In some embodiments, the antibody or antigen binding fragment provided herein binds Fn14 with a K D of less than 10 nM. In some embodiments, the antibody or antigen binding fragment provided herein binds Fn14 with a K D of less than 9 nM. In some embodiments, the antibody or antigen binding fragment provided herein binds Fn14 with a K D of less than 8 nM. In some embodiments, the antibody or antigen binding fragment provided herein binds Fn14 with a K D of less than 7 nM. In some embodiments, the antibody or antigen binding fragment provided herein binds Fn14 with a K D of less than 6 nM. In some embodiments, the antibody or antigen binding fragment provided herein binds Fn14 with a K D of less than 5 nM. In some embodiments, the antibody or antigen binding fragment provided herein binds Fn14 with a K D of less than 4 nM. In some embodiments, the antibody or antigen binding fragment provided herein binds Fn14 with a K D of less than 3 nM. In some embodiments, the antibody or antigen binding fragment provided herein binds Fn14 with a K D of less than 2 nM. In some embodiments, the antibody or antigen binding fragment provided herein binds Fn14 with a K D of less than 1 nM. In some embodiments, the antibody or antigen binding fragment provided herein binds Fn14 with a K D of less than 0.1 nM. In some embodiments, the antibody or antigen binding fragment provided herein binds Fn14 with a K D of less than 0.01 nM. The K D or K D value may also be measured by any known methods in the art, for example, using biolayer interferometry (BLI) or surface plasmon resonance (SPR) assays by Octet®, using, for example, an Octet®Red96 system, or by Biacore®, using, for example, a Biacore®™-2000 or a Biacore®™-3000. An “on-rate” or “rate of association” or “association rate” or “kon” may also be determined with the same biolayer interferometry (BLI) or surface plasmon resonance (SPR) techniques described above using, for example, the Octet®Red96, the Biacore®TM-2000, or the Biacore®TM-3000 system. In a specific embodiment, the K D is determined by a Biacore® assay. In some embodiments, Fn14 is a human Fn14. In some embodiments, Fn14 is a cynomolgus macaque Fn14. In some embodiments, Fn14 is a rat Fn14. In other embodiments, Fn14 is mouse Fn14.

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In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 100 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 100 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 100 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 100 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 90 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 90 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 90 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 90 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 80 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 80 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 80 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 80 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 70 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 70 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 70 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 70 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 60 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 60 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 60 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 60 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 50 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 50 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 50 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 50 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 40 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 40 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 40 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 40 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 30 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 30 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 30 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 30 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 20 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 20 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 20 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 20 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

›SEQUENCE LISTING · 21 of 77

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 10 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 10 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 10 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 10 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 9 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 9 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 9 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 9 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 8 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 8 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 8 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 8 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 7 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 7 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 7 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 7 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 6 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 6 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 6 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 6 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 5 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 5 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 5 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 5 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 4 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 4 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 4 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 4 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 3 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 3 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 3 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 3 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 2 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 2 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 2 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 2 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

›SEQUENCE LISTING · 22 of 77

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 1 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 1 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 1 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 1 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 0.5 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 0.5 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 0.5 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 0.5 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 0.1 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 0.1 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 0.1 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 0.1 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of less than 0.01 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of less than 0.01 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of less than 0.01 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of less than 0.01 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In some embodiments, the antibody or antigen binding fragment provided herein binds human Fn14 with a K D of 1 nM to 0.001 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds cynomolgus macaque Fn14 with a K D of 1 nM to 0.001 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), the antibody or antigen binding fragment binds rat Fn14 with a K D of 1 nM to 0.001 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay), and the antibody or antigen binding fragment binds mouse Fn14 with a K D of 1 nM to 0.001 nM as determined by a surface plasmon resonance method (e.g. a Biacore® assay).

In one aspect, provided herein are antibodies that specifically bind to Fn14 and can modulate Fn14 activity and/or expression (e.g., inhibit Fn14 mediated signaling). In certain embodiments, an Fn14 antagonist is provided herein that is an antibody described herein that specifically binds to Fn14 and inhibits (including partially inhibits) at least one Fn14 activity. In some embodiments, the antibodies provided herein inhibit (including partially inhibit or reduce) the binding of Fn14 to its ligand.

An Fn14 activity can relate to any activity of Fn14 such as those known or described in the art. In certain embodiments, Fn14 activity and Fn14 signaling (or Fn14 mediated signaling) are used interchangeably herein. In certain aspects, Fn14 activity is induced by TWEAK (e.g., through Fn14 binding to TWEAK). In certain embodiments, provided herein are antibodies that specifically bind to Fn14 and inhibit (or reduce) chemokine and/or cytokine production. In some embodiments, the antibodies provided herein do not inhibit the binding of Fn14 to TWEAK, but nevertheless inhibit or reduce the Fn14 mediated or TWEAK mediated signaling.

In certain embodiments, the antibody described herein attenuates (e.g., partially attenuates) an Fn14 activity. In some embodiments, the antibody provided herein attenuates an Fn14 activity by at least about 10%. In some embodiments, the antibody provided herein attenuates an Fn14 activity by at least about 20%. In some embodiments, the antibody provided herein attenuates an Fn14 activity by at least about 30%. In some embodiments, the antibody provided herein attenuates an Fn14 activity by at least about 40%. In some embodiments, the antibody provided herein attenuates an Fn14 activity by at least about 50%. In some embodiments, the antibody provided herein attenuates an Fn14 activity by at least about 60%. In some embodiments, the antibody provided herein attenuates an Fn14 activity by at least about 70%. In some embodiments, the antibody provided herein attenuates an Fn14 activity by at least about 80%. In some embodiments, the antibody provided herein attenuates an Fn14 activity by at least about 90%. In some embodiments, the antibody provided herein attenuates an Fn14 activity by at least about 95%. In certain embodiments, the antibody described herein can attenuate (e.g., partially attenuate) an Fn14 activity by at least about 15% to about 65%. In certain embodiments, the antibody described herein can attenuate (e.g., partially attenuate) an Fn14 activity by at least about 20% to about 65%. In certain embodiments, the antibody described herein can attenuate (e.g., partially attenuate) an Fn14 activity by at least about 30% to about 65%.

›SEQUENCE LISTING · 23 of 77

In specific embodiments, the attenuation of an Fn14 activity is assessed by methods described herein. In specific embodiments, the attenuation of an Fn14 activity is assessed by methods known to one of skill in the art. In certain embodiments, the attenuation of an Fn14 activity is relative to the Fn14 activity in the presence of stimulation without any anti-Fn14 antibody. In certain embodiments, the attenuation of an Fn14 activity is relative to the Fn14 activity in the presence of stimulation with an unrelated antibody (e.g., an antibody that does not specifically bind to Fn14).

A non-limiting example of an Fn14 activity is Fn14 mediated signaling. Thus, in certain embodiments, the antibody described herein attenuates (e.g., partially attenuates) Fn14 mediated signaling. In some embodiments, the antibody provided herein attenuates Fn14 mediated signaling by at least about 10%. In some embodiments, the antibody provided herein attenuates Fn14 mediated signaling by at least about 20%. In some embodiments, the antibody provided herein attenuates Fn14 mediated signaling by at least about 30%. In some embodiments, the antibody provided herein attenuates Fn14 mediated signaling by at least about 40%. In some embodiments, the antibody provided herein attenuates Fn14 mediated signaling by at least about 50%. In some embodiments, the antibody provided herein attenuates Fn14 mediated signaling by at least about 60%. In some embodiments, the antibody provided herein attenuates Fn14 mediated signaling by at least about 70%. In some embodiments, the antibody provided herein attenuates Fn14 mediated signaling by at least about 80%. In some embodiments, the antibody provided herein attenuates Fn14 mediated signaling by at least about 90%. In some embodiments, the antibody provided herein attenuates Fn14 mediated signaling by at least about 95%. In certain embodiments, the antibody described herein can attenuate (e.g., partially attenuate) Fn14 mediated signaling by at least about 15% to about 65%. In certain embodiments, the antibody described herein can attenuate (e.g., partially attenuate) Fn14 mediated signaling by at least about 20% to about 65%. In certain embodiments, the antibody described herein can attenuate (e.g., partially attenuate) Fn14 mediated signaling by at least about 30% to about 65%.

Another non-limiting example of an Fn14 activity is binding to TWEAK. Thus, in certain embodiments, the antibody described herein attenuates (e.g., partially attenuates) the binding of Fn14 to TWEAK. In some embodiments, the antibody provided herein attenuates the binding of Fn14 to TWEAK by at least about 10%. In some embodiments, the antibody provided herein attenuates the binding of Fn14 to TWEAK by at least about 20%. In some embodiments, the antibody provided herein attenuates the binding of Fn14 to TWEAK by at least about 30%. In some embodiments, the antibody provided herein attenuates the binding of Fn14 to TWEAK by at least about 40%. In some embodiments, the antibody provided herein attenuates the binding of Fn14 to TWEAK by at least about 50%. In some embodiments, the antibody provided herein attenuates the binding of Fn14 to TWEAK by at least about 60%. In some embodiments, the antibody provided herein attenuates the binding of Fn14 to TWEAK by at least about 70%. In some embodiments, the antibody provided herein attenuates the binding of Fn14 to TWEAK by at least about 80%. In some embodiments, the antibody provided herein attenuates the binding of Fn14 to TWEAK by at least about 90%. In some embodiments, the antibody provided herein attenuates the binding of Fn14 to TWEAK by at least about 95%. In certain embodiments, the antibody described herein can attenuate (e.g., partially attenuate) the binding of Fn14 to TWEAK by at least about 15% to about 65%. In certain embodiments, the antibody described herein can attenuate (e.g., partially attenuate) the binding of Fn14 to TWEAK by at least about 20% to about 65%. In certain embodiments, the antibody described herein can attenuate (e.g., partially attenuate) the binding of Fn14 to TWEAK by at least about 30% to about 65%.

Another non-limiting example of an Fn14 activity is signaling mediated by TWEAK. Thus, in certain embodiments, the antibody described herein attenuates (e.g., partially attenuates) TWEAK mediated signaling. In some embodiments, the antibody provided herein attenuates TWEAK mediated signaling by at least about 10%. In some embodiments, the antibody provided herein attenuates TWEAK mediated signaling by at least about 20%. In some embodiments, the antibody provided herein attenuates TWEAK mediated signaling by at least about 30%. In some embodiments, the antibody provided herein attenuates TWEAK mediated signaling by at least about 40%. In some embodiments, the antibody provided herein attenuates TWEAK mediated signaling by at least about 50%. In some embodiments, the antibody provided herein attenuates TWEAK mediated signaling by at least about 60%. In some embodiments, the antibody provided herein attenuates TWEAK mediated signaling by at least about 70%. In some embodiments, the antibody provided herein attenuates TWEAK mediated signaling by at least about 80%. In some embodiments, the antibody provided herein attenuates TWEAK mediated signaling by at least about 90%. In some embodiments, the antibody provided herein attenuates TWEAK mediated signaling by at least about 95%. In certain embodiments, the antibody described herein can attenuate (e.g., partially attenuate) TWEAK mediated signaling by at least about 15% to about 65%. In certain embodiments, the antibody described herein can attenuate (e.g., partially attenuate) TWEAK mediated signaling by at least about 20% to about 65%. In certain embodiments, the antibody described herein can attenuate (e.g., partially attenuate) TWEAK mediated signaling by at least about 30% to about 65%.

In specific embodiments, antibodies provided herein specifically bind to Fn14 and inhibit the secretion of one or more cytokines and/or chemokines induced by TWEAK. In some embodiments, the one or more cytokines and/or chemokines are selected from a group consisting of IL-8, CCL2, IL-1(3, TGF(3, CCL21, TNFα, IL-6, CXCL1, CCL3, CCL4, CXCL12, CCLS, CXCL10, and CXCL16.

›SEQUENCE LISTING · 24 of 77

For example, in one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 5%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 10%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 15%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 20%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 25%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 30%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 35%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 40%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 45%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 50%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 55%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 60%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 65%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 70%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 75%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 80%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 85%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 90%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 95%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 96%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 97%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 98%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits IL-8 secretion by at least about 99%. In some embodiments, the inhibition of IL-8 secretion is assessed by methods described herein. In other embodiments, the inhibition of IL-8 secretion is assessed by methods known to one of skill in the art. In a specific embodiment, the IL-8 secretion is inhibited relative to IL-8 secretion in the absence of anti-Fn14 antibody. In other embodiments, the IL-8 secretion is inhibited relative to IL-8 secretion in the presence of an unrelated antibody (e.g., an antibody that does not specifically bind to Fn14).

In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 5%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 10%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 15%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 20%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 25%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 30%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 35%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 40%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 45%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 50%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 55%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 60%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 65%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 70%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 75%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 80%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 85%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 90%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 95%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 96%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 97%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 98%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits CCL2 expression by at least about 99%. In some embodiments, the inhibition of CCL2 expression is assessed by methods described herein. In other embodiments, the inhibition of CCL2 expression is assessed by methods known to one of skill in the art. In a specific embodiment, the CCL2 expression is inhibited relative to CCL2 expression in the absence of anti-Fn14 antibody. In other embodiments, the CCL2 expression is inhibited relative to CCL2 expression in the presence of an unrelated antibody (e.g., an antibody that does not specifically bind to Fn14).

›SEQUENCE LISTING · 25 of 77

In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits TWEAK induced ICAM-1 expression. In some embodiments, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 5%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 10%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 15%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 20%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 25%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 30%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 35%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 40%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 45%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 50%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 55%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 60%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 65%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 70%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 75%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 80%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 85%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 90%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 95%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 96%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 97%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 98%. In one embodiment, an antibody provided herein specifically binds to Fn14 and inhibits ICAM-1 expression by at least about 99%. In some embodiments, the inhibition of ICAM-1 expression is assessed by methods described herein. In other embodiments, the inhibition of ICAM-1 expression is assessed by methods known to one of skill in the art. In a specific embodiment, the ICAM-1 expression is inhibited relative to ICAM-1 expression in the absence of anti-Fn14 antibody. In other embodiments, the ICAM-1 expression is inhibited relative to ICAM-1 expression in the presence of an unrelated antibody (e.g., an antibody that does not specifically bind to Fn14).

Antibodies provided herein are not agonists of Fn14. In some embodiments, the antibody or antigen binding fragment provided herein does not stimulate an Fn14 activity. In some embodiments, the antibody or antigen binding fragment provided herein does not stimulate Fn14 mediated signaling. In some embodiments, the antibody or antigen binding fragment provided herein does not stimulate TWEAK mediated signaling.

In some embodiments, the antibody or antigen binding fragment thereof provided herein comprises one or more CDRs from the antibodies descrbied in Section 6 below including antibodies KO41c, KO42d, R35B9, and variants thereof.

In some embodments, the antibody or antigen binding fragment thereof provided herein is antibody KO42d or variants thereof. In some embodiments, the antibody or antigen binding fragment thereof provided herein comprises CDR H1 comprising an amino acid sequence of SEQ ID NO: 113, CDR H2 comprising an amino acid sequence of SEQ ID NO: 114, CDR H3 comprising an amino acid sequence of SEQ ID NO: 115, CDR L1 comprising an amino acid sequence of SEQ ID NO: 116, CDR L2 comprising an amino acid sequence of SEQ ID NO: 117, CDR L3 comprising an amino acid sequence of SEQ ID NO: 118. In some embodiments, the antibody or antigen binding fragment thereof provided herein comprises a VH comprising an amino acid sequence of SEQ ID NO: 44 and a VL comprising an amino acid sequence of SEQ ID NO: 48.

In other embodiments, the antibody or antigen binding fragment thereof provided herein is KO41c, R35B9 or a variant thereof.

In some embodiments, the antibody or antigen binding fragment thereof provided herein comprises:

(a) a heavy chain variable region (VH) comprising (i) VH complementarity determining region 1 (CDR H1) comprising an amino acid sequence of GYX 1 FX 2 DYNMH (SEQ ID NO: 184), wherein X 1 is T, I or R, and X 2 is T or Q; (ii) VH complementarity determining region 2 (CDR H2) comprising an amino acid sequence of X 3 INPX 4 NX 5 X 6 TNYNX 9 KFXioG (SEQ ID NO: 257), wherein X 3 is Y or S, X 4 is N or R, X 5 is A or G, X 6 is G or W, X 9 is Q or D, and X 10 is K, G, H, or D; (iii) VH complementarity determining region 3 (CDR H3) comprising an amino acid sequence of SGWFTY (SEQ ID NO: 121); (b) a light chain variable region (VL) comprising (i) VL complementarity determining region 1 (CDR L1) comprising an amino acid sequence of KSSQSLLNSAGKTYLN (SEQ ID NO: 127); (ii) VL complementarity determining region 2 (CDR L2) comprising an amino acid sequence of LVXiiXi2LDXi3 (SEQ ID NO: 258), wherein X 11 is S or A, X 12 is Q or E, and X 13 is S or D; (iii) VL complementarity determining region 3 (CDR L3) comprising an amino acid sequence of WQGTX 7 X 8 PWT (SEQ ID NO: 186), wherein X 7 is H or F, and X 8 is F or Y.

›SEQUENCE LISTING · 26 of 77

In some embodiments, the antibody or antigen binding fragment thereof provided herein comprises:

(a) a heavy chain variable region (VH) comprising (i) VH complementarity determining region 1 (CDR H1) comprising an amino acid sequence of GYX 1 FX 2 DYNMH (SEQ ID NO: 184), wherein X 1 is T, I or R, and X 2 is T or Q; (ii) VH complementarity determining region 2 (CDR H2) comprising an amino acid sequence of X 3 INPX 4 NX 5 X 6 TNYNQKFKG (SEQ ID NO: 185), wherein X 3 is Y or S, X 4 is N or R; X 5 is A or G, and X 6 is G or W; (iii) VH complementarity determining region 3 (CDR H3) comprising an amino acid sequence of SGWFTY (SEQ ID NO: 121); (b) a light chain variable region (VL) comprising (i) VL complementarity determining region 1 (CDR L1) comprising an amino acid sequence of KSSQSLLNSAGKTYLN (SEQ ID NO: 127); (ii) VL complementarity determining region 2 (CDR L2) comprising an amino acid sequence of LVSQLDS (SEQ ID NO: 128); (iii) VL complementarity determining region 3 (CDR L3) comprising an amino acid sequence of WQGTX 7 X 8 PWT (SEQ ID NO: 186), wherein X 7 is H or F, and X 8 is F or Y.

In some embodiments, X 1 is T or I.

In some embodiments, the antibody provided herein comprises one or more CDRs listed in Table 26 below.

In some embodiments, the antibody or antigen binding fragment thereof comprises:

(a) a heavy chain variable region (VH) comprising (i) VH complementarity determining region 1 (CDR H1) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 119 and SEQ ID NO: 122; (ii)VH complementarity determining region 2 (CDR H2) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 120, SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 149; SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, and SEQ ID NO: 250; and (iii) VH complementarity determining region 3 (CDR H3) comprising an amino acid sequence of SEQ ID NO: 121, and (b) a light chain variable region (VL) comprising (i) VL complementarity determining region 1 (CDR L1) comprising an amino acid sequence of SEQ ID NO: 127; (ii) VL complementarity determining region 2 (CDR L2) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 128, SEQ ID NO: 254, SEQ ID NO: 255, and SEQ ID NO: 256; and (iii) VL complementarity determining region 3 (CDR L3) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 129, SEQ ID NO: 130, and SEQ ID NO: 131.

In some embodiments, the antibody or antigen binding fragment thereof provided herein comprises:

(a) a heavy chain variable region (VH) comprising (i) VH complementarity determining region 1 (CDR H1) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 119 and SEQ ID NO: 122; (ii) VH complementarity determining region 2 (CDR H2) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 120, SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, and SEQ ID NO: 149; and (iii) VH complementarity determining region 3 (CDR H3) comprising an amino acid sequence of SEQ ID NO: 121, and (b) a light chain variable region (VL) comprising (i) VL complementarity determining region 1 (CDR L1) comprising an amino acid sequence of SEQ ID NO: 127; (ii) VL complementarity determining region 2 (CDR L2) comprising an amino acid sequence of SEQ ID NO: 128; and (iii) VL complementarity determining region 3 (CDR L3) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 129, SEQ ID NO: 130, and SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 119 and SEQ ID NO: 122. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122.

In some embodiments, the antibody comprises a CDR H2 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 120, SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 149, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249 and SEQ ID NO: 250. In some embodiments, the antibody comprises a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120. In some embodiments, the antibody comprises a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123. In some embodiments, the antibody comprises a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124. In some embodiments, the antibody comprises a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125. In some embodiments, the antibody comprises a CDR H2 comprising an amino acid of SEQ ID NO: 126. In some embodiments, the antibody comprises a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149. In some embodiments, the antibody comprises a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247. In some embodiments, the antibody comprises a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248. In some embodiments, the antibody comprises a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249. In some embodiments, the antibody comprises a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250.

In some embodiments, the antibody comprises a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121.

In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127.

In some embodiments, the antibody comprises a CDR L2 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 128, SEQ ID NO: 254, SEQ ID NO: 255, and SEQ ID NO: 256. In some embodiments, the antibody comprises a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128. In some embodiments, the antibody comprises a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254. In some embodiments, the antibody comprises a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255. In some embodiments, the antibody comprises a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256.

›SEQUENCE LISTING · 27 of 77

In some embodiments, the antibody comprises a CDR L3 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 129, SEQ ID NO: 130 and SEQ ID NO: 131. In some embodiments, the antibody comprises a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129. In some embodiments, the antibody comprises a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130. In some embodiments, the antibody comprises a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 119 and SEQ ID NO: 122 and a CDR H2 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 120, SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 149, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249 and SEQ ID NO: 250.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122 and a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 119 and SEQ ID NO: 122 and a CDR H3 comprising an amino acid of SEQ ID NO: 121.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121.

In some embodiments, the antibody comprises a CDR H2 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 123, SEQ ID NO: 124, and SEQ ID NO: 126, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249 and SEQ ID NO: 250 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121.

›SEQUENCE LISTING · 28 of 77

In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127 and a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128, SEQ ID NO: 254, SEQ ID NO: 255 or SEQ ID NO: 256. In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127 and a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128. In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127 and a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254. In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127 and a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255. In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127 and a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256.

In some embodiments, the antibody comprise a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127 and a CDR L3 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 129, SEQ ID NO: 130 and SEQ ID NO: 131. In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129. In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130. In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprise a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128, SEQ ID NO: 254, SEQ ID NO: 255, or SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 129, SEQ ID NO: 130 and SEQ ID NO: 131. In some embodiments, the antibody comprises a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129. In some embodiments, the antibody comprises a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130. In some embodiments, the antibody comprises a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131. In some embodiments, the antibody comprises a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129. In some embodiments, the antibody comprises a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130. In some embodiments, the antibody comprises a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131. In some embodiments, the antibody comprises a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129. In some embodiments, the antibody comprises a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130. In some embodiments, the antibody comprises a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131. In some embodiments, the antibody comprises a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129. In some embodiments, the antibody comprises a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130. In some embodiments, the antibody comprises a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121.

›SEQUENCE LISTING · 29 of 77

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121. In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149 and a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121.

In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127; a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128, SEQ ID NO: 254, SEQ ID NO: 255 or SEQ ID NO: 256; and a CDR L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 129, SEQ ID NO: 130, and SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254, and a CDR L3 comprising an amino acid sequence of 129. In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254, and a CDR L3 comprising an amino acid sequence of 130. In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254, and a CDR L3 comprising an amino acid sequence of 131.

In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255, and a CDR L3 comprising an amino acid sequence of 129. In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255, and a CDR L3 comprising an amino acid sequence of 130. In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255, and a CDR L3 comprising an amino acid sequence of 131.

In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256, and a CDR L3 comprising an amino acid sequence of 129. In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256, and a CDR L3 comprising an amino acid sequence of 130. In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256, and a CDR L3 comprising an amino acid sequence of 131.

In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128, and a CDR L3 comprising an amino acid sequence of 129. In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128, and a CDR L3 comprising an amino acid sequence of 130. In some embodiments, the antibody comprises a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128, and a CDR L3 comprising an amino acid sequence of 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 119 and SEQ ID NO: 122; a CDR H2 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 120, SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 149, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249 and SEQ ID NO: 250; a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121; a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127; a CDR L2 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 128, SEQ ID NO: 254, SEQ ID NO: 255 and SEQ ID NO: 256; and a CDR L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 129, SEQ ID NO: 130, and SEQ ID NO: 131.

›SEQUENCE LISTING · 30 of 77

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

›SEQUENCE LISTING · 31 of 77

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

›SEQUENCE LISTING · 32 of 77

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

›SEQUENCE LISTING · 33 of 77

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

›SEQUENCE LISTING · 34 of 77

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

›SEQUENCE LISTING · 35 of 77

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

›SEQUENCE LISTING · 36 of 77

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

›SEQUENCE LISTING · 37 of 77

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 119, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

›SEQUENCE LISTING · 38 of 77

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 120, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

›SEQUENCE LISTING · 39 of 77

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 123, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

›SEQUENCE LISTING · 40 of 77

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 124, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

›SEQUENCE LISTING · 41 of 77

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 125, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 126, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

›SEQUENCE LISTING · 42 of 77

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 149, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

›SEQUENCE LISTING · 43 of 77

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 247, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

›SEQUENCE LISTING · 44 of 77

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 248, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

›SEQUENCE LISTING · 45 of 77

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 249, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 128 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 254 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 255 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 129.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 130.

In some embodiments, the antibody comprises a CDR H1 comprising an amino acid sequence of SEQ ID NO: 122, a CDR H2 comprising an amino acid sequence of SEQ ID NO: 250, a CDR H3 comprising an amino acid sequence of SEQ ID NO: 121, a CDR L1 comprising an amino acid sequence of SEQ ID NO: 127, a CDR L2 comprising an amino acid sequence of SEQ ID NO: 256 and a CDR L3 comprising an amino acid sequence of SEQ ID NO: 131.

›SEQUENCE LISTING · 46 of 77

In some embodiments, the antibody or antigen binding fragment thereof provided herein comprise CDRs having amino acid sequences of the CDRs contained in VH and VL sequences in Table 6, Table 28, Table 29, Table 31, Table 5 and Table 17 below.

In some embodiments, the antibody comprises a VH comprising CDRs having amino acid sequences of the CDRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 35 and a VL comprising CDRs having amino acid sequences of the CDRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody comprises a VH comprising CDRs having amino acid sequences of the CDRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 50 and a VL comprising CDRs having amino acid sequences of the CDRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody comprises a VH comprising CDRs having amino acid sequences of the CDRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 54 and a VL comprising CDRs having amino acid sequences of the CDRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody comprises a VH comprising CDRs having amino acid sequences of the CDRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 56 and a VL comprising CDRs having amino acid sequences of the CDRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody comprises a VH comprising CDRs having amino acid sequences of the CDRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 60 and a VL comprising CDRs having amino acid sequences of the CDRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

›SEQUENCE LISTING · 47 of 77

In some embodiments, the antibody comprises a VH comprising CDRs having amino acid sequences of the CDRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 181 and a VL comprising CDRs having amino acid sequences of the CDRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody comprises a VH comprising CDRs having amino acid sequences of the CDRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 190 and a VL comprising CDRs having amino acid sequences of the CDRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody comprises a VH comprising CDRs having amino acid sequences of the CDRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 192 and a VL comprising CDRs having amino acid sequences of the CDRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody comprises a VH comprising CDRs having amino acid sequences of the CDRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 194 and a VL comprising CDRs having amino acid sequences of the CDRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody comprises a VH comprising CDRs having amino acid sequences of the CDRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 196 and a VL comprising CDRs having amino acid sequences of the CDRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

›SEQUENCE LISTING · 48 of 77

In some embodiments, the antibody comprises a VH comprising CDRs having amino acid sequences of the CDRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 198 and a VL comprising CDRs having amino acid sequences of the CDRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

The residues from each of these CDR regions are noted in the Sequence Listing provided herein. In some embodiments, the CDRs are according to Kabat numbering. In some embodiments, the CDRs are according to AbM numbering. In other embodiments, the CDRs are according to Chothia numbering. In other embodiments, the CDRs are according to Contact numbering. In some embodiments, the CDRs are according to IMGT numbering. In certain embodiments, the CDRs in an antibody can be determined according to a combination of various numbering systems, for example, Kabat in combination with Chothia. In certain embodiments, one or more CDRs in an antibody are determined according to Kabat numbering and other CDRs in the antibody are determined according Chothia numbering.

In certain embodiments, the antibody or antigen binding fragment thereof provided herein further comprises one or more FR regions from antibodies provided herein.

In some embodiments, the antibody provided herein comprises one or more mouse framework regions in Table 27 above.

In some embodiments, the antibody comprises FR H1 comprising an amino acid sequence of SEQ ID NO: 132. In some embodiments, the antibody comprises FR H2 comprising an amino acid sequence of SEQ ID NO: 138. In some embodiments, the antibody comprises FR H3 comprising an amino acid sequence of SEQ ID NO: 145. In some embodiments, the antibody comprises FR H4 comprising an amino acid sequence of SEQ ID NO: 158.

In some embodiments, the antibody comprises FR L1 comprising an amino acid sequence of SEQ ID NO: 160. In some embodiments, the antibody comprises FR L2 comprising an amino acid sequence of SEQ ID NO: 163. In some embodiments, the antibody comprises FR L3 comprising an amino acid sequence of SEQ ID NO: 169. In some embodiments, the antibody comprises FR L4 comprising an amino acid sequence of SEQ ID NO: 171.

In some embodiments, the antibody provided herein comprises a VH comprising FR H1 comprising an amino acid sequence of SEQ ID NO: 132, FR H2 comprising an amino acid sequence of SEQ ID NO: 138, FR H3 comprising an amino acid sequence of SEQ ID NO: 145, and FR H4 comprising an amino acid sequence of SEQ ID NO: 158.

In some embodiments, the antibody provided herein comprises a VL comprising FR L1 comprising an amino acid sequence of SEQ ID NO: 160, FR L2 comprising an amino acid sequence of SEQ ID NO: 163, FR L3 comprising an amino acid sequence of SEQ ID NO: 169, and FR L4 comprising an amino acid sequence of SEQ ID NO: 171.

In some embodiments, the antibody or antigen binding fragment thereof provided herein comprise FRs having amino acid sequences of the FRs contained in VH and VL sequences in Table 28, Table 29, and Table 30 below.

In some embodiments, the antibody comprises a VH comprising FRs having amino acid sequences of the FRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 35 and a VL comprising FRs having amino acid sequences of the FRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody comprises a VH comprising FRs having amino acid sequences of the FRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 50 and a VL comprising FRs having amino acid sequences of the FRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

›SEQUENCE LISTING · 49 of 77

In some embodiments, the antibody comprises a VH comprising FRs having amino acid sequences of the FRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 54 and a VL comprising FRs having amino acid sequences of the FRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody comprises a VH comprising FRs having amino acid sequences of the FRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 56 and a VL comprising FRs having amino acid sequences of the FRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody comprises a VH comprising FRs having amino acid sequences of the FRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 60 and a VL comprising FRs having amino acid sequences of the FRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody comprises a VH comprising FRs having amino acid sequences of the FRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 181 and a VL comprising FRs having amino acid sequences of the FRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody comprises a VH comprising FRs having amino acid sequences of the FRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 190 and a VL comprising FRs having amino acid sequences of the FRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

›SEQUENCE LISTING · 50 of 77

In some embodiments, the antibody comprises a VH comprising FRs having amino acid sequences of the FRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 192 and a VL comprising FRs having amino acid sequences of the FRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody comprises a VH comprising FRs having amino acid sequences of the FRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 194 and a VL comprising FRs having amino acid sequences of the FRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody comprises a VH comprising FRs having amino acid sequences of the FRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 196 and a VL comprising FRs having amino acid sequences of the FRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody comprises a VH comprising FRs having amino acid sequences of the FRs contained in the VH comprising an amino acid sequence of SEQ ID NO: 198 and a VL comprising FRs having amino acid sequences of the FRs contained in the VL comprising an amino acid sequence of SEQ ID NO: 40.

In certain embodiments, the antibody or antigen binding fragment thereof provided herein further comprises one or more FR regions from the humanized antibodies provided herein. FR regions from the humanized antibodies provided herein are described in more detail in Section 5.2.5 below.

Framework regions described herein are determined based upon the boundaries of the CDR numbering system. In other words, if the CDRs are determined by, e.g., Kabat, IMGT, or Chothia, or any combination thereof, then the framework regions are the amino acid residues surrounding the CDRs in the variable region in the format, from the N-terminus to C-terminus: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. For example, FR1 is defined as the amino acid residues N-terminal to the CDR1 amino acid residues as defined by, e.g., the Kabat numbering system, the IMGT numbering system, and/or the Chothia numbering system, FR2 is defined as the amino acid residues between CDR1 and CDR2 amino acid residues as defined by, e.g., the Kabat numbering system, the IMGT numbering system, and/or the Chothia numbering system, FR3 is defined as the amino acid residues between CDR2 and CDR3 amino acid residues as defined by, e.g., the Kabat numbering system, the IMGT numbering system, and/or the Chothia numbering system, and FR4 is defined as the amino acid residues C-terminal to the CDR3 amino acid residues as defined by, e.g., the Kabat numbering system, the IMGT numbering system, and/or the Chothia numbering system.

›SEQUENCE LISTING · 51 of 77

In certain embodiments, the antibody or antigen binding fragments provided herein comprises VH and/VL regions of the antibodies provided herein including those described in Section 6 below.

In some embodiments, the antibody or antigen binding fragments provided herein comprises one or more VH sequences listed in Table 28 below.

In some embodiments, the VH is 41c-VH comprising an amino acid sequence of SEQ ID NO: 35. In some embodiments, the VH is R35B9-VH comprising an amino acid sequence of SEQ ID NO: 50. In some embodiments, the VH is R35B9(Y50G57)-VH comprising an amino acid sequence of SEQ ID NO: 54. In some embodiments, the VH is R35B9(Y50A56G57)-VH comprising an amino acid sequence of SEQ ID NO: 56. In some embodiments, the VH is R35B9(A56)-VH comprising an amino acid sequence of SEQ ID NO: 60. In some embodiments, the VH is R35B9(Y50)-VH comprising an amino acid sequence of SEQ ID NO: 181. In some embodiments, the VH is R35B9(G57)-VH comprising an amino acid sequence of SEQ ID NO: 190. In some embodiments, the VH is R35B9(T28)-VH comprising an amino acid sequence of SEQ ID NO: 192. In some embodiments, the VH is R35B9(T30)-VH comprising an amino acid sequence of SEQ ID NO: 194. In some embodiments, the VH is R35B9(N54)-VH comprising an amino acid sequence of SEQ ID NO: 196. In some embodiments, the VH is 41C(R28Q30R54)-VH comprising an amino acid sequence of SEQ ID NO: 198.

In some embodiments, the antibodies provided herein comprise one or more VL sequences listed in Table 29 below.

In some embodiments, the VL is 41c-VL comprising an amino acid sequence of SEQ ID NO: 40. In some embodiments, the VL is R35B9-VL comprising an amino acid sequence of SEQ ID NO: 52. In some embodiments, the VL is R35B9(H98)-VL comprising an amino acid sequence of SEQ ID NO: 58. In some embodiments, the VL is R35B9(F99)-VL comprising an amino acid sequence of SEQ ID NO: 200.

In yet other embodiments, the antibody provided herein comprises a VH and/or a VL from Table 30 below.

In some embodiments, the antibody is A291/A290 comprising a VH comprising an amino acid sequence of SEQ ID NO: 35 and a VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody is A291/A403 comprising a VH comprising an amino acid sequence of SEQ ID NO: 35 and a VL comprising an amino acid sequence of SEQ ID NO: 52.

In some embodiments, the antibody is A291/A439 comprising a VH comprising an amino acid sequence of SEQ ID NO: 35 and a VL comprising an amino acid sequence of SEQ ID NO: 58.

In some embodiments, the antibody is A291/A440 comprising a VH comprising an amino acid sequence of SEQ ID NO: 35 and a VL comprising an amino acid sequence of SEQ ID NO: 200.

In some embodiments, the antibody is A402/A290 comprising a VH comprising an amino acid sequence of SEQ ID NO: 50 and a VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody is A402/A403 comprising a VH comprising an amino acid sequence of SEQ ID NO: 50 and a VL comprising an amino acid sequence of SEQ ID NO: 52.

In some embodiments, the antibody is A402/A439 comprising a VH comprising an amino acid sequence of SEQ ID NO: 50 and a VL comprising an amino acid sequence of SEQ ID NO: 58.

In some embodiments, the antibody is A402/A440 comprising a VH comprising an amino acid sequence of SEQ ID NO: 50 and a VL comprising an amino acid sequence of SEQ ID NO: 200.

In some embodiments, the antibody is A448/A290 comprising a VH comprising an amino acid sequence of SEQ ID NO: 54 and a VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody is A448/A403 comprising a VH comprising an amino acid sequence of SEQ ID NO: 54 and a VL comprising an amino acid sequence of SEQ ID NO: 52.

In some embodiments, the antibody is A448/A439 comprising a VH comprising an amino acid sequence of SEQ ID NO: 54 and a VL comprising an amino acid sequence of SEQ ID NO: 58.

In some embodiments, the antibody is A448/A440 comprising a VH comprising an amino acid sequence of SEQ ID NO: 54 and a VL comprising an amino acid sequence of SEQ ID NO: 200.

In some embodiments, the antibody is A490/A290 comprising a VH comprising an amino acid sequence of SEQ ID NO: 56 and a VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody is A490/A403 comprising a VH comprising an amino acid sequence of SEQ ID NO: 56 and a VL comprising an amino acid sequence of SEQ ID NO: 52.

In some embodiments, the antibody is A490/A439 comprising a VH comprising an amino acid sequence of SEQ ID NO: 56 and a VL comprising an amino acid sequence of SEQ ID NO: 58.

In some embodiments, the antibody is A490/A440 comprising a VH comprising an amino acid sequence of SEQ ID NO: 56 and a VL comprising an amino acid sequence of SEQ ID NO: 200.

In some embodiments, the antibody is A486/A290 comprising a VH comprising an amino acid sequence of SEQ ID NO: 60 and a VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody is A486/A403 comprising a VH comprising an amino acid sequence of SEQ ID NO: 60 and a VL comprising an amino acid sequence of SEQ ID NO: 52.

In some embodiments, the antibody is A486/A439 comprising a VH comprising an amino acid sequence of SEQ ID NO: 60 and a VL comprising an amino acid sequence of SEQ ID NO: 58.

In some embodiments, the antibody is A486/A440 comprising a VH comprising an amino acid sequence of SEQ ID NO: 60 and a VL comprising an amino acid sequence of SEQ ID NO: 200.

In some embodiments, the antibody is A437/A290 comprising a VH comprising an amino acid sequence of SEQ ID NO: 181 and a VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody is A437/A403 comprising a VH comprising an amino acid sequence of SEQ ID NO: 181 and a VL comprising an amino acid sequence of SEQ ID NO: 52.

In some embodiments, the antibody is A437/A439 comprising a VH comprising an amino acid sequence of SEQ ID NO: 181 and a VL comprising an amino acid sequence of SEQ ID NO: 58.

›SEQUENCE LISTING · 52 of 77

In some embodiments, the antibody is A437/A440 comprising a VH comprising an amino acid sequence of SEQ ID NO: 181 and a VL comprising an amino acid sequence of SEQ ID NO: 200.

In some embodiments, the antibody is A428/A290 comprising a VH comprising an amino acid sequence of SEQ ID NO: 190 and a VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody is A428/A403 comprising a VH comprising an amino acid sequence of SEQ ID NO: 190 and a VL comprising an amino acid sequence of SEQ ID NO: 52.

In some embodiments, the antibody is A428/A439 comprising a VH comprising an amino acid sequence of SEQ ID NO: 190 and a VL comprising an amino acid sequence of SEQ ID NO: 58.

In some embodiments, the antibody is A428/A440 comprising a VH comprising an amino acid sequence of SEQ ID NO: 190 and a VL comprising an amino acid sequence of SEQ ID NO: 200.

In some embodiments, the antibody is A435/A290 comprising a VH comprising an amino acid sequence of SEQ ID NO: 192 and a VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody is A435/A403 comprising a VH comprising an amino acid sequence of SEQ ID NO: 192 and a VL comprising an amino acid sequence of SEQ ID NO: 52.

In some embodiments, the antibody is A435/A439 comprising a VH comprising an amino acid sequence of SEQ ID NO: 192 and a VL comprising an amino acid sequence of SEQ ID NO: 58.

In some embodiments, the antibody is A435/A440 comprising a VH comprising an amino acid sequence of SEQ ID NO: 192 and a VL comprising an amino acid sequence of SEQ ID NO: 200.

In some embodiments, the antibody is A436/A290 comprising a VH comprising an amino acid sequence of SEQ ID NO: 194 and a VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody is A436/A403 comprising a VH comprising an amino acid sequence of SEQ ID NO: 194 and a VL comprising an amino acid sequence of SEQ ID NO: 52.

In some embodiments, the antibody is A436/A439 comprising a VH comprising an amino acid sequence of SEQ ID NO: 194 and a VL comprising an amino acid sequence of SEQ ID NO: 58.

In some embodiments, the antibody is A436/A440 comprising a VH comprising an amino acid sequence of SEQ ID NO: 194 and a VL comprising an amino acid sequence of SEQ ID NO: 200.

In some embodiments, the antibody is A438/A290 comprising a VH comprising an amino acid sequence of SEQ ID NO: 196 and a VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody is A438/A403 comprising a VH comprising an amino acid sequence of SEQ ID NO: 196 and a VL comprising an amino acid sequence of SEQ ID NO: 52.

In some embodiments, the antibody is A438/A439 comprising a VH comprising an amino acid sequence of SEQ ID NO: 196 and a VL comprising an amino acid sequence of SEQ ID NO: 58.

In some embodiments, the antibody is A438/A440 comprising a VH comprising an amino acid sequence of SEQ ID NO: 196 and a VL comprising an amino acid sequence of SEQ ID NO: 200.

In some embodiments, the antibody is A450/A290 comprising a VH comprising an amino acid sequence of SEQ ID NO: 198 and a VL comprising an amino acid sequence of SEQ ID NO: 40.

In some embodiments, the antibody is A450/A403 comprising a VH comprising an amino acid sequence of SEQ ID NO: 198 and a VL comprising an amino acid sequence of SEQ ID NO: 52.

In some embodiments, the antibody is A450/A439 comprising a VH comprising an amino acid sequence of SEQ ID NO: 198 and a VL comprising an amino acid sequence of SEQ ID NO: 58.

In some embodiments, the antibody is A450/A440 comprising a VH comprising an amino acid sequence of SEQ ID NO: 198 and a VL comprising an amino acid sequence of SEQ ID NO: 200.

In yet another aspect, provided herein are antibodies that compete with one of the antibodies or antigen binding fragments thereof described above. Such antibodies may also bind to the same epitope as one of the above mentioned antibodies, or an overlapping epitope. Antibodies and fragments that compete with or bind to the same epitope as the above-mentioned antibodies are expected to show similar functional properties. The exemplified antigen binding proteins and fragments include those with the VH regions, VL regions and CDRs provided herein, including those in the Sequence Listing provided herein and Tables 26-35.

In certain embodiments, an antibody described herein or an antigen-binding fragment thereof comprises amino acid sequences with certain percent identity relative to the antibodies described above including the exemplary antibodies described in Section 6 below.

The determination of percent identity between two sequences (e.g., amino acid sequences or nucleic acid sequences) can be accomplished using a mathematical algorithm. A preferred, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul, 1990, Proc. Natl. Acad. Sci. U.S.A. 87:2264 2268, modified as in Karlin and Altschul, 1993, Proc. Natl. Acad. Sci. U.S.A. 90:5873 5877. Such an algorithm is incorporated into the NBLAST and)(BLAST programs of Altschul et al., 1990, J. Mol. Biol. 215:403. BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score=100, word length=12 to obtain nucleotide sequences homologous to a nucleic acid molecules described herein. BLAST protein searches can be performed with the XBLAST program parameters set, e.g., to score 50, word length=3 to obtain amino acid sequences homologous to a protein molecule described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et aL , 1997, Nucleic Acids Res. 25:3389 3402. Alternatively, PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilizing BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see, e.g., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov). Another preferred, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4:11 17. Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used.

›SEQUENCE LISTING · 53 of 77

The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 35, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 35, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 35, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 35, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 35, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 35, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 35, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 35, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 35, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 35, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 35, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

›SEQUENCE LISTING · 54 of 77

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 35, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 50, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 50, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 50, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 50, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 50, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 50, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 50, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 50, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 50, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 50, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 50, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

›SEQUENCE LISTING · 55 of 77

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 50, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 54, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 54, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 54, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 54, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 54, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 54, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 54, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 54, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 54, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 54, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 54, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

›SEQUENCE LISTING · 56 of 77

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 54, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 56, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 56, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 56, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 56, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 56, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 56, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 56, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 56, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 56, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 56, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 56, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

›SEQUENCE LISTING · 57 of 77

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 56, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 60, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 60, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 60, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 60, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 60, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 60, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 60, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 60, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 60, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 60, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 60, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

›SEQUENCE LISTING · 58 of 77

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 60, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 181, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 181, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 181, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 181, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 181, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 181, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 181, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 181, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 181, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 181, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 181, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

›SEQUENCE LISTING · 59 of 77

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 181, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 190, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 190, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 190, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 190, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 190, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 190, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 190, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 190, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 190, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 190, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 190, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

›SEQUENCE LISTING · 60 of 77

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 190, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 192, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 192, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 192, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 192, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 192, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 192, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 192, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 192, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 192, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 192, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 192, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

›SEQUENCE LISTING · 61 of 77

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 192, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 194, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 194, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 194, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 194, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 194, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 194, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 194, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 194, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 194, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 194, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 194, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

›SEQUENCE LISTING · 62 of 77

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 194, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 196, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 196, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 196, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 196, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 196, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 196, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 196, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 196, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 196, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 196, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 196, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

›SEQUENCE LISTING · 63 of 77

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 196, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 198, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 198, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 198, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 40, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 198, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 198, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 198, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 52, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 198, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 198, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 198, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 58, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 198, and/or a VL region having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 198, and/or a VL region comprising CDRs having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the CDRs contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

›SEQUENCE LISTING · 64 of 77

In certain embodiments, an antibody provided herein or an antigen-binding fragment thereof comprises a VH region comprising VH framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence of the framework regions contained in SEQ ID NO: 198, and/or a VL region comprising VL framework regions having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to the amino acid sequence the framework regions contained in SEQ ID NO: 200, wherein the antibody immunospecifically binds to Fn14.

5.2.2 Polyclonal Antibodies

The antibodies of the present disclosure may comprise polyclonal antibodies. Methods of preparing polyclonal antibodies are known to the skilled artisan. Polyclonal antibodies can be raised in a mammal, for example, by one or more injections of an immunizing agent and, if desired, an adjuvant. Typically, the immunizing agent and/or adjuvant will be injected in the mammal by multiple subcutaneous or intraperitoneal injections. The immunizing agent may include an Fn14 polypeptide or a fusion protein thereof. It may be useful to conjugate the immunizing agent to a protein known to be immunogenic in the mammal being immunized or to immunize the mammal with the protein and one or more adjuvants. Examples of such immunogenic proteins include, but are not limited to, keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. Examples of adjuvants which may be employed include Ribi, CpG, Poly (I:C), Freund's complete adjuvant, and MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate). The immunization protocol may be selected by one skilled in the art without undue experimentation. The mammal can then be bled, and the serum assayed for anti-Fn14 antibody titer. If desired, the mammal can be boosted until the antibody titer increases or plateaus. Additionally or alternatively, lymphocytes may be obtained from the immunized animal for fusion and preparation of monoclonal antibodies from hybridoma as described below.

5.2.3 Monoclonal Antibodies

The antibodies of the present disclosure may alternatively be monoclonal antibodies. Monoclonal antibodies may be made using the hybridoma method first described by Kohler et al., 1975, Nature 256:495-97, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567).

In the hybridoma method, a mouse or other appropriate host animal, such as a hamster, is immunized as described above to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the protein used for immunization. Alternatively, lymphocytes may be immunized in vitro. After immunization, lymphocytes are isolated and then fused with a myeloma cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice 59-103 (1986)).

The hybridoma cells thus prepared are seeded and grown in a suitable culture medium, which, in certain embodiments, contains one or more substances that inhibit the growth or survival of the unfused, parental myeloma cells (also referred to as fusion partner). For example, if the parental myeloma cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the selective culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (HAT medium), which prevent the growth of HGPRT-deficient cells.

Exemplary fusion partner myeloma cells are those that fuse efficiently, support stable high-level production of antibody by the selected antibody-producing cells, and are sensitive to a selective medium that selects against the unfused parental cells. Exemplary myeloma cell lines are murine myeloma lines, such as SP-2 and derivatives, for example, X 63 -Ag8-653 cells available from the American Type Culture Collection (Manassas, VA), and those derived from MOPC-21 and MPC-11 mouse tumors available from the Salk Institute Cell Distribution Center (San Diego, CA). Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies (Kozbor, 1984, Immunol. 133:3001-05; and Brodeur et al., 1987, Monoclonal Antibody Production Techniques and Applications 51-63).

Culture medium in which hybridoma cells are growing is assayed for production of monoclonal antibodies directed against the antigen. The binding specificity of monoclonal antibodies produced by hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as RIA or ELISA. The binding affinity of the monoclonal antibody can,for example, be determined by the Scatchard analysis described in Munson et al., 1980, Anal. Biochem. 107:220-39.

Once hybridoma cells that produce antibodies of the desired specificity, affinity, and/or activity are identified, the clones may be subcloned by limiting dilution procedures and grown by standard methods (Goding, supra). Suitable culture media for this purpose include, for example, DMEM or RPMI-1640 medium. In addition, the hybridoma cells may be grown in vivo as ascites tumors in an animal, for example, by i.p. injection of the cells into mice.

The monoclonal antibodies secreted by the subclones are suitably separated from the culture medium, ascites fluid, or serum by conventional antibody purification procedures such as, for example, affinity chromatography (e.g., using protein A or protein G-Sepharose) or ion-exchange chromatography, hydroxylapatite chromatography, gel electrophoresis, dialysis, etc.

DNA encoding the monoclonal antibodies is readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells can serve as a source of such DNA. Once isolated, the DNA may be placed into expression vectors, which are then transfected into host cells, such as E. coli cells, simian COS cells, Chinese Hamster Ovary (CHO) cells, or myeloma cells that do not otherwise produce antibody protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. Review articles on recombinant expression in bacteria of DNA encoding the antibody include Skerra et al., 1993, Curr. Opinion in Immunol. 5:256-62 and Phickthun, 1992, Immunol. Revs. 130:151-88.

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In some embodiments, an antibody that binds an Fn14 epitope comprises an amino acid sequence of a VH domain and/or an amino acid sequence of a VL domain encoded by a nucleotide sequence that hybridizes to (1) the complement of a nucleotide sequence encoding any one of the VH and/or VL domain described herein under stringent conditions (e.g., hybridization to filter-bound DNA in 6× sodium chloride/sodium citrate (SSC) at about 45° C. followed by one or more washes in 0.2× SSC/0.1% SDS at about 50-65° C.), under highly stringent conditions (e.g., hybridization to filter-bound nucleic acid in 6× SSC at about 45° C. followed by one or more washes in 0.1× SSC/0.2% SDS at about 68° C.), or under other stringent hybridization conditions which are known to those of skill in the art. See, e.g., Current Protocols in Molecular Biology Vol. I, 6.3.1-6.3.6 and 2.10.3 (Ausubel et al. eds., 1989).

In some embodiments, an antibody that binds an Fn14 epitope comprises an amino acid sequence of a VH CDR or an amino acid sequence of a VL CDR encoded by a nucleotide sequence that hybridizes to the complement of a nucleotide sequence encoding any one of the VH CDRs and/or VL CDRs depicted in the Sequence Listing provided herein under stringent conditions (e.g., hybridization to filter-bound DNA in 6× SSC at about 45° C. followed by one or more washes in 0.2× SSC/0.1% SDS at about 50-65° C.), under highly stringent conditions (e.g., hybridization to filter-bound nucleic acid in 6× SSC at about 45° C. followed by one or more washes in 0.1× SSC/0.2% SDS at about 68° C.), or under other stringent hybridization conditions which are known to those of skill in the art (see, e.g., Ausubel et al., supra).

In a further embodiment, monoclonal antibodies or antibody fragments can be isolated from antibody phage libraries generated using the techniques described in, for example, Antibody Phage Display: Methods and Protocols (O'Brien and Aitken eds., 2002). In phage display methods, functional antibody domains are displayed on the surface of phage particles which carry the polynucleotide sequences encoding them. Examples of phage display methods that can be used to make the antibodies described herein include those disclosed in Brinkman et al., 1995, J. Immunol. Methods 182:41-50; Ames et al., 1995, J. Immunol. Methods 184:177-186; Kettleborough et al., 1994, Eur. J. Immunol. 24:952-958; Persic et al., 1997, Gene 187:9-18; Burton et al., 1994, Advances in Immunology 57:191-280; PCT Application No. PCT/GB91/O1 134; International Publication Nos. WO 90/02809, WO 91/10737, WO 92/01047, WO 92/18619, WO 93/1 1236, WO 95/15982, WO 95/20401, and WO97/13844; and U.S. Pat. Nos. 5,698,426, 5,223,409, 5,403,484, 5,580,717, 5,427,908, 5,750,753, 5,821,047, 5,571,698, 5,427,908, 5,516,637, 5,780,225, 5,658,727, 5,733,743 and 5,969,108.

In principle, synthetic antibody clones are selected by screening phage libraries containing phages that display various fragments of antibody variable region (Fv) fused to phage coat protein. Such phage libraries are screened against the desired antigen. Clones expressing Fv fragments capable of binding to the desired antigen are adsorbed to the antigen and thus separated from the non-binding clones in the library. The binding clones are then eluted from the antigen and can be further enriched by additional cycles of antigen adsorption/elution.

Variable domains can be displayed functionally on phage, either as single-chain Fv (scFv) fragments, in which VH and VL are covalently linked through a short, flexible peptide, or as Fab fragments, in which they are each fused to a constant domain and interact non-covalently, as described, for example, in Winter et al., 1994, Ann. Rev. Immunol. 12:433-55.

Repertoires of VH and VL genes can be separately cloned by PCR and recombined randomly in phage libraries, which can then be searched for antigen-binding clones as described in Winter et al., supra. Libraries from immunized sources provide high-affinity antibodies to the immunogen without the requirement of constructing hybridomas. Alternatively, the naive repertoire can be cloned to provide a single source of human antibodies to a wide range of non-self and also self antigens without any immunization as described by Griffiths et al., 1993, EMBO J 12:725-34. Finally, naive libraries can also be made synthetically by cloning the unrearranged V-gene segments from stem cells, and using PCR primers containing random sequence to encode the highly variable CDR3 regions and to accomplish rearrangement in vitro as described, for example, by Hoogenboom and Winter, 1992, J. Mol. Biol. 227:381-88.

Screening of the libraries can be accomplished by various techniques known in the art. For example, Fn14 (e.g., an Fn14 polypeptide, fragment, or epitope) can be used to coat the wells of adsorption plates, expressed on host cells affixed to adsorption plates or used in cell sorting, conjugated to biotin for capture with streptavidin-coated beads, or used in any other method for panning display libraries. The selection of antibodies with slow dissociation kinetics (e.g., good binding affinities) can be promoted by use of long washes and monovalent phage display as described in Bass et al., 1990, Proteins 8:309-14 and WO 92/09690, and by use of a low coating density of antigen as described in Marks et al., 1992, Biotechnol. 10:779-83.

Anti-Fn14 antibodies can be obtained by designing a suitable antigen screening procedure to select for the phage clone of interest followed by construction of a full length antibody clone using VH and/or VL sequences (e.g., the Fv sequences), or various CDR sequences from VH and VL sequences, from the phage clone of interest and suitable constant region (e.g., Fc) sequences described in Kabat et al., supra.

Antibodies described herein can also, for example, include chimeric antibodies. A chimeric antibody is a molecule in which different portions of the antibody are derived from different immunoglobulin molecules. For example, a chimeric antibody can contain a variable region of a mouse or rat monoclonal antibody fused to a constant region of a human antibody. Methods for producing chimeric antibodies are known in the art. See, e.g., Morrison, 1985, Science 229:1202; Oi et al., 1986, BioTechniques 4:214; Gillies et al., 1989, J. Immunol. Methods 125:191-202; and U.S. Pat. Nos. 5,807,715, 4,816,567, 4,816,397, and 6,331,415.

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Antibodies or antigen binding fragments produced using techniques such as those described herein can be isolated using standard, well known techniques. For example, antibodies or antigen binding fragments can be suitably separated from, e.g., culture medium, ascites fluid, serum, cell lysate, synthesis reaction material or the like by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography. As used herein, an “isolated” or “purified” antibody is substantially free of cellular material or other proteins from the cell or tissue source from which the antibody is derived, or substantially free of chemical precursors or other chemicals when chemically synthesized.

In some specific embodiments, monoclonal antibodies are generated using the methods exemplified in Section 6 below. In some specific embodiments, hybridoma isgenerated using the methods exemplified in Section 6 below. In some specific embodiments, chimeric antibodies are generated using the methods exemplified in Section 6 below.

5.2.4 Antibody Fragments

The present disclosure provides antibodies and antibody fragments that bind to Fn14. In certain circumstances, there are advantages of using antibody fragments rather than whole antibodies. The smaller size of the fragments allows for rapid clearance, and may lead to improved access to cells, tissues, or organs. For a review of certain antibody fragments, see Hudson et al., 2003, Nature Med. 9:129-34.

Various techniques have been developed for the production of antibody fragments. Traditionally, these fragments were derived via proteolytic digestion of intact antibodies (see, e.g., Morimoto et al., 1992, J. Biochem. Biophys. Methods 24:107-17; and Brennan et aL , 1985, Science 229:81-83). However, these fragments can now be produced directly by recombinant host cells. Fab, Fv, and scFv antibody fragments can all be expressed in and secreted from E. coli or yeast cells, thus allowing the facile production of large amounts of these fragments. Antibody fragments can be isolated from the antibody phage libraries discussed above. Alternatively, Fab′-SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab′)2 fragments (Carter et al., 1992, Bio/Technology 10:163-67). According to another approach, F(ab′)2 fragments can be isolated directly from recombinant host cell culture. Fab and F(ab′)2 fragment with increased in vivo half-life comprising salvage receptor binding epitope residues are described in, for example, U.S. Pat. No. 5,869,046. Other techniques for the production of antibody fragments will be apparent to the skilled practitioner. In certain embodiments, an antibody is a single chain Fv fragment (scFv) (see, e.g., WO 93/16185; U.S. Pat. Nos. 5,571,894 and 5,587,458). Fv and scFv have intact combining sites that are devoid of constant regions; thus, they may be suitable for reduced nonspecific binding during in vivo use. scFv fusion proteins may be constructed to yield fusion of an effector protein at either the amino or the carboxy terminus of an scFv (See, e.g., Borrebaeck ed., supra). The antibody fragment may also be a “linear antibody,” for example, as described in the references cited above. Such linear antibodies may be monospecific or multi-specific, such as bispecific.

Smaller antibody-derived binding structures are the separate variable domains (V domains) also termed single variable domain antibodies (sdAbs). Certain types of organisms, the camelids and cartilaginous fish, possess high affinity single V-like domains mounted on an Fc equivalent domain structure as part of their immune system. (Woolven et al., 1999, Immunogenetics 50: 98-101; and Streltsov et al., 2004, Proc Natl Acad Sci USA. 101:12444-49). The V-like domains (called VhH in camelids and V-NAR in sharks) typically display long surface loops, which allow penetration of cavities of target antigens. They also stabilize isolated VH domains by masking hydrophobic surface patches.

These VhH and V-NAR domains have been used to engineer sdAbs. Human V domain variants have been designed using selection from phage libraries and other approaches that have resulted in stable, high binding VL- and VH-derived domains.

Antibodies provided herein include, but are not limited to, immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, for example, molecules that contain an antigen binding site that bind to an Fn14 epitope. The immunoglobulin molecules provided herein can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) of immunoglobulin molecule.

Variants and derivatives of antibodies include antibody functional fragments that retain the ability to bind to an Fn14 epitope. Exemplary functional fragments include Fab fragments (e.g., an antibody fragment that contains the antigen-binding domain and comprises a light chain and part of a heavy chain bridged by a disulfide bond); Fab′ (e.g., an antibody fragment containing a single antigen-binding domain comprising an Fab and an additional portion of the heavy chain through the hinge region); F(ab′)2 (e.g., two Fab′ molecules joined by interchain disulfide bonds in the hinge regions of the heavy chains; the Fab′ molecules may be directed toward the same or different epitopes); a bispecific Fab (e.g., a Fab molecule having two antigen binding domains, each of which may be directed to a different epitope); a single chain comprising a variable region, also known as, scFv (e.g., the variable, antigen-binding determinative region of a single light and heavy chain of an antibody linked together by a chain of 10-25 amino acids); a disulfide-linked Fv, or dsFv (e.g., the variable, antigen-binding determinative region of a single light and heavy chain of an antibody linked together by a disulfide bond); a camelized VH (e.g., the variable, antigen-binding determinative region of a single heavy chain of an antibody in which some amino acids at the VH interface are those found in the heavy chain of naturally occurring camel antibodies); a bispecific scFv (e.g., an scFv or a dsFv molecule having two antigen-binding domains, each of which may be directed to a different epitope); a diabody (e.g., a dimerized scFv formed when the VH domain of a first scFv assembles with the VL domain of a second scFv and the VL domain of the first scFv assembles with the VH domain of the second scFv; the two antigen-binding regions of the diabody may be directed towards the same or different epitopes); a triabody (e.g., a trimerized scFv, formed in a manner similar to a diabody, but in which three antigen-binding domains are created in a single complex; the three antigen binding domains may be directed towards the same or different epitopes) ; and a tetrabody (e.g., a tetramerized scFv, formed in a manner similar to a diabody, but in which four antigen-binding domains are created in a single complex; the four antigen binding domains may be directed towards the same or different epitopes).

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5.2.5 Humanized Antibodies

The antibodies described herein can, for example, include humanized antibodies, e.g., deimmunized or composite human antibodies.

A humanized antibody can comprise human framework region and human constant region sequences. For example, a humanized antibody can comprise human constant region sequences. In certain embodiments, a humanized antibody can be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA and IgE, and any isotype, including IgG1, IgG2, IgG3 and IgG4 (e.g., variants of IgG4 and IgG4 nullbody). In certain embodiments, a humanized antibody can comprise kappa or lambda light chain constant sequences.

Humanized antibodies can be produced using a variety of techniques known in the art, including but not limited to, CDR-grafting (European Patent No. EP 239,400; International publication No. WO 91/09967; and U.S. Pat. Nos. 5,225,539, 5,530,101, and 5,585,089), veneering or resurfacing (European Patent Nos. EP 592,106 and EP 519,596; Padlan, 1991, Molecular Immunology 28(4/5):489-498; Studnicka et al., 1994, Protein Engineering 7(6):805-814; and Roguska et al., 1994, PNAS 91:969-973), chain shuffling (U.S. Pat. No. 5,565,332), and techniques disclosed in, e.g., U .S. Pat. No. 6,407,213, U.S. Pat. No. 5,766,886, WO 93/17105, Tan et al., J. Immunol. 169:1119 25 (2002), Caldas et al., Protein Eng. 13(5):353-60 (2000), Morea et al., Methods 20(3):267 79 (2000), Baca et al., J. Biol. Chem. 272(16):10678-84 (1997), Roguska et al., Protein Eng. 9(10):895 904 (1996), Couto et al., Cancer Res. 55 (23 Supp):5973s- 5977s (1995), Couto et al., Cancer Res. 55(8):1717-22 (1995), Sandhu JS, Gene 150(2):409-10 (1994), and Pedersen et al., J. Mol. Biol. 235(3):959-73 (1994). See also U.S. Patent Pub. No. US 2005/0042664 A1 (Feb. 24, 2005), each of which is incorporated by reference herein in its entirety.

In some embodiments, antibodies provided herein can be humanized antibodies that bind Fn14, including human, cynomolgus macaque, rat and mouse Fn14. For example, humanized antibodies of the present disclosure may comprise one or more CDRs as shown in the Sequence Listing provided herein. Various methods for humanizing non-human antibodies are known in the art. For example, a humanized antibody can have one or more amino acid residues introduced into it from a source that is non-human. These non-human amino acid residues are often referred to as “import” residues, which are typically taken from an “import” variable domain. Humanization may be performed, for example, following the method of Jones et al., 1986, Nature 321:522-25; Riechmann et al., 1988, Nature 332:323-27; and Verhoeyen et al., 1988, Science 239:1534-36), by substituting hypervariable region sequences for the corresponding sequences of a human antibody.

In some cases, the humanized antibodies are constructed by CDR grafting, in which the amino acid sequences of the six CDRs of the parent non-human antibody (e.g., rodent) are grafted onto a human antibody framework. For example, Padlan et al. determined that only about one third of the residues in the CDRs actually contact the antigen, and termed these the “specificity determining residues,” or SDRs (Padlan et al., 1995, FASEB J. 9:133-39). In the technique of SDR grafting, only the SDR residues are grafted onto the human antibody framework (see, e.g., Kashmiri et al., 2005, Methods 36:25-34).

The choice of human variable domains, both light and heavy, to be used in making the humanized antibodies can be important to reduce antigenicity. For example, according to the so-called “best-fit” method, the sequence of the variable domain of a non-human (e.g., rodent) antibody is screened against the entire library of known human variable-domain sequences. The human sequence that is closest to that of the rodent may be selected as the human framework for the humanized antibody (Sims et al., 1993, J. Immunol. 151:2296-308; and Chothia et al., 1987, J. Mol. Biol. 196:901-17). Another method uses a particular framework derived from the consensus sequence of all human antibodies of a particular subgroup of light or heavy chains. The same framework may be used for several different humanized antibodies (Carter et al., 1992, Proc. Natl. Acad. Sci. USA 89:4285-89; and Presta et al., 1993, J. Immunol. 151:2623-32). In some cases, the framework is derived from the consensus sequences of the most abundant human subclasses, VL6 subgroup I (VL6I) and VH subgroup III (VHIII). In another method, human germline genes are used as the source of the framework regions.

In an alternative paradigm based on comparison of CDRs, called superhumanization, FR homology is irrelevant. The method consists of comparison of the non-human sequence with the functional human germline gene repertoire. Those genes encoding the same or closely related canonical structures to the murine sequences are then selected. Next, within the genes sharing the canonical structures with the non-human antibody, those with highest homology within the CDRs are chosen as FR donors. Finally, the non-human CDRs are grafted onto these FRs (see, e.g., Tan et al., 2002, J. Immunol. 169:1119-25).

It is further generally desirable that antibodies be humanized with retention of their affinity for the antigen and other favorable biological properties. To achieve this goal, according to one method, humanized antibodies are prepared by a process of analysis of the parental sequences and various conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. These include, for example, WAM (Whitelegg and Rees, 2000, Protein Eng. 13:819-24), Modeller (Sali and Blundell, 1993, J. Mol. Biol. 234:779-815), and Swiss PDB Viewer (Guex and Peitsch, 1997, Electrophoresis 18:2714-23). Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, e.g., the analysis of residues that influence the ability of the candidate immunoglobulin to bind its antigen. In this way, FR residues can be selected and combined from the recipient and import sequences so that the desired antibody characteristic, such as increased affinity for the target antigen(s), is achieved. In general, the hypervariable region residues are directly and most substantially involved in influencing antigen binding.

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Another method for antibody humanization is based on a metric of antibody humanness termed Human String Content (HSC). This method compares the mouse sequence with the repertoire of human germline genes, and the differences are scored as HSC. The target sequence is then humanized by maximizing its HSC rather than using a global identity measure to generate multiple diverse humanized variants (Lazar et al., 2007, Mol. Immunol. 44:1986-98).

In addition to the methods described above, empirical methods may be used to generate and select humanized antibodies. These methods include those that are based upon the generation of large libraries of humanized variants and selection of the best clones using enrichment technologies or high throughput screening techniques. Antibody variants may be isolated from phage, ribosome, and yeast display libraries as well as by bacterial colony screening (see, e.g., Hoogenboom, 2005, Nat. Biotechnol. 23:1105-16; Dufner et al., 2006, Trends Biotechnol. 24:523-29; Feldhaus et al., 2003, Nat. Biotechnol. 21:163-70; and Schlapschy et al., 2004, Protein Eng. Des. Sel. 17:847-60).

In the FR library approach, a collection of residue variants are introduced at specific positions in the FR followed by screening of the library to select the FR that best supports the grafted CDR. The residues to be substituted may include some or all of the “Vernier” residues identified as potentially contributing to CDR structure (see, e.g., Foote and Winter, 1992, J. Mol. Biol. 224:487-99), or from the more limited set of target residues identified by Baca et al. (1997, J. Biol. Chem. 272:10678-84).

In FR shuffling, whole FRs are combined with the non-human CDRs instead of creating combinatorial libraries of selected residue variants (see, e.g., Dall' Acqua et al., 2005, Methods 36:43-60). The libraries may be screened for binding in a two-step process, first humanizing VL, followed by VH. Alternatively, a one-step FR shuffling process may be used. Such a process has been shown to be more efficient than the two-step screening, as the resulting antibodies exhibited improved biochemical and physicochemical properties including enhanced expression, increased affinity, and thermal stability (see, e.g., Damschroder et al., 2007, Mol. Immunol. 44:3049-60).

The “humaneering” method is based on experimental identification of essential minimum specificity determinants (MSDs) and is based on sequential replacement of non-human fragments into libraries of human FRs and assessment of binding. It begins with regions of the CDR3 of non-human VH and VL chains and progressively replaces other regions of the non-human antibody into the human FRs, including the CDR1 and CDR2 of both VH and VL. This methodology typically results in epitope retention and identification of antibodies from multiple subclasses with distinct human V-segment CDRs. Humaneering allows for isolation of antibodies that are 91-96% homologous to human germline gene antibodies (see, e.g., Alfenito, Cambridge Healthtech Institute's Third Annual PEGS, The Protein Engineering Summit, 2007).

The “human engineering” method involves altering a non-human antibody or antibody fragment, such as a mouse or chimeric antibody or antibody fragment, by making specific changes to the amino acid sequence of the antibody so as to produce a modified antibody with reduced immunogenicity in a human that nonetheless retains the desirable binding properties of the original non-human antibodies. Generally, the technique involves classifying amino acid residues of a non-human (e.g., mouse) antibody as “low risk,” “moderate risk,” or “high risk” residues. The classification is performed using a global risk/reward calculation that evaluates the predicted benefits of making particular substitution (e.g., for immunogenicity in humans) against the risk that the substitution will affect the resulting antibody's folding. The particular human amino acid residue to be substituted at a given position (e.g., low or moderate risk) of a non-human (e.g., mouse) antibody sequence can be selected by aligning an amino acid sequence from the non-human antibody's variable regions with the corresponding region of a specific or consensus human antibody sequence. The amino acid residues at low or moderate risk positions in the non-human sequence can be substituted for the corresponding residues in the human antibody sequence according to the alignment. Techniques for making human engineered proteins are described in greater detail in Studnicka et al., 1994, Protein Engineering 7:805-14; U.S. Pat. Nos. 5,766,886; 5,770,196; 5,821,123; and 5,869,619; and PCT Publication WO 93/11794.

A composite human antibody can be generated using, for example, Composite Human Antibody™ technology (Antitope Ltd., Cambridge, United Kingdom). To generate composite human antibodies, variable region sequences are designed from fragments of multiple human antibody variable region sequences in a manner that avoids T cell epitopes, thereby minimizing the immunogenicity of the resulting antibody. Such antibodies can comprise human constant region sequences, e.g., human light chain and/or heavy chain constant regions.

A deimmunized antibody is an antibody in which T-cell epitopes have been removed. Methods for making deimmunized antibodies have been described. See, e.g., Jones et al., Methods Mol Biol. 2009;525:405-23, xiv, and De Groot et al., Cell. Immunol. 244:148-153(2006)). Deimmunized antibodies comprise T-cell epitope-depleted variable regions and human constant regions. Briefly, VH and VL of an antibody are cloned and T-cell epitopes are subsequently identified by testing overlapping peptides derived from the VH and VL of the antibody in a T cell proliferation assay. T cell epitopes are identified via in silico methods to identify peptide binding to human MHC class II. Mutations are introduced in the VH and VL to abrogate binding to human MHC class II. Mutated VH and VL are then utilized to generate the deimmunized antibody.

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In some specific embodiments, humanized antibodies are generated using the methods exemplified in Section 6 below.

In some embodiments, the humanized antibodies comprises one or more CDRs listed in Table 26 and/or described in Section 5.2.1 above.

More specifically, in some embodiments, the humanized antibody or antigen binding fragment thereof provided herein comprises:

(a) a heavy chain variable region (VH) comprising (i) VH complementarity determining region 1 (CDR H1) comprising an amino acid sequence of GYX 1 FX 2 DYNMH (SEQ ID NO: 184), wherein X 1 is T, I or R, and X 2 is T or Q; (ii) VH complementarity determining region 2 (CDR H2) comprising an amino acid sequence of X 3 INPX 4 NX 5 X 6 TNYNQKFKG (SEQ ID NO: 185), wherein X 3 is Y or S, X 4 is N or R; X 5 is A or G, and X 6 is G or W; (iii) VH complementarity determining region 3 (CDR H3) comprising an amino acid sequence of SGWFTY (SEQ ID NO: 121); (b) a light chain variable region (VL) comprising (i) VL complementarity determining region 1 (CDR L1) comprising an amino acid sequence of KS SQSLLNSAGKTYLN (SEQ ID NO: 127); (ii) VL complementarity determining region 2 (CDR L2) comprising an amino acid sequence of LVSQLDS (SEQ ID NO: 128); (iii) VL complementarity determining region 3 (CDR L3) comprising an amino acid sequence of WQGTX 7 X 8 PWT (SEQ ID NO: 186), wherein X 7 is H or F, and X 8 is F or Y.

In some more specific embodiments, the humanized antibody or antigen binding fragment thereof provided herein comprises:

(a) a heavy chain variable region (VH) comprising (i)VH complementarity determining region 1 (CDR H1) comprising an amino acid sequence of GYIFQDYNMEI (SEQ ID NO: 122); (ii) VH complementarity determining region 2 (CDR H2) comprising an amino acid sequence of X 3 INPRNX 5 X 6 TNYNQKFKG (SEQ ID NO: 187), wherein X 3 is Y or S, X 5 is A or G; and X 6 is G or W; and (iii) VH complementarity determining region 3 (CDR H3) comprising an amino acid sequence of SGWFTY (SEQ ID NO: 121); (b) a light chain variable region (VL) comprising (i) VL complementarity determining region 1 (CDR L1) comprising an amino acid sequence of KSSQSLLNSAGKTYLN (SEQ ID NO: 127); (ii) VL complementarity determining region 2 (CDR L2) comprising an amino acid sequence of LVSQLDS (SEQ ID NO: 128); and (iii) VL complementarity determining region 3 (CDR L3) comprising an amino acid sequence of WQGTX 7 YPWT (SEQ ID NO: 188), wherein X 7 is H or F.

In some embodiments, the antibody or antigen binding fragment thereof comprises:

(a) a heavy chain variable region (VH) comprising (i) VH complementarity determining region 1 (CDR H1) comprising an amino acid sequence of GYIFQDYNIVIII (SEQ ID NO: 122); (ii) VH complementarity determining region 2 (CDR H2) comprising an amino acid sequence of X 3 INPRNX 5 X 6 TNYNX 9 KFXioG (SEQ ID NO: 259), wherein X 3 is Y or S, X 5 is A or G; X 6 is G or W, X 9 is Q or D, and X 10 is K, G, H, or D; (iii) VH complementarity determining region 3 (CDR H3) comprising an amino acid sequence of SGWFTY (SEQ ID NO: 121); (b) a light chain variable region (VL) comprising (i) VL complementarity determining region 1 (CDR L1) comprising an amino acid sequence of KSSQSLLNSAGKTYLN (SEQ ID NO: 127); (ii) VL complementarity determining region 2 (CDR L2) comprising an amino acid sequence of LVX 11 X 12 LDX 13 (SEQ ID NO: 258), wherein X 11 is S or A, X 12 is Q or E, and X 13 is S or D; (iii) VL complementarity determining region 3 (CDR L3) comprising an amino acid sequence of WQGTX 7 YPWT (SEQ ID NO: 188), wherein X 7 is H or F.

In other more specific embodiments, the humanized antibody or antigen binding fragment thereof provided herein comprises one or more CDRs from Table 31 below.

Thus, in some more specific embodiments, the humanized antibody or antigen binding fragment thereof provided herein comprises:

(a) a heavy chain variable region (VH) comprising (i) VH complementarity determining region 1 (CDR H1) comprising an amino acid sequence of SEQ ID NO: 122; (ii) VH complementarity determining region 2 (CDR H2) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 126, SEQ ID NO: 247, SEQ ID NO: 248, SEQ ID NO: 249, and SEQ ID NO: 250; and (iii) VH complementarity determining region 3 (CDR H3) comprising an amino acid sequence of SEQ ID NO: 121, and (b) a light chain variable region (VL) comprising (i) VL complementarity determining region 1 (CDR L1) comprising an amino acid sequence of SEQ ID NO: 127; (ii) VL complementarity determining region 2 (CDR L2) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 128, SEQ ID NO: 254, SEQ ID NO: 255, and SEQ ID NO: 256; and (iii) VL complementarity determining region 3 (CDR L3) comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 130 and SEQ ID NO: 131.

In other more specific embodiments, the humanized antibody or antigen binding fragment thereof provided herein comprises a VH comprising CDRs comprising amino acid sequences of the CDRs contained in the VH selected from a group consisting of SEQ ID NO: 179, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 106, SEQ ID NO: 108, SEQ ID NO: 110, SEQ ID NO: 203, SEQ ID NO: 205, SEQ ID NO: 207, SEQ ID NO: 209, SEQ ID NO: 211, SEQ ID NO: 213, SEQ ID NO: 215, SEQ ID NO: 217, SEQ ID NO: 219, SEQ ID NO: 221, SEQ ID NO: 223, SEQ ID NO: 225 and SEQ ID NO: 227; and a VL comprising CDRs comprising amino acid sequences of the CDRs contained in the VL selected from a group consisting of SEQ ID NO: 92, SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 98, SEQ ID NO: 100, SEQ ID NO: 102, SEQ ID NO: 104, SEQ ID NO: 112, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 233, SEQ ID NO: 235 and SEQ ID NO: 237.

›SEQUENCE LISTING · 70 of 77

In some embodiments, the humanized antibody or antigen binding fragment provided herein further comprises one or more FRs from the humanized antibodies described herein including those in Section 6 below. In some embodiments, the humanized antibody or antigen binding fragment thereof provided herein comprises one or more FR sequences listed in Table 32 below.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 133, SEQ ID NO: 134, SEQ ID NO: 135, SEQ ID NO: 136, SEQ ID NO: 137, SEQ ID NO: 238 and SEQ ID NO: 239. In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 133. In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 134. In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 135. In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 136. In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 137. In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 238. In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 239.

In some embodiments, the antibody comprises a FR H2 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 141, SEQ ID NO: 142, and SEQ ID NO: 143, SEQ ID NO: 144, SEQ ID NO: 173, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 245 and SEQ ID NO: 246. In some embodiments, the antibody comprises a FR H2 comprising an amino acid sequence of SEQ ID NO: 139. In some embodiments, the antibody comprises a FR H2 comprising an amino acid sequence of SEQ ID NO: 140. In some embodiments, the antibody comprises a FR H2 comprising an amino acid sequence of SEQ ID NO: 141. In some embodiments, the antibody comprises a FR H2 comprising an amino acid sequence of SEQ ID NO: 142. In some embodiments, the antibody comprises a FR H2 comprising an amino acid sequence of SEQ ID NO: 143. In some embodiments, the antibody comprises a FR H2 comprising an amino acid sequence of SEQ ID NO: 144. In some embodiments, the antibody comprises a FR H2 comprising an amino acid sequence of SEQ ID NO: 173. In some embodiments, the antibody comprises a FR H2 comprising an amino acid sequence of SEQ ID NO: 240. In some embodiments, the antibody comprises a FR H2 comprising an amino acid sequence of SEQ ID NO: 241. In some embodiments, the antibody comprises a FR H2 comprising an amino acid sequence of SEQ ID NO: 242. In some embodiments, the antibody comprises a FR H2 comprising an amino acid sequence of SEQ ID NO: 243. In some embodiments, the antibody comprises a FR H2 comprising an amino acid sequence of SEQ ID NO: 244. In some embodiments, the antibody comprises a FR H2 comprising an amino acid sequence of SEQ ID NO: 245. In some embodiments, the antibody comprises a FR H2 comprising an amino acid sequence of SEQ ID NO: 246.

In some embodiments, the antibody comprises a FR H3 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 146, SEQ ID NO: 147, SEQ ID NO: 148, SEQ ID NO: 150, SEQ ID NO: 151, SEQ ID NO: 152, SEQ ID NO: 153, SEQ ID NO: 154, SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 157, SEQ ID NO: 174, and SEQ ID NO: 251. In some embodiments, the antibody comprises a FR H3 comprising an amino acid sequence of SEQ ID NO: 146. In some embodiments, the antibody comprises a FR H3 comprising an amino acid sequence of SEQ ID NO: 147. In some embodiments, the antibody comprises a FR H3 comprising an amino acid sequence of SEQ ID NO: 148. In some embodiments, the antibody comprises a FR H3 comprising an amino acid sequence of SEQ ID NO: 150. In some embodiments, the antibody comprises a FR H3 comprising an amino acid sequence of SEQ ID NO: 151. In some embodiments, the antibody comprises a FR H3 comprising an amino acid sequence of SEQ ID NO: 152. In some embodiments, the antibody comprises a FR H3 comprising an amino acid sequence of SEQ ID NO: 153. In some embodiments, the antibody comprises a FR H3 comprising an amino acid sequence of SEQ ID NO: 154. In some embodiments, the antibody comprises a FR H3 comprising an amino acid sequence of SEQ ID NO: 155. In some embodiments, the antibody comprises a FR H3 comprising an amino acid sequence of SEQ ID NO: 156. In some embodiments, the antibody comprises a FR H3 comprising an amino acid sequence of SEQ ID NO: 157. In some embodiments, the antibody comprises a FR H3 comprising an amino acid sequence of SEQ ID NO: 174. In some embodiments, the antibody comprises a FR H3 comprising an amino acid sequence of SEQ ID NO: 251.

In some embodiments, the antibody comprises a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR L1 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 161 and SEQ ID NO: 162. In some embodiments, the antibody comprises a FR L1 of SEQ ID NO: 161. In some embodiments, the antibody comprises a FR L1 of SEQ ID NO: 162.

In some embodiments, the antibody comprises a FR L2 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 163, SEQ ID NO: 164, SEQ ID NO: 165, SEQ ID NO: 166, SEQ ID NO: 167, SEQ ID NO: 168, SEQ ID NO: 252 and SEQ ID NO: 253. In some embodiments, the antibody comprises a FR L2 of SEQ ID NO: 163. In some embodiments, the antibody comprises a FR L2 of SEQ ID NO: 164. In some embodiments, the antibody comprises a FR L2 of SEQ ID NO: 165. In some embodiments, the antibody comprises a FR L2 of SEQ ID NO: 166. In some embodiments, the antibody comprises a FR L2 of SEQ ID NO: 167. In some embodiments, the antibody comprises a FR L2 of SEQ ID NO: 168. In some embodiments, the antibody comprises a FR L2 of SEQ ID NO: 252. In some embodiments, the antibody comprises a FR L2 of SEQ ID NO: 253.

›SEQUENCE LISTING · 71 of 77

In some embodiments, the antibody comprises a FR L3 of SEQ ID NO: 170.

In some embodiments, the antibody comprises a FR L4 comprising an amino acid sequence selected from a group consisting of SEQ ID NO: 171 and SEQ ID NO: 172. In some embodiments, the antibody comprises a FR L4 of SEQ ID NO: 171. In some embodiments, the antibody comprises a FR L4 of SEQ ID NO: 172.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 133, a FR H2 comprising an amino acid sequence of SEQ ID NO: 139, a FR H3 comprising an amino acid sequence of SEQ ID NO: 146, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 133, a FR H2 comprising an amino acid sequence of SEQ ID NO: 142, a FR H3 comprising an amino acid sequence of SEQ ID NO: 146, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 133, a FR H2 comprising an amino acid sequence of SEQ ID NO: 142, a FR H3 comprising an amino acid sequence of SEQ ID NO: 148, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 133, a FR H2 comprising an amino acid sequence of SEQ ID NO: 142, a FR H3 comprising an amino acid sequence of SEQ ID NO: 155, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 133, a FR H2 comprising an amino acid sequence of SEQ ID NO: 143, a FR H3 comprising an amino acid sequence of SEQ ID NO: 152, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 133, a FR H2 comprising an amino acid sequence of SEQ ID NO: 144, a FR H3 comprising an amino acid sequence of SEQ ID NO: 154, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 133, a FR H2 comprising an amino acid sequence of SEQ ID NO: 173, a FR H3 comprising an amino acid sequence of SEQ ID NO: 174, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 134, a FR H2 comprising an amino acid sequence of SEQ ID NO: 140, a FR H3 comprising an amino acid sequence of SEQ ID NO: 147, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 134, a FR H2 comprising an amino acid sequence of SEQ ID NO: 140, a FR H3 comprising an amino acid sequence of SEQ ID NO: 151, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 134, a FR H2 comprising an amino acid sequence of SEQ ID NO: 141, a FR H3 comprising an amino acid sequence of SEQ ID NO: 147, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 134, a FR H2 comprising an amino acid sequence of SEQ ID NO: 141, a FR H3 comprising an amino acid sequence of SEQ ID NO: 150, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 135, a FR H2 comprising an amino acid sequence of SEQ ID NO: 139, a FR H3 comprising an amino acid sequence of SEQ ID NO: 153, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 136, a FR H2 comprising an amino acid sequence of SEQ ID NO: 141, a FR H3 comprising an amino acid sequence of SEQ ID NO: 156, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 136, a FR H2 comprising an amino acid sequence of SEQ ID NO: 240, a FR H3 comprising an amino acid sequence of SEQ ID NO: 156, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 136, a FR H2 comprising an amino acid sequence of SEQ ID NO: 241, a FR H3 comprising an amino acid sequence of SEQ ID NO: 156, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 136, a FR H2 comprising an amino acid sequence of SEQ ID NO: 242, a FR H3 comprising an amino acid sequence of SEQ ID NO: 156, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 136, a FR H2 comprising an amino acid sequence of SEQ ID NO: 243, a FR H3 comprising an amino acid sequence of SEQ ID NO: 156, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 136, a FR H2 comprising an amino acid sequence of SEQ ID NO: 244, a FR H3 comprising an amino acid sequence of SEQ ID NO: 156, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 137, a FR H2 comprising an amino acid sequence of SEQ ID NO: 144, a FR H3 comprising an amino acid sequence of SEQ ID NO: 157, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 238, a FR H2 comprising an amino acid sequence of SEQ ID NO: 245, a FR H3 comprising an amino acid sequence of SEQ ID NO: 251, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

›SEQUENCE LISTING · 72 of 77

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 238, a FR H2 comprising an amino acid sequence of SEQ ID NO: 246, a FR H3 comprising an amino acid sequence of SEQ ID NO: 251, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR H1 comprising an amino acid sequence of SEQ ID NO: 239, a FR H2 comprising an amino acid sequence of SEQ ID NO: 245, a FR H3 comprising an amino acid sequence of SEQ ID NO: 251, and a FR H4 comprising an amino acid sequence of SEQ ID NO: 159.

In some embodiments, the antibody comprises a FR L1 comprising an amino acid sequence of SEQ ID NO: 161, a FR L2 comprising an amino acid sequence of SEQ ID NO: 252, a FR L3 comprising an amino acid sequence of SEQ ID NO: 170, and a FR L4 comprising an amino acid sequence of SEQ ID NO: 171.

In some embodiments, the antibody comprises a FR L1 comprising an amino acid sequence of SEQ ID NO: 161, a FR L2 comprising an amino acid sequence of SEQ ID NO: 253, a FR L3 comprising an amino acid sequence of SEQ ID NO: 170, and a FR L4 comprising an amino acid sequence of SEQ ID NO: 171.

In some embodiments, the antibody comprises a FR L1 comprising an amino acid sequence of SEQ ID NO: 162, a FR L2 comprising an amino acid sequence of SEQ ID NO: 252, a FR L3 comprising an amino acid sequence of SEQ ID NO: 170, and a FR L4 comprising an amino acid sequence of SEQ ID NO: 171.

In some embodiments, the antibody comprises a FR L1 comprising an amino acid sequence of SEQ ID NO: 162, a FR L2 comprising an amino acid sequence of SEQ ID NO: 253, a FR L3 comprising an amino acid sequence of SEQ ID NO: 170, and a FR L4 comprising an amino acid sequence of SEQ ID NO: 171.

In some embodiments, the antibody comprises a FR L1 comprising an amino acid sequence of SEQ ID NO: 161, a FR L2 comprising an amino acid sequence of SEQ ID NO: 163, a FR L3 comprising an amino acid sequence of SEQ ID NO: 170, and a FR L4 comprising an amino acid sequence of SEQ ID NO: 171.

In some embodiments, the antibody comprises a FR L1 comprising an amino acid sequence of SEQ ID NO: 161, a FR L2 comprising an amino acid sequence of SEQ ID NO: 164, a FR L3 comprising an amino acid sequence of SEQ ID NO: 170, and a FR L4 comprising an amino acid sequence of SEQ ID NO: 171.

In some embodiments, the antibody comprises a FR L1 comprising an amino acid sequence of SEQ ID NO: 161, a FR L2 comprising an amino acid sequence of SEQ ID NO: 165, a FR L3 comprising an amino acid sequence of SEQ ID NO: 170, and a FR L4 comprising an amino acid sequence of SEQ ID NO: 171.

In some embodiments, the antibody comprises a FR L1 comprising an amino acid sequence of SEQ ID NO: 161, a FR L2 comprising an amino acid sequence of SEQ ID NO: 166, a FR L3 comprising an amino acid sequence of SEQ ID NO: 170, and a FR L4 comprising an amino acid sequence of SEQ ID NO: 171.

In some embodiments, the antibody comprises a FR L1 comprising an amino acid sequence of SEQ ID NO: 161, a FR L2 comprising an amino acid sequence of SEQ ID NO: 167, a FR L3 comprising an amino acid sequence of SEQ ID NO: 170, and a FR L4 comprising an amino acid sequence of SEQ ID NO: 171.

In some embodiments, the antibody comprises a FR L1 comprising an amino acid sequence of SEQ ID NO: 161, a FR L2 comprising an amino acid sequence of SEQ ID NO: 168, a FR L3 comprising an amino acid sequence of SEQ ID NO: 170, and a FR L4 comprising an amino acid sequence of SEQ ID NO: 171.

›SEQUENCE LISTING · 73 of 77

In some embodiments, the antibody comprises a FR L1 comprising an amino acid sequence of SEQ ID NO: 162, a FR L2 comprising an amino acid sequence of SEQ ID NO: 163, a FR L3 comprising an amino acid sequence of SEQ ID NO: 170, and a FR L4 comprising an amino acid sequence of SEQ ID NO: 171.

In some embodiments, the antibody comprises a FR L1 comprising an amino acid sequence of SEQ ID NO: 162, a FR L2 comprising an amino acid sequence of SEQ ID NO: 164, a FR L3 comprising an amino acid sequence of SEQ ID NO: 170, and a FR L4 comprising an amino acid sequence of SEQ ID NO: 171.

In some embodiments, the antibody comprises a FR L1 comprising an amino acid sequence of SEQ ID NO: 162, a FR L2 comprising an amino acid sequence of SEQ ID NO: 165, a FR L3 comprising an amino acid sequence of SEQ ID NO: 170, and a FR L4 comprising an amino acid sequence of SEQ ID NO: 171.

In some embodiments, the antibody comprises a FR L1 comprising an amino acid sequence of SEQ ID NO: 162, a FR L2 comprising an amino acid sequence of SEQ ID NO: 166, a FR L3 comprising an amino acid sequence of SEQ ID NO: 170, and a FR L4 comprising an amino acid sequence of SEQ ID NO: 171.

In some embodiments, the antibody comprises a FR L1 comprising an amino acid sequence of SEQ ID NO: 162, a FR L2 comprising an amino acid sequence of SEQ ID NO: 167, a FR L3 comprising an amino acid sequence of SEQ ID NO: 170, and a FR L4 comprising an amino acid sequence of SEQ ID NO: 171.

In some embodiments, the antibody comprises a FR L1 comprising an amino acid sequence of SEQ ID NO: 162, a FR L2 comprising an amino acid sequence of SEQ ID NO: 168, a FR L3 comprising an amino acid sequence of SEQ ID NO: 170, and a FR L4 comprising an amino acid sequence of SEQ ID NO: 171.

In other more specific embodiments, the humanized antibody or antigen binding fragment thereof provided herein comprises a VH comprising FRs comprising amino acid sequences of the FRs contained in the VH selected from a group consisting of SEQ ID NO: 179, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 106, SEQ ID NO: 108, SEQ ID NO: 110, SEQ ID NO: 203, SEQ ID NO: 205, SEQ ID NO: 207, SEQ ID NO: 209, SEQ ID NO: 211, SEQ ID NO: 213, SEQ ID NO: 215, SEQ ID NO: 217, SEQ ID NO: 219, SEQ ID NO: 221, SEQ ID NO: 223, SEQ ID NO: 225 and SEQ ID NO: 227; and a VL comprising FRs comprising amino acid sequences of the FRs contained in the VL selected from a group consisting of SEQ ID NO: 92, SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 98, SEQ ID NO: 100, SEQ ID NO: 102, SEQ ID NO: 104, SEQ ID NO: 112, SEQ ID NO: 229, SEQ ID NO: 231, SEQ ID NO: 233, SEQ ID NO: 235 and SEQ ID NO: 237.

As described above, framework regions described herein are determined based upon the boundaries of the CDR numbering system. In other words, if the CDRs are determined by,e.g., Kabat, IMGT, or Chothia, or any combination thereof, then the framework regions are the amino acid residues surrounding the CDRs in the variable region in the format, from the N-terminus to C-terminus: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. For example, FR1 is defined as the amino acid residues N-terminal to the CDR1 amino acid residues as defined by,e.g., the Kabat numbering system, the IMGT numbering system, and/or the Chothia numbering system, FR2 is defined as the amino acid residues between CDR1 and CDR2 amino acid residues as defined by, e.g., the Kabat numbering system, the IMGT numbering system, and/or the Chothia numbering system, FR3 is defined as the amino acid residues between CDR2 and CDR3 amino acid residues as defined by, e.g., the Kabat numbering system, the IMGT numbering system, and/or the Chothia numbering system, and FR4 is defined as the amino acid residues C-terminal to the CDR3 amino acid residues as defined by, e.g., the Kabat numbering system, the IMGT numbering system, and/or the Chothia numbering system.

›SEQUENCE LISTING · 74 of 77

In some embodiments, the humanized antibody or antigen binding fragment thereof provided herein comprise a VH listed in Table 33 below.

In some embodiments, the VH is hzR35B9(A56)-HV12a comprising an amino acid sequence of SEQ ID NO: 203. In some embodiments, the VH is hzR35B9(A56)-HV12b comprising an amino acid sequence of SEQ ID NO: 205. In some embodiments, the VH is hzR35B9(A56)-HV13a comprising an amino acid sequence of SEQ ID NO: 207. In some embodiments, the VH is hzR35B9(A56)-HV13b comprising an amino acid sequence of SEQ ID NO: 209. In some embodiments, the VH is hzR35B9(A56)-HV13d comprising an amino acid sequence of SEQ ID NO: 211. In some embodiments, the VH is hzR35B9(A56)-HV13f comprising an amino acid sequence of SEQ ID NO: 213. In some embodiments, the VH is hzR35B9(A56)-HV13g comprising an amino acid sequence of SEQ ID NO: 215. In some embodiments, the VH is hzR35B9(A56)-HV16 comprising an amino acid sequence of SEQ ID NO: 217. In some embodiments, the VH is hzR35B9(A56)-HV17a comprising an amino acid sequence of SEQ ID NO: 219. In some embodiments, the VH is hzR35B9(A56)-HV17b comprising an amino acid sequence of SEQ ID NO: 221. In some embodiments, the VH is hzR35B9(A56)-HV17d comprising an amino acid sequence of SEQ ID NO: 223. In some embodiments, the VH is hzR35B9(A56)-HV17g comprising an amino acid sequence of SEQ ID NO: 225. In some embodiments, the VH is hzR35B9(A56)-HV17i comprising an amino acid sequence of SEQ ID NO: 227.

In some embodiments, the VH is hzR35B9-HV0 comprising an amino acid sequence of SEQ ID NO: 179. In some embodiments, the VH is hzR35B9-HV5a comprising an amino acid sequence of SEQ ID NO: 66. In some embodiments, the VH is AhzR35B9-HV5b comprising an amino acid sequence of SEQ ID NO: 68. In some embodiments, the VH is hzR35B9-HV6a comprising an amino acid sequence of SEQ ID NO: 70. In some embodiments, the VH is hzR35B9-HV6b comprising an amino acid sequence of SEQ ID NO: 72. In some embodiments, the VH is hzR35B9-HV6c comprising an amino acid sequence of SEQ ID NO: 74. In some embodiments, the VH is hzR35B9-HV7a comprising an amino acid sequence of SEQ ID NO: 76. In some embodiments, the VH is hzR35B9-HV7b comprising an amino acid sequence of SEQ ID NO: 78. In some embodiments, the VH is hzR35B9-HV7c comprising an amino acid sequence of SEQ ID NO: 80. In some embodiments, the VH is hzR35B9-HV9a comprising an amino acid sequence of SEQ ID NO: 82. In some embodiments, the VH is hzR35B9-HV9b comprising an amino acid sequence of SEQ ID NO: 84. In some embodiments, the VH is hzR35B9-HV10 comprising an amino acid sequence of SEQ ID NO: 86. In some embodiments, the VH is hzR35B9-HV11 comprising an amino acid sequence of SEQ ID NO: 88. In some embodiments, the VH is hzR35B9-HV18 comprising an amino acid sequence of SEQ ID NO: 90. In some embodiments, the VH is hzR35B9(A56)-HV11 comprising an amino acid sequence of SEQ ID NO: 108. In some embodiments, the VH is hzR35B9(Y50A56G57)-HV7b comprising an amino acid sequence of SEQ ID NO: 110. In some embodiments, the VH is hzR35B9(A56)-HV7c comprising an amino acid sequence of SEQ ID NO: 106.

In some embodiments, the humanized antibody or antigen binding fragment thereof provided herein comprises a VL listed in Table 34 below.

In some embodiments, the VL is hzR35B9-LV0 comprising an amino acid sequence of SEQ ID NO: 92. In some embodiments, the VL is hzR35B9-LV1a comprising an amino acid sequence of SEQ ID NO: 94. In some embodiments, the VL is hzR35B9-LV1b comprising an amino acid sequence of SEQ ID NO: 96. In some embodiments, the VL is hzR35B9-LV3a comprising an amino acid sequence of SEQ ID NO: 98. In some embodiments, the VL is hzR35B9-LV3b comprising an amino acid sequence of SEQ ID NO: 100. In some embodiments, the VL is hzR35B9-LV4 comprising an amino acid sequence of SEQ ID NO: 102. In some embodiments, the VL is hzR35B9-LV5 comprising an amino acid sequence of SEQ ID NO: 104. In some embodiments, the VL is hzR35B9(H98)-LV1a comprising an amino acid sequence of SEQ ID NO: 112.

In some embodiments, the VL is hzR35B9(A56)-LV2a comprising an amino acid sequence of SEQ ID NO: 229. In some embodiments, the VL is hzR35B9(A56)-LV2b comprising an amino acid sequence of SEQ ID NO: 231. In some embodiments, the VL is hzR35B9(A56)-LV2c comprising an amino acid sequence of SEQ ID NO: 233. In some embodiments, the VL is hzR35B9(A56)-LV2d comprising an amino acid sequence of SEQ ID NO: 235. In some embodiments, the VL is hzR35B9(A56)-LV2f comprising an amino acid sequence of SEQ ID NO: 237.

In certain embodiments, the humanized antibody or antigen binding fragment thereof provided herein comprises VH and/or VL in Table 35.

In some embodiments, the antibody is A631/A467 comprising a VH comprising an amino acid sequence of SEQ ID NO: 203 and a VL comprising an amino acid sequence of SEQ ID NO: 92. In some embodiments, the antibody is A631/A468 comprising a VH comprising an amino acid sequence of SEQ ID NO: 203 and a VL comprising an amino acid sequence of SEQ ID NO: 94. In some embodiments, the antibody is A631/A469 comprising a VH comprising an amino acid sequence of SEQ ID NO: 203 and a VL comprising an amino acid sequence of SEQ ID NO: 96. In some embodiments, the antibody is A631/A470 comprising a VH comprising an amino acid sequence of SEQ ID NO: 203 and a VL comprising an amino acid sequence of SEQ ID NO: 98. In some embodiments, the antibody is A631/A471 comprising a VH comprising an amino acid sequence of SEQ ID NO: 203 and a VL comprising an amino acid sequence of SEQ ID NO: 100. In some embodiments, the antibody is A631/A472 comprising a VH comprising an amino acid sequence of SEQ ID NO: 203 and a VL comprising an amino acid sequence of SEQ ID NO: 102. In some embodiments, the antibody is A631/A473 comprising a VH comprising an amino acid sequence of SEQ ID NO: 203 and a VL comprising an amino acid sequence of SEQ ID NO: 104. In some embodiments, the antibody is A631/A518 comprising a VH comprising an amino acid sequence of SEQ ID NO: 203 and a VL comprising an amino acid sequence of SEQ ID NO: 112. In some embodiments, the antibody is A631/A651 comprising a VH comprising an amino acid sequence of SEQ ID NO: 203 and a VL comprising an amino acid sequence of SEQ ID NO: 229. In some embodiments, the antibody is A631/A652 comprising a VH comprising an amino acid sequence of SEQ ID NO: 203 and a VL comprising an amino acid sequence of SEQ ID NO: 231. In some embodiments, the antibody is A631/A653 comprising a VH comprising an amino acid sequence of SEQ ID NO: 203 and a VL comprising an amino acid sequence of SEQ ID NO: 233. In some embodiments, the antibody is A631/A654 comprising a VH comprising an amino acid sequence of SEQ ID NO: 203 and a VL comprising an amino acid sequence of SEQ ID NO: 235. In some embodiments, the antibody is A631/A656 comprising a VH comprising an amino acid sequence of SEQ ID NO: 203 and a VL comprising an amino acid sequence of SEQ ID NO: 237.

›SEQUENCE LISTING · 75 of 77

In some embodiments, the antibody is A632/A467 comprising a VH comprising an amino acid sequence of SEQ ID NO: 205 and a VL comprising an amino acid sequence of SEQ ID NO: 92. In some embodiments, the antibody is A632/A468 comprising a VH comprising an amino acid sequence of SEQ ID NO: 205 and a VL comprising an amino acid sequence of SEQ ID NO: 94. In some embodiments, the antibody is A632/A469 comprising a VH comprising an amino acid sequence of SEQ ID NO: 205 and a VL comprising an amino acid sequence of SEQ ID NO: 96. In some embodiments, the antibody is A632/A470 comprising a VH comprising an amino acid sequence of SEQ ID NO: 205 and a VL comprising an amino acid sequence of SEQ ID NO: 98. In some embodiments, the antibody is A632/A471 comprising a VH comprising an amino acid sequence of SEQ ID NO: 205 and a VL comprising an amino acid sequence of SEQ ID NO: 100. In some embodiments, the antibody is A632/A472 comprising a VH comprising an amino acid sequence of SEQ ID NO: 205 and a VL comprising an amino acid sequence of SEQ ID NO: 102. In some embodiments, the antibody is A632/A473 comprising a VH comprising an amino acid sequence of SEQ ID NO: 205 and a VL comprising an amino acid sequence of SEQ ID NO: 104. In some embodiments, the antibody is A632/A518 comprising a VH comprising an amino acid sequence of SEQ ID NO: 205 and a VL comprising an amino acid sequence of SEQ ID NO: 112. In some embodiments, the antibody is A632/A651 comprising a VH comprising an amino acid sequence of SEQ ID NO: 205 and a VL comprising an amino acid sequence of SEQ ID NO: 229. In some embodiments, the antibody is A632/A652 comprising a VH comprising an amino acid sequence of SEQ ID NO: 205 and a VL comprising an amino acid sequence of SEQ ID NO: 231. In some embodiments, the antibody is A632/A653 comprising a VH comprising an amino acid sequence of SEQ ID NO: 205 and a VL comprising an amino acid sequence of SEQ ID NO: 233. In some embodiments, the antibody is A632/A654 comprising a VH comprising an amino acid sequence of SEQ ID NO: 205 and a VL comprising an amino acid sequence of SEQ ID NO: 235. In some embodiments, the antibody is A632/A656 comprising a VH comprising an amino acid sequence of SEQ ID NO: 205 and a VL comprising an amino acid sequence of SEQ ID NO: 237.

In some embodiments, the antibody is A633/A467 comprising a VH comprising an amino acid sequence of SEQ ID NO: 207 and a VL comprising an amino acid sequence of SEQ ID NO: 92. In some embodiments, the antibody is A633/A468 comprising a VH comprising an amino acid sequence of SEQ ID NO: 207 and a VL comprising an amino acid sequence of SEQ ID NO: 94. In some embodiments, the antibody is A633/A469 comprising a VH comprising an amino acid sequence of SEQ ID NO: 207 and a VL comprising an amino acid sequence of SEQ ID NO: 96. In some embodiments, the antibody is A633/A470 comprising a VH comprising an amino acid sequence of SEQ ID NO: 207 and a VL comprising an amino acid sequence of SEQ ID NO: 98. In some embodiments, the antibody is A633/A471 comprising a VH comprising an amino acid sequence of SEQ ID NO: 207 and a VL comprising an amino acid sequence of SEQ ID NO: 100. In some embodiments, the antibody is A633/A472 comprising a VH comprising an amino acid sequence of SEQ ID NO: 207 and a VL comprising an amino acid sequence of SEQ ID NO: 102. In some embodiments, the antibody is A633/A473 comprising a VH comprising an amino acid sequence of SEQ ID NO: 207 and a VL comprising an amino acid sequence of SEQ ID NO: 104. In some embodiments, the antibody is A633/A518 comprising a VH comprising an amino acid sequence of SEQ ID NO: 207 and a VL comprising an amino acid sequence of SEQ ID NO: 112. In some embodiments, the antibody is A633/A651 comprising a VH comprising an amino acid sequence of SEQ ID NO: 207 and a VL comprising an amino acid sequence of SEQ ID NO: 229. In some embodiments, the antibody is A633/A652 comprising a VH comprising an amino acid sequence of SEQ ID NO: 207 and a VL comprising an amino acid sequence of SEQ ID NO: 231. In some embodiments, the antibody is A633/A653 comprising a VH comprising an amino acid sequence of SEQ ID NO: 207 and a VL comprising an amino acid sequence of SEQ ID NO: 233. In some embodiments, the antibody is A633/A654 comprising a VH comprising an amino acid sequence of SEQ ID NO: 207 and a VL comprising an amino acid sequence of SEQ ID NO: 235. In some embodiments, the antibody is A633/A656 comprising a VH comprising an amino acid sequence of SEQ ID NO: 207 and a VL comprising an amino acid sequence of SEQ ID NO: 237.

In some embodiments, the antibody is A634/A467 comprising a VH comprising an amino acid sequence of SEQ ID NO: 209 and a VL comprising an amino acid sequence of SEQ ID NO: 92. In some embodiments, the antibody is A634/A468 comprising a VH comprising an amino acid sequence of SEQ ID NO: 209 and a VL comprising an amino acid sequence of SEQ ID NO: 94. In some embodiments, the antibody is A634/A469 comprising a VH comprising an amino acid sequence of SEQ ID NO: 209 and a VL comprising an amino acid sequence of SEQ ID NO: 96. In some embodiments, the antibody is A634/A470 comprising a VH comprising an amino acid sequence of SEQ ID NO: 209 and a VL comprising an amino acid sequence of SEQ ID NO: 98. In some embodiments, the antibody is A634/A471 comprising a VH comprising an amino acid sequence of SEQ ID NO: 209 and a VL comprising an amino acid sequence of SEQ ID NO: 100. In some embodiments, the antibody is A634/A472 comprising a VH comprising an amino acid sequence of SEQ ID NO: 209 and a VL comprising an amino acid sequence of SEQ ID NO: 102. In some embodiments, the antibody is A634/A473 comprising a VH comprising an amino acid sequence of SEQ ID NO: 209 and a VL comprising an amino acid sequence of SEQ ID NO: 104. In some embodiments, the antibody is A634/A518 comprising a VH comprising an amino acid sequence of SEQ ID NO: 209 and a VL comprising an amino acid sequence of SEQ ID NO: 112. In some embodiments, the antibody is A634/A651 comprising a VH comprising an amino acid sequence of SEQ ID NO: 209 and a VL comprising an amino acid sequence of SEQ ID NO: 229. In some embodiments, the antibody is A634/A652 comprising a VH comprising an amino acid sequence of SEQ ID NO: 209 and a VL comprising an amino acid sequence of SEQ ID NO: 231. In some embodiments, the antibody is A634/A653 comprising a VH comprising an amino acid sequence of SEQ ID NO: 209 and a VL comprising an amino acid sequence of SEQ ID NO: 233. In some embodiments, the antibody is A634/A654 comprising a VH comprising an amino acid sequence of SEQ ID NO: 209 and a VL comprising an amino acid sequence of SEQ ID NO: 235. In some embodiments, the antibody is A634/A656 comprising a VH comprising an amino acid sequence of SEQ ID NO: 209 and a VL comprising an amino acid sequence of SEQ ID NO: 237.

›SEQUENCE LISTING · 76 of 77

In some embodiments, the antibody is A636/A467 comprising a VH comprising an amino acid sequence of SEQ ID NO: 211 and a VL comprising an amino acid sequence of SEQ ID NO: 92. In some embodiments, the antibody is A636/A468 comprising a VH comprising an amino acid sequence of SEQ ID NO: 211 and a VL comprising an amino acid sequence of SEQ ID NO: 94. In some embodiments, the antibody is A636/A469 comprising a VH comprising an amino acid sequence of SEQ ID NO: 211 and a VL comprising an amino acid sequence of SEQ ID NO: 96. In some embodiments, the antibody is A636/A470 comprising a VH comprising an amino acid sequence of SEQ ID NO: 211 and a VL comprising an amino acid sequence of SEQ ID NO: 98. In some embodiments, the antibody is A636/A471 comprising a VH comprising an amino acid sequence of SEQ ID NO: 211 and a VL comprising an amino acid sequence of SEQ ID NO: 100. In some embodiments, the antibody is A636/A472 comprising a VH comprising an amino acid sequence of SEQ ID NO: 211 and a VL comprising an amino acid sequence of SEQ ID NO: 102. In some embodiments, the antibody is A636/A473 comprising a VH comprising an amino acid sequence of SEQ ID NO: 211 and a VL comprising an amino acid sequence of SEQ ID NO: 104. In some embodiments, the antibody is A636/A518 comprising a VH comprising an amino acid sequence of SEQ ID NO: 211 and a VL comprising an amino acid sequence of SEQ ID NO: 112. In some embodiments, the antibody is A636/A651 comprising a VH comprising an amino acid sequence of SEQ ID NO: 211 and a VL comprising an amino acid sequence of SEQ ID NO: 229. In some embodiments, the antibody is A636/A652 comprising a VH comprising an amino acid sequence of SEQ ID NO: 211 and a VL comprising an amino acid sequence of SEQ ID NO: 231. In some embodiments, the antibody is A636/A653 comprising a VH comprising an amino acid sequence of SEQ ID NO: 211 and a VL comprising an amino acid sequence of SEQ ID NO: 233. In some embodiments, the antibody is A636/A654 comprising a VH comprising an amino acid sequence of SEQ ID NO: 211 and a VL comprising an amino acid sequence of SEQ ID NO: 235. In some embodiments, the antibody is A636/A656 comprising a VH comprising an amino acid sequence of SEQ ID NO: 211 and a VL comprising an amino acid sequence of SEQ ID NO: 237.

In some embodiments, the antibody is A638/A467 comprising a VH comprising an amino acid sequence of SEQ ID NO: 213 and a VL comprising an amino acid sequence of SEQ ID NO: 92. In some embodiments, the antibody is A638/A468 comprising a VH comprising an amino acid sequence of SEQ ID NO: 213 and a VL comprising an amino acid sequence of SEQ ID NO: 94. In some embodiments, the antibody is A638/A469 comprising a VH comprising an amino acid sequence of SEQ ID NO: 213 and a VL comprising an amino acid sequence of SEQ ID NO: 96. In some embodiments, the antibody is A638/A470 comprising a VH comprising an amino acid sequence of SEQ ID NO: 213 and a VL comprising an amino acid sequence of SEQ ID NO: 98. In some embodiments, the antibody is A638/A471 comprising a VH comprising an amino acid sequence of SEQ ID NO: 213 and a VL comprising an amino acid sequence of SEQ ID NO: 100. In some embodiments, the antibody is A638/A472 comprising a VH comprising an amino acid sequence of SEQ ID NO: 213 and a VL comprising an amino acid sequence of SEQ ID NO: 102. In some embodiments, the antibody is A638/A473 comprising a VH comprising an amino acid sequence of SEQ ID NO: 213 and a VL comprising an amino acid sequence of SEQ ID NO: 104. In some embodiments, the antibody is A638/A518 comprising a VH comprising an amino acid sequence of SEQ ID NO: 213 and a VL comprising an amino acid sequence of SEQ ID NO: 112. In some embodiments, the antibody is A638/A651 comprising a VH comprising an amino acid sequence of SEQ ID NO: 213 and a VL comprising an amino acid sequence of SEQ ID NO: 229. In some embodiments, the antibody is A638/A652 comprising a VH comprising an amino acid sequence of SEQ ID NO: 213 and a VL comprising an amino acid sequence of SEQ ID NO: 231. In some embodiments, the antibody is A638/A653 comprising a VH comprising an amino acid sequence of SEQ ID NO: 213 and a VL comprising an amino acid sequence of SEQ ID NO: 233. In some embodiments, the antibody is A638/A654 comprising a VH comprising an amino acid sequence of SEQ ID NO: 213 and a VL comprising an amino acid sequence of SEQ ID NO: 235. In some embodiments, the antibody is A638/A656 comprising a VH comprising an amino acid sequence of SEQ ID NO: 213 and a VL comprising an amino acid sequence of SEQ ID NO: 237.

In some embodiments, the antibody is A639/A467 comprising a VH comprising an amino acid sequence of SEQ ID NO: 215 and a VL comprising an amino acid sequence of SEQ ID NO: 92. In some embodiments, the antibody is A639/A468 comprising a VH comprising an amino acid sequence of SEQ ID NO: 215 and a VL comprising an amino acid sequence of SEQ ID NO: 94. In some embodiments, the antibody is A639/A469 comprising a VH comprising an amino acid sequence of SEQ ID NO: 215 and a VL comprising an amino acid sequence of SEQ ID NO: 96. In some embodiments, the antibody is A639/A470 comprising a VH comprising an amino acid sequence of SEQ ID NO: 215 and a VL comprising an amino acid sequence of SEQ ID NO: 98. In some embodiments, the antibody is A639/A471 comprising a VH comprising an amino acid sequence of SEQ ID NO: 215 and a VL comprising an amino acid sequence of SEQ ID NO: 100. In some embodiments, the antibody is A639/A472 comprising a VH comprising an amino acid sequence of SEQ ID NO: 215 and a VL comprising an amino acid sequence of SEQ ID NO: 102. In some embodiments, the antibody is A639/A473 comprising a VH comprising an amino acid sequence of SEQ ID NO: 215 and a VL comprising an amino acid sequence of SEQ ID NO: 104. In some embodiments, the antibody is A639/A518 comprising a VH comprising an amino acid sequence of SEQ ID NO: 215 and a VL comprising an amino acid sequence of SEQ ID NO: 112. In some embodiments, the antibody is A639/A651 comprising a VH comprising an amino acid sequence of SEQ ID NO: 215 and a VL comprising an amino acid sequence of SEQ ID NO: 229. In some embodiments, the antibody is A639/A652 comprising a VH comprising an amino acid sequence of SEQ ID NO: 215 and a VL comprising an amino acid sequence of SEQ ID NO: 231. In some embodiments, the antibody is A639/A653 comprising a VH comprising an amino acid sequence of SEQ ID NO: 215 and a VL comprising an amino acid sequence of SEQ ID NO: 233. In some embodiments, the antibody is A639/A654 comprising a VH comprising an amino acid sequence of SEQ ID NO: 215 and a VL comprising an amino acid sequence of SEQ ID NO: 235. In some embodiments, the antibody is A639/A656 comprising a VH comprising an amino acid sequence of SEQ ID NO: 215 and a VL comprising an amino acid sequence of SEQ ID NO: 237.

›SEQUENCE LISTING · 77 of 77

In some embodiments, the antibody is A641/A467 comprising a VH comprising an amino acid sequence of SEQ ID NO: 217 and a VL comprising an amino acid sequence of SEQ ID NO: 92. In some embodiments, the antibody is A641/A468 comprising a VH comprising an amino acid sequence of SEQ ID NO: 217 and a VL comprising an amino acid sequence of SEQ ID NO: 94. In some embodiments, the antibody is A641/A469 comprising a VH comprising an amino acid sequence of SEQ ID NO: 217 and a VL comprising an amino acid sequence of SEQ ID NO: 96. In some embodiments, the antibody is A641/A470 comprising a VH comprising an amino acid sequence of SEQ ID NO: 217 and a VL comprising an amino acid sequence of SEQ ID NO: 98. In some embodiments, the antibody is A641/A471 comprising a VH comprising an amino acid sequence of SEQ ID NO: 217 and a VL comprising an amino acid sequence of SEQ ID NO: 100. In some embodiments, the antibody is A641/A472 comprising a VH comprising an amino acid sequence of SEQ ID NO: 217 and a VL comprising an amino acid sequence of SEQ ID NO: 102. In some embodiments, the antibody is A641/A473 comprising a VH comprising an amino acid sequence of SEQ ID NO: 217 and a VL comprising an amino acid sequence of SEQ ID NO: 104. In some embodiments, the antibody is A641/A518 comprising a VH comprising an amino acid sequence of SEQ ID NO: 217 and a VL comprising an amino acid sequence of SEQ ID NO: 112. In some embodiments, the antibody is A641/A651 comprising a VH comprising an amino acid sequence of SEQ ID NO: 217 and a VL comprising an amino acid sequence of SEQ ID NO: 229. In some embodiments, the antibody is A641/A652 comprising a VH comprising an amino acid sequence of SEQ ID NO: 217 and a VL comprising an amino acid sequence of SEQ ID NO: 231. In some embodiments, the antibody is A641/A653 comprising a VH comprising an amino acid sequence of SEQ ID NO: 217 and a VL comprising an amino acid sequence of SEQ ID NO: 233. In some embodiments, the antibody is A641/A654 comprising a VH comprising an amino acid sequence of SEQ ID NO: 217 and a VL comprising an amino acid sequence of SEQ ID NO: 235. In some embodiments, the antibody is A641/A656 comprising a VH comprising an amino acid sequence of SEQ ID NO: 217 and a VL comprising an amino acid sequence of SEQ ID NO: 237.

In some embodiments, the antibody is A642/A467 comprising a VH comprising an amino acid sequence of SEQ ID NO: 219 and a VL comprising an amino acid sequence of SEQ ID NO: 92. In some embodiments, the antibody is A642/A468 comprising a VH comprising an amino acid sequence of SEQ ID NO: 219 and a VL comprising an amino acid sequence of SEQ ID NO: 94. In some embodiments, the antibody is A642/A469 comprising a VH comprising an amino acid sequence of SEQ ID NO: 219 and a VL comprising an amino acid sequence of SEQ ID NO: 96. In some embodiments, the antibody is A642/A470 comprising a VH comprising an amino acid sequence of SEQ ID NO: 219 and a VL comprising an amino acid sequence of SEQ ID NO: 98. In some embodiments, the antibody is A642/A471 comprising a VH comprising an amino acid sequence of SEQ ID NO: 219 and a VL comprising an amino acid sequence of SEQ ID NO: 100. In some embodiments, the antibody is A642/A472 comprising a VH comprising an amino acid sequence of SEQ ID NO: 219 and a VL comprising an amino acid sequence of SEQ ID NO: 102. In some embodiments, the antibody is A642/A473 comprising a VH comprising an amino acid sequence of SEQ ID NO: 219 and a VL comprising an amino acid sequence of SEQ ID NO: 104. In some embodiments, the antibody is A642/A518 comprising a VH comprising an amino acid sequence of SEQ ID NO: 219 and a VL comprising an amino acid sequence of SEQ ID NO: 112. In some embodiments, the antibody is A642/A651 comprising a VH comprising an amino acid sequence of SEQ ID NO: 219 and a VL comprising an amino acid sequence of SEQ ID NO: 229. In some embodiments, the antibody is A642/A652 comprising a VH comprising an amino acid sequence of SEQ ID NO: 219 and a VL comprising an amino acid sequence of SEQ ID NO: 231. In some embodiments, the antibody is A642/A653 comprising a VH comprising an amino acid sequence of SEQ ID NO: 219 and a VL comprising an amino acid sequence of SEQ ID NO: 233. In some embodiments, the antibody is A642/A654 comprising a VH comprising an amino acid sequence of SEQ ID NO: 219 and a VL comprising an amino acid sequence of SEQ ID NO: 235. In some embodiments, the antibody is A642/A656 comprising a VH comprising an amino acid sequence of SEQ ID NO: 219 and a VL comprising an amino acid sequence of SEQ ID NO: 237.

In some embodiments, the antibody is A643/A467 comprising a VH comprising an amino acid sequence of SEQ ID NO: 221 and a VL comprising an amino acid sequence of SEQ ID NO: 92. In some embodiments, the antibody is A643/A468 comprising a VH comprising an amino acid sequence of SEQ ID NO: 221 and a VL comprising an amino acid sequence of SEQ ID NO: 94. In some embodiments, the antibody is A643/A469 comprising a VH comprising an amino acid sequence of SEQ ID NO: 221 and a VL comprising an amino acid sequence of SEQ ID NO: 96. In some embodiments, the antibody is A643/A470 comprising a VH comprising an amino acid sequence of SEQ ID NO: 221 and a VL comprising an amino acid sequence of SEQ ID NO: 98. In some embodiments, the antibody is A643/A471 comprising a VH compri

›Tables in the description — 34

TABLE 25

Loop	Kabat	AbM	Chothia	Contact	IMGT
CDRL1	L24--L34	L24--L34	L24--L34	L30--L36	L27--L38
CDRL2	L50--L56	L50--L56	L50--L56	L46--L55	L56--L65
CDRL3	L89--L97	L89--L97	L89--L97	L89--L96	L105-L117
CDRH1	H31--H35B	H26--H35B	H26--	H30--H35B	H27--H38
	(Kabat		H32 . . . 34
	Numbering)
CDRH1	H31--H35	H26--H35	H26--H32	H30--H35
	(Chothia
	Numbering)
CDRH2	H50--H65	H50--H58	H52--H56	H47--H58	H56--H65
CDRH3	H95--H102	H95--H102	H95--H102	H93--H101	H105-H117

TABLE 26 — CDRs of exemplary antibodies

	CDR1	CDR2	CDR3
VH	SEQ ID NO: 119	SEQ ID NO: 120	SEQ ID NO: 121
	SEQ ID NO: 122	SEQ ID NO: 123
		SEQ ID NO: 124
		SEQ ID NO: 125
		SEQ ID NO: 126
		SEQ ID NO: 149
		SEQ ID NO: 247
		SEQ ID NO: 248
		SEQ ID NO: 249
		SEQ ID NO: 250
VL	SEQ ID NO: 127	SEQ ID NO: 128	SEQ ID NO: 129
		SEQ ID NO: 254	SEQ ID NO: 130
		SEQ ID NO: 255	SEQ ID NO: 131
		SEQ ID NO: 256

TABLE 27 — Exemplary mouse frameworks

	FR1	FR2	FR3	FR4
VH	SEQ ID NO: 132	SEQ ID NO: 138	SEQ ID NO: 145	SEQ ID NO: 158
VL	SEQ ID NO: 160	SEQ ID NO: 163	SEQ ID NO: 169	SEQ ID NO: 171

TABLE 28 — VH amino acid sequences of exemplary mouse antibodies

Heavy Vector ID	VH Name	Variable sequence
A291	41c-VH	SEQ ID NO: 35
A402	R35B9-VH	SEQ ID NO: 50
A448	R35B9(Y50G57)-VH	SEQ ID NO: 54
A490	R35B9(Y50A56G57)-VH	SEQ ID NO: 56
A486	R35B9(A56)-VH	SEQ ID NO: 60
A437	R35B9(Y50)-VH	SEQ ID NO: 181
A428	R35B9(G57)-VH	SEQ ID NO: 190
A435	R35B9(T28)-VH	SEQ ID NO: 192
A436	R35B9(T30)-VH	SEQ ID NO: 194
A438	R35B9(N54)-VH	SEQ ID NO: 196
A450	41C(R28Q30R54)-VH	SEQ ID NO: 198

TABLE 29 — VL amino acid sequences of exemplary mouse antibodies

Light Vector ID	VL Name	Variable sequence
A290	41c-VL	SEQ ID NO: 40
A403	R35B9-VL	SEQ ID NO: 52
A439	R35B9(H98)-VL	SEQ ID NO: 58
A440	R35B9(F99)-VL	SEQ ID NO: 200

TABLE 30 — Amino acid sequences of exemplary mouse antibodies

Antibody Name	VH	VL
A291/A290	SEQ ID NO: 35	SEQ ID NO: 40
A291/A403	SEQ ID NO: 35	SEQ ID NO: 52
A291/A439	SEQ ID NO: 35	SEQ ID NO: 58
A291/A440	SEQ ID NO: 35	SEQ ID NO: 200
A402/A290	SEQ ID NO: 50	SEQ ID NO: 40
A402/A403	SEQ ID NO: 50	SEQ ID NO: 52
A402/A439	SEQ ID NO: 50	SEQ ID NO: 58
A402/A440	SEQ ID NO: 50	SEQ ID NO: 200
A448/A290	SEQ ID NO: 54	SEQ ID NO: 40
A448/A403	SEQ ID NO: 54	SEQ ID NO: 52
A448/A439	SEQ ID NO: 54	SEQ ID NO: 58
A448/A440	SEQ ID NO: 54	SEQ ID NO: 200
A490/A290	SEQ ID NO: 56	SEQ ID NO: 40
A490/A403	SEQ ID NO: 56	SEQ ID NO: 52
A490/A439	SEQ ID NO: 56	SEQ ID NO: 58
A490/A440	SEQ ID NO: 56	SEQ ID NO: 200
A486/A290	SEQ ID NO: 60	SEQ ID NO: 40
A486/A403	SEQ ID NO: 60	SEQ ID NO: 52
A486/A439	SEQ ID NO: 60	SEQ ID NO: 58
A486/A440	SEQ ID NO: 60	SEQ ID NO: 200
A437/A290	SEQ ID NO: 181	SEQ ID NO: 40
A437/A403	SEQ ID NO: 181	SEQ ID NO: 52
A437/A439	SEQ ID NO: 181	SEQ ID NO: 58
A437/A440	SEQ ID NO: 181	SEQ ID NO: 200
A428/A290	SEQ ID NO: 190	SEQ ID NO: 40
A428/A403	SEQ ID NO: 190	SEQ ID NO: 52
A428/A439	SEQ ID NO: 190	SEQ ID NO: 58
A428/A440	SEQ ID NO: 190	SEQ ID NO: 200
A435/A290	SEQ ID NO: 192	SEQ ID NO: 40
A435/A403	SEQ ID NO: 192	SEQ ID NO: 52
A435/A439	SEQ ID NO: 192	SEQ ID NO: 58
A435/A440	SEQ ID NO: 192	SEQ ID NO: 200
A436/A290	SEQ ID NO: 194	SEQ ID NO: 40
A436/A403	SEQ ID NO: 194	SEQ ID NO: 52
A436/A439	SEQ ID NO: 194	SEQ ID NO: 58
A436/A440	SEQ ID NO: 194	SEQ ID NO: 200
A438/A290	SEQ ID NO: 196	SEQ ID NO: 40
A438/A403	SEQ ID NO: 196	SEQ ID NO: 52
A438/A439	SEQ ID NO: 196	SEQ ID NO: 58
A438/A440	SEQ ID NO: 196	SEQ ID NO: 200
A450/A290	SEQ ID NO: 198	SEQ ID NO: 40
A450/A403	SEQ ID NO: 198	SEQ ID NO: 52
A450/A439	SEQ ID NO: 198	SEQ ID NO: 58
A450/A440	SEQ ID NO: 198	SEQ ID NO: 200

TABLE 31 — CDRs of exemplary humanized antibodies

	CDR1	CDR2	CDR3
VH	SEQ ID NO: 122	SEQ ID NO: 123	SEQ ID NO: 121
		SEQ ID NO: 124
		SEQ ID NO: 126
		SEQ ID NO: 247
		SEQ ID NO: 248
		SEQ ID NO: 249
		SEQ ID NO: 250
VL	SEQ ID NO: 127	SEQ ID NO: 128	SEQ ID NO: 130
		SEQ ID NO: 254	SEQ ID NO: 131
		SEQ ID NO: 255
		SEQ ID NO: 256

TABLE 32 — FRs of exemplary humanized antibodies

	FR1	FR2	FR3	FR4
VH	SEQ ID NO: 133	SEQ ID NO: 139	SEQ ID NO: 146	SEQ ID NO: 159
	SEQ ID NO: 134	SEQ ID NO: 140	SEQ ID NO: 147
	SEQ ID NO: 135	SEQ ID NO: 141	SEQ ID NO: 148
	SEQ ID NO: 136	SEQ ID NO: 142	SEQ ID NO: 150
	SEQ ID NO: 137	SEQ ID NO: 143	SEQ ID NO: 151
	SEQ ID NO: 238	SEQ ID NO: 144	SEQ ID NO: 152
	SEQ ID NO: 239	SEQ ID NO: 173	SEQ ID NO: 153
		SEQ ID NO: 240	SEQ ID NO: 154
		SEQ ID NO: 241	SEQ ID NO: 155
		SEQ ID NO: 242	SEQ ID NO: 156
		SEQ ID NO: 243	SEQ ID NO: 157
		SEQ ID NO: 244	SEQ ID NO: 174
		SEQ ID NO: 245	SEQ ID NO: 251
		SEQ ID NO: 246
VL	SEQ ID NO: 161	SEQ ID NO: 163	SEQ ID NO: 170	SEQ ID NO: 171
	SEQ ID NO: 162	SEQ ID NO: 164		SEQ ID NO: 172
		SEQ ID NO: 165
		SEQ ID NO: 166
		SEQ ID NO: 167
		SEQ ID NO: 168
		SEQ ID NO: 252
		SEQ ID NO: 253

TABLE 33 — VH amino acid sequences of exemplary humanized antibodies

Heavy Vector ID	VH Name	Variable sequence
A700	hzR35B9-HV0	SEQ ID NO: 179
A454	hzR35B9-HV5a	SEQ ID NO: 66
A455	hzR35B9-HV5b	SEQ ID NO: 68
A456	hzR35B9-HV6a	SEQ ID NO: 70
A457	hzR35B9-HV6b	SEQ ID NO: 72
A458	hzR35B9-HV6c	SEQ ID NO: 74
A459	hzR35B9-HV7a	SEQ ID NO: 76
A460	hzR35B9-HV7b	SEQ ID NO: 78
A461	hzR35B9-HV7c	SEQ ID NO: 80
A462	hzR35B9-HV9a	SEQ ID NO: 82
A463	hzR35B9-HV9b	SEQ ID NO: 84
A464	hzR35B9-HV10	SEQ ID NO: 86
A465	hzR35B9-HV11	SEQ ID NO: 88
A466	hzR35B9-HV18	SEQ ID NO: 90
A512	hzR35B9(A56)-HV11	SEQ ID NO: 108
A515	hzR35B9(Y50A56G57)-HV7b	SEQ ID NO: 110
A553	hzR35B9(A56)-HV7c	SEQ ID NO: 106
A631	hzR35B9(A56)-HV12a	SEQ ID NO: 203
A632	hzR35B9(A56)-HV12b	SEQ ID NO: 205
A633	hzR35B9(A56)-HV13a	SEQ ID NO: 207
A634	hzR35B9(A56)-HV13b	SEQ ID NO: 209
A636	hzR35B9(A56)-HV13d	SEQ ID NO: 211
A638	hzR35B9(A56)-HV13f	SEQ ID NO: 213
A639	hzR35B9(A56)-HV13g	SEQ ID NO: 215
A641	hzR35B9(A56)-HV16	SEQ ID NO: 217
A642	hzR35B9(A56)-HV17a	SEQ ID NO: 219
A643	hzR35B9(A56)-HV17b	SEQ ID NO: 221
A645	hzR35B9(A56)-HV17d	SEQ ID NO: 223
A648	hzR35B9(A56)-HV17g	SEQ ID NO: 225
A650	hzR35B9(A56)-HV17i	SEQ ID NO: 227

TABLE 34 — VL amino acid sequences of exemplary humanized antibodies

Light Vector ID	VL Name	Variable sequence
A467	hzR35B9-LV0	SEQ ID NO: 92
A468	hzR35B9-LV1a	SEQ ID NO: 94
A469	hzR35B9-LV1b	SEQ ID NO: 96
A470	hzR35B9-LV3a	SEQ ID NO: 98
A471	hzR35B9-LV3b	SEQ ID NO: 100
A472	hzR35B9-LV4	SEQ ID NO: 102
A473	hzR35B9-LV5	SEQ ID NO: 104
A518	hzR35B9(H98)-LV1a	SEQ ID NO: 112
A651	hzR35B9(A56)-LV2a	SEQ ID NO: 229
A652	hzR35B9(A56)-LV2b	SEQ ID NO: 231
A653	hzR35B9(A56)-LV2c	SEQ ID NO: 233
A654	hzR35B9(A56)-LV2d	SEQ ID NO: 235
A656	hzR35B9(A56)-LV2f	SEQ ID NO: 237

TABLE 35 — Amino acid sequences of exemplary humanized antibodies

Antibody Name	VH	VL
A700/A467	SEQ ID NO: 179	SEQ ID NO: 92
A700/A468	SEQ ID NO: 179	SEQ ID NO: 94
A700/A469	SEQ ID NO: 179	SEQ ID NO: 96
A700/A470	SEQ ID NO: 179	SEQ ID NO: 98
A700/A471	SEQ ID NO: 179	SEQ ID NO: 100
A700/A472	SEQ ID NO: 179	SEQ ID NO: 102
A700/A473	SEQ ID NO: 179	SEQ ID NO: 104
A700/A518	SEQ ID NO: 179	SEQ ID NO: 112
A700/A651	SEQ ID NO: 179	SEQ ID NO: 229
A700/A652	SEQ ID NO: 179	SEQ ID NO: 231
A700/A653	SEQ ID NO: 179	SEQ ID NO: 233
A700/A654	SEQ ID NO: 179	SEQ ID NO: 235
A700/A656	SEQ ID NO: 179	SEQ ID NO: 237
A454/A467	SEQ ID NO: 66	SEQ ID NO: 92
A454/A468	SEQ ID NO: 66	SEQ ID NO: 94
A454/A469	SEQ ID NO: 66	SEQ ID NO: 96
A454/A470	SEQ ID NO: 66	SEQ ID NO: 98
A454/A471	SEQ ID NO: 66	SEQ ID NO: 100
A454/A472	SEQ ID NO: 66	SEQ ID NO: 102
A454/A473	SEQ ID NO: 66	SEQ ID NO: 104
A454/A518	SEQ ID NO: 66	SEQ ID NO: 112
A454/A651	SEQ ID NO: 66	SEQ ID NO: 229
A454/A652	SEQ ID NO: 66	SEQ ID NO: 231
A454/A653	SEQ ID NO: 66	SEQ ID NO: 233
A454/A654	SEQ ID NO: 66	SEQ ID NO: 235
A454/A656	SEQ ID NO: 66	SEQ ID NO: 237
A455/A467	SEQ ID NO: 68	SEQ ID NO: 92
A455/A468	SEQ ID NO: 68	SEQ ID NO: 94
A455/A469	SEQ ID NO: 68	SEQ ID NO: 96
A455/A470	SEQ ID NO: 68	SEQ ID NO: 98
A455/A471	SEQ ID NO: 68	SEQ ID NO: 100
A455/A472	SEQ ID NO: 68	SEQ ID NO: 102
A455/A473	SEQ ID NO: 68	SEQ ID NO: 104
A455/A518	SEQ ID NO: 68	SEQ ID NO: 112
A455/A651	SEQ ID NO: 68	SEQ ID NO: 229
A455/A652	SEQ ID NO: 68	SEQ ID NO: 231
A455/A653	SEQ ID NO: 68	SEQ ID NO: 233
A455/A654	SEQ ID NO: 68	SEQ ID NO: 235
A455/A656	SEQ ID NO: 68	SEQ ID NO: 237
A456/A467	SEQ ID NO: 70	SEQ ID NO: 92
A456/A468	SEQ ID NO: 70	SEQ ID NO: 94
A456/A469	SEQ ID NO: 70	SEQ ID NO: 96
A456/A470	SEQ ID NO: 70	SEQ ID NO: 98
A456/A471	SEQ ID NO: 70	SEQ ID NO: 100
A456/A472	SEQ ID NO: 70	SEQ ID NO: 102
A456/A473	SEQ ID NO: 70	SEQ ID NO: 104
A456/A518	SEQ ID NO: 70	SEQ ID NO: 112
A456/A651	SEQ ID NO: 70	SEQ ID NO: 229
A456/A652	SEQ ID NO: 70	SEQ ID NO: 231
A456/A653	SEQ ID NO: 70	SEQ ID NO: 233
A456/A654	SEQ ID NO: 70	SEQ ID NO: 235
A456/A656	SEQ ID NO: 70	SEQ ID NO: 237
A457/A467	SEQ ID NO: 72	SEQ ID NO: 92
A457/A468	SEQ ID NO: 72	SEQ ID NO: 94
A457/A469	SEQ ID NO: 72	SEQ ID NO: 96
A457/A470	SEQ ID NO: 72	SEQ ID NO: 98
A457/A471	SEQ ID NO: 72	SEQ ID NO: 100
A457/A472	SEQ ID NO: 72	SEQ ID NO: 102
A457/A473	SEQ ID NO: 72	SEQ ID NO: 104
A457/A518	SEQ ID NO: 72	SEQ ID NO: 112
A457/A651	SEQ ID NO: 72	SEQ ID NO: 229
A457/A652	SEQ ID NO: 72	SEQ ID NO: 231
A457/A653	SEQ ID NO: 72	SEQ ID NO: 233
A457/A654	SEQ ID NO: 72	SEQ ID NO: 235
A457/A656	SEQ ID NO: 72	SEQ ID NO: 237
A458/A467	SEQ ID NO: 74	SEQ ID NO: 92
A458/A468	SEQ ID NO: 74	SEQ ID NO: 94
A458/A469	SEQ ID NO: 74	SEQ ID NO: 96
A458/A470	SEQ ID NO: 74	SEQ ID NO: 98
A458/A471	SEQ ID NO: 74	SEQ ID NO: 100
A458/A472	SEQ ID NO: 74	SEQ ID NO: 102
A458/A473	SEQ ID NO: 74	SEQ ID NO: 104
A458/A518	SEQ ID NO: 74	SEQ ID NO: 112
A458/A651	SEQ ID NO: 74	SEQ ID NO: 229
A458/A652	SEQ ID NO: 74	SEQ ID NO: 231
A458/A653	SEQ ID NO: 74	SEQ ID NO: 233
A458/A654	SEQ ID NO: 74	SEQ ID NO: 235
A458/A656	SEQ ID NO: 74	SEQ ID NO: 237
A459/A467	SEQ ID NO: 76	SEQ ID NO: 92
A459/A468	SEQ ID NO: 76	SEQ ID NO: 94
A459/A469	SEQ ID NO: 76	SEQ ID NO: 96
A459/A470	SEQ ID NO: 76	SEQ ID NO: 98
A459/A471	SEQ ID NO: 76	SEQ ID NO: 100
A459/A472	SEQ ID NO: 76	SEQ ID NO: 102
A459/A473	SEQ ID NO: 76	SEQ ID NO: 104
A459/A518	SEQ ID NO: 76	SEQ ID NO: 112
A459/A651	SEQ ID NO: 76	SEQ ID NO: 229
A459/A652	SEQ ID NO: 76	SEQ ID NO: 231
A459/A653	SEQ ID NO: 76	SEQ ID NO: 233
A459/A654	SEQ ID NO: 76	SEQ ID NO: 235
A459/A656	SEQ ID NO: 76	SEQ ID NO: 237
A460/A467	SEQ ID NO: 78	SEQ ID NO: 92
A460/A468	SEQ ID NO: 78	SEQ ID NO: 94
A460/A469	SEQ ID NO: 78	SEQ ID NO: 96
A460/A470	SEQ ID NO: 78	SEQ ID NO: 98
A460/A471	SEQ ID NO: 78	SEQ ID NO: 100
A460/A472	SEQ ID NO: 78	SEQ ID NO: 102
A460/A473	SEQ ID NO: 78	SEQ ID NO: 104
A460/A518	SEQ ID NO: 78	SEQ ID NO: 112
A460/A651	SEQ ID NO: 78	SEQ ID NO: 229
A460/A652	SEQ ID NO: 78	SEQ ID NO: 231
A460/A653	SEQ ID NO: 78	SEQ ID NO: 233
A460/A654	SEQ ID NO: 78	SEQ ID NO: 235
A460/A656	SEQ ID NO: 78	SEQ ID NO: 237
A461/A467	SEQ ID NO: 80	SEQ ID NO: 92
A461/A468	SEQ ID NO: 80	SEQ ID NO: 94
A461/A469	SEQ ID NO: 80	SEQ ID NO: 96
A461/A470	SEQ ID NO: 80	SEQ ID NO: 98
A461/A471	SEQ ID NO: 80	SEQ ID NO: 100
A461/A472	SEQ ID NO: 80	SEQ ID NO: 102
A461/A473	SEQ ID NO: 80	SEQ ID NO: 104
A461/A518	SEQ ID NO: 80	SEQ ID NO: 112
A461/A651	SEQ ID NO: 80	SEQ ID NO: 229
A461/A652	SEQ ID NO: 80	SEQ ID NO: 231
A461/A653	SEQ ID NO: 80	SEQ ID NO: 233
A461/A654	SEQ ID NO: 80	SEQ ID NO: 235
A461/A656	SEQ ID NO: 80	SEQ ID NO: 237
A462/A467	SEQ ID NO: 82	SEQ ID NO: 92
A462/A468	SEQ ID NO: 82	SEQ ID NO: 94
A462/A469	SEQ ID NO: 82	SEQ ID NO: 96
A462/A470	SEQ ID NO: 82	SEQ ID NO: 98
A462/A471	SEQ ID NO: 82	SEQ ID NO: 100
A462/A472	SEQ ID NO: 82	SEQ ID NO: 102
A462/A473	SEQ ID NO: 82	SEQ ID NO: 104
A462/A518	SEQ ID NO: 82	SEQ ID NO: 112
A462/A651	SEQ ID NO: 82	SEQ ID NO: 229
A462/A652	SEQ ID NO: 82	SEQ ID NO: 231
A462/A653	SEQ ID NO: 82	SEQ ID NO: 233
A462/A654	SEQ ID NO: 82	SEQ ID NO: 235
A462/A656	SEQ ID NO: 82	SEQ ID NO: 237
A463/A467	SEQ ID NO: 84	SEQ ID NO: 92
A463/A468	SEQ ID NO: 84	SEQ ID NO: 94
A463/A469	SEQ ID NO: 84	SEQ ID NO: 96
A463/A470	SEQ ID NO: 84	SEQ ID NO: 98
A463/A471	SEQ ID NO: 84	SEQ ID NO: 100
A463/A472	SEQ ID NO: 84	SEQ ID NO: 102
A463/A473	SEQ ID NO: 84	SEQ ID NO: 104
A463/A518	SEQ ID NO: 84	SEQ ID NO: 112
A463/A651	SEQ ID NO: 84	SEQ ID NO: 229
A463/A652	SEQ ID NO: 84	SEQ ID NO: 231
A463/A653	SEQ ID NO: 84	SEQ ID NO: 233
A463/A654	SEQ ID NO: 84	SEQ ID NO: 235
A463/A656	SEQ ID NO: 84	SEQ ID NO: 237
A464/A467	SEQ ID NO: 86	SEQ ID NO: 92
A464/A468	SEQ ID NO: 86	SEQ ID NO: 94
A464/A469	SEQ ID NO: 86	SEQ ID NO: 96
A464/A470	SEQ ID NO: 86	SEQ ID NO: 98
A464/A471	SEQ ID NO: 86	SEQ ID NO: 100
A464/A472	SEQ ID NO: 86	SEQ ID NO: 102
A464/A473	SEQ ID NO: 86	SEQ ID NO: 104
A464/A518	SEQ ID NO: 86	SEQ ID NO: 112
A464/A651	SEQ ID NO: 86	SEQ ID NO: 229
A464/A652	SEQ ID NO: 86	SEQ ID NO: 231
A464/A653	SEQ ID NO: 86	SEQ ID NO: 233
A464/A654	SEQ ID NO: 86	SEQ ID NO: 235
A464/A656	SEQ ID NO: 86	SEQ ID NO: 237
A465/A467	SEQ ID NO: 88	SEQ ID NO: 92
A465/A468	SEQ ID NO: 88	SEQ ID NO: 94
A465/A469	SEQ ID NO: 88	SEQ ID NO: 96
A465/A470	SEQ ID NO: 88	SEQ ID NO: 98
A465/A471	SEQ ID NO: 88	SEQ ID NO: 100
A465/A472	SEQ ID NO: 88	SEQ ID NO: 102
A465/A473	SEQ ID NO: 88	SEQ ID NO: 104
A465/A518	SEQ ID NO: 88	SEQ ID NO: 112
A465/A651	SEQ ID NO: 88	SEQ ID NO: 229
A465/A652	SEQ ID NO: 88	SEQ ID NO: 231
A465/A653	SEQ ID NO: 88	SEQ ID NO: 233
A465/A654	SEQ ID NO: 88	SEQ ID NO: 235
A465/A656	SEQ ID NO: 88	SEQ ID NO: 237
A466/A467	SEQ ID NO: 90	SEQ ID NO: 92
A466/A468	SEQ ID NO: 90	SEQ ID NO: 94
A466/A469	SEQ ID NO: 90	SEQ ID NO: 96
A466/A470	SEQ ID NO: 90	SEQ ID NO: 98
A466/A471	SEQ ID NO: 90	SEQ ID NO: 100
A466/A472	SEQ ID NO: 90	SEQ ID NO: 102
A466/A473	SEQ ID NO: 90	SEQ ID NO: 104
A466/A518	SEQ ID NO: 90	SEQ ID NO: 112
A466/A651	SEQ ID NO: 90	SEQ ID NO: 229
A466/A652	SEQ ID NO: 90	SEQ ID NO: 231
A466/A653	SEQ ID NO: 90	SEQ ID NO: 233
A466/A654	SEQ ID NO: 90	SEQ ID NO: 235
A466/A656	SEQ ID NO: 90	SEQ ID NO: 237
A512/A467	SEQ ID NO: 108	SEQ ID NO: 92
A512/A468	SEQ ID NO: 108	SEQ ID NO: 94
A512/A469	SEQ ID NO: 108	SEQ ID NO: 96
A512/A470	SEQ ID NO: 108	SEQ ID NO: 98
A512/A471	SEQ ID NO: 108	SEQ ID NO: 100
A512/A472	SEQ ID NO: 108	SEQ ID NO: 102
A512/A473	SEQ ID NO: 108	SEQ ID NO: 104
A512/A518	SEQ ID NO: 108	SEQ ID NO: 112
A512/A651	SEQ ID NO: 108	SEQ ID NO: 229
A512/A652	SEQ ID NO: 108	SEQ ID NO: 231
A512/A653	SEQ ID NO: 108	SEQ ID NO: 233
A512/A654	SEQ ID NO: 108	SEQ ID NO: 235
A512/A656	SEQ ID NO: 108	SEQ ID NO: 237
A515/A467	SEQ ID NO: 110	SEQ ID NO: 92
A515/A468	SEQ ID NO: 110	SEQ ID NO: 94
A515/A469	SEQ ID NO: 110	SEQ ID NO: 96
A515/A470	SEQ ID NO: 110	SEQ ID NO: 98
A515/A471	SEQ ID NO: 110	SEQ ID NO: 100
A515/A472	SEQ ID NO: 110	SEQ ID NO: 102
A515/A473	SEQ ID NO: 110	SEQ ID NO: 104
A515/A518	SEQ ID NO: 110	SEQ ID NO: 112
A515/A651	SEQ ID NO: 110	SEQ ID NO: 229
A515/A652	SEQ ID NO: 110	SEQ ID NO: 231
A515/A653	SEQ ID NO: 110	SEQ ID NO: 233
A515/A654	SEQ ID NO: 110	SEQ ID NO: 235
A515/A656	SEQ ID NO: 110	SEQ ID NO: 237
A553/A467	SEQ ID NO: 106	SEQ ID NO: 92
A553/A468	SEQ ID NO: 106	SEQ ID NO: 94
A553/A469	SEQ ID NO: 106	SEQ ID NO: 96
A553/A470	SEQ ID NO: 106	SEQ ID NO: 98
A553/A471	SEQ ID NO: 106	SEQ ID NO: 100
A553/A472	SEQ ID NO: 106	SEQ ID NO: 102
A553/A473	SEQ ID NO: 106	SEQ ID NO: 104
A553/A518	SEQ ID NO: 106	SEQ ID NO: 112
A553/A651	SEQ ID NO: 106	SEQ ID NO: 229
A553/A652	SEQ ID NO: 106	SEQ ID NO: 231
A553/A653	SEQ ID NO: 106	SEQ ID NO: 233
A553/A654	SEQ ID NO: 106	SEQ ID NO: 235
A553/A656	SEQ ID NO: 106	SEQ ID NO: 237
A631/A467	SEQ ID NO: 203	SEQ ID NO: 92
A631/A468	SEQ ID NO: 203	SEQ ID NO: 94
A631/A469	SEQ ID NO: 203	SEQ ID NO: 96
A631/A470	SEQ ID NO: 203	SEQ ID NO: 98
A631/A471	SEQ ID NO: 203	SEQ ID NO: 100
A631/A472	SEQ ID NO: 203	SEQ ID NO: 102
A631/A473	SEQ ID NO: 203	SEQ ID NO: 104
A631/A518	SEQ ID NO: 203	SEQ ID NO: 112
A631/A651	SEQ ID NO: 203	SEQ ID NO: 229
A631/A652	SEQ ID NO: 203	SEQ ID NO: 231
A631/A653	SEQ ID NO: 203	SEQ ID NO: 233
A631/A654	SEQ ID NO: 203	SEQ ID NO: 235
A631/A656	SEQ ID NO: 203	SEQ ID NO: 237
A632/A467	SEQ ID NO: 205	SEQ ID NO: 92
A632/A468	SEQ ID NO: 205	SEQ ID NO: 94
A632/A469	SEQ ID NO: 205	SEQ ID NO: 96
A632/A470	SEQ ID NO: 205	SEQ ID NO: 98
A632/A471	SEQ ID NO: 205	SEQ ID NO: 100
A632/A472	SEQ ID NO: 205	SEQ ID NO: 102
A632/A473	SEQ ID NO: 205	SEQ ID NO: 104
A632/A518	SEQ ID NO: 205	SEQ ID NO: 112
A632/A651	SEQ ID NO: 205	SEQ ID NO: 229
A632/A652	SEQ ID NO: 205	SEQ ID NO: 231
A632/A653	SEQ ID NO: 205	SEQ ID NO: 233
A632/A654	SEQ ID NO: 205	SEQ ID NO: 235
A632/A656	SEQ ID NO: 205	SEQ ID NO: 237
A633/A467	SEQ ID NO: 207	SEQ ID NO: 92
A633/A468	SEQ ID NO: 207	SEQ ID NO: 94
A633/A469	SEQ ID NO: 207	SEQ ID NO: 96
A633/A470	SEQ ID NO: 207	SEQ ID NO: 98
A633/A471	SEQ ID NO: 207	SEQ ID NO: 100
A633/A472	SEQ ID NO: 207	SEQ ID NO: 102
A633/A473	SEQ ID NO: 207	SEQ ID NO: 104
A633/A518	SEQ ID NO: 207	SEQ ID NO: 112
A633/A651	SEQ ID NO: 207	SEQ ID NO: 229
A633/A652	SEQ ID NO: 207	SEQ ID NO: 231
A633/A653	SEQ ID NO: 207	SEQ ID NO: 233
A633/A654	SEQ ID NO: 207	SEQ ID NO: 235
A633/A656	SEQ ID NO: 207	SEQ ID NO: 237
A634/A467	SEQ ID NO: 209	SEQ ID NO: 92
A634/A468	SEQ ID NO: 209	SEQ ID NO: 94
A634/A469	SEQ ID NO: 209	SEQ ID NO: 96
A634/A470	SEQ ID NO: 209	SEQ ID NO: 98
A634/A471	SEQ ID NO: 209	SEQ ID NO: 100
A634/A472	SEQ ID NO: 209	SEQ ID NO: 102
A634/A473	SEQ ID NO: 209	SEQ ID NO: 104
A634/A518	SEQ ID NO: 209	SEQ ID NO: 112
A634/A651	SEQ ID NO: 209	SEQ ID NO: 229
A634/A652	SEQ ID NO: 209	SEQ ID NO: 231
A634/A653	SEQ ID NO: 209	SEQ ID NO: 233
A634/A654	SEQ ID NO: 209	SEQ ID NO: 235
A634/A656	SEQ ID NO: 209	SEQ ID NO: 237
A636/A467	SEQ ID NO: 211	SEQ ID NO: 92
A636/A468	SEQ ID NO: 211	SEQ ID NO: 94
A636/A469	SEQ ID NO: 211	SEQ ID NO: 96
A636/A470	SEQ ID NO: 211	SEQ ID NO: 98
A636/A471	SEQ ID NO: 211	SEQ ID NO: 100
A636/A472	SEQ ID NO: 211	SEQ ID NO: 102
A636/A473	SEQ ID NO: 211	SEQ ID NO: 104
A636/A518	SEQ ID NO: 211	SEQ ID NO: 112
A636/A651	SEQ ID NO: 211	SEQ ID NO: 229
A636/A652	SEQ ID NO: 211	SEQ ID NO: 231
A636/A653	SEQ ID NO: 211	SEQ ID NO: 233
A636/A654	SEQ ID NO: 211	SEQ ID NO: 235
A636/A656	SEQ ID NO: 211	SEQ ID NO: 237
A638/A467	SEQ ID NO: 213	SEQ ID NO: 92
A638/A468	SEQ ID NO: 213	SEQ ID NO: 94
A638/A469	SEQ ID NO: 213	SEQ ID NO: 96
A638/A470	SEQ ID NO: 213	SEQ ID NO: 98
A638/A471	SEQ ID NO: 213	SEQ ID NO: 100
A638/A472	SEQ ID NO: 213	SEQ ID NO: 102
A638/A473	SEQ ID NO: 213	SEQ ID NO: 104
A638/A518	SEQ ID NO: 213	SEQ ID NO: 112
A638/A651	SEQ ID NO: 213	SEQ ID NO: 229
A638/A652	SEQ ID NO: 213	SEQ ID NO: 231
A638/A653	SEQ ID NO: 213	SEQ ID NO: 233
A638/A654	SEQ ID NO: 213	SEQ ID NO: 235
A638/A656	SEQ ID NO: 213	SEQ ID NO: 237
A639/A467	SEQ ID NO: 215	SEQ ID NO: 92
A639/A468	SEQ ID NO: 215	SEQ ID NO: 94
A639/A469	SEQ ID NO: 215	SEQ ID NO: 96
A639/A470	SEQ ID NO: 215	SEQ ID NO: 98
A639/A471	SEQ ID NO: 215	SEQ ID NO: 100
A639/A472	SEQ ID NO: 215	SEQ ID NO: 102
A639/A473	SEQ ID NO: 215	SEQ ID NO: 104
A639/A518	SEQ ID NO: 215	SEQ ID NO: 112
A639/A651	SEQ ID NO: 215	SEQ ID NO: 229
A639/A652	SEQ ID NO: 215	SEQ ID NO: 231
A639/A653	SEQ ID NO: 215	SEQ ID NO: 233
A639/A654	SEQ ID NO: 215	SEQ ID NO: 235
A639/A656	SEQ ID NO: 215	SEQ ID NO: 237
A641/A467	SEQ ID NO: 217	SEQ ID NO: 92
A641/A468	SEQ ID NO: 217	SEQ ID NO: 94
A641/A469	SEQ ID NO: 217	SEQ ID NO: 96
A641/A470	SEQ ID NO: 217	SEQ ID NO: 98
A641/A471	SEQ ID NO: 217	SEQ ID NO: 100
A641/A472	SEQ ID NO: 217	SEQ ID NO: 102
A641/A473	SEQ ID NO: 217	SEQ ID NO: 104
A641/A518	SEQ ID NO: 217	SEQ ID NO: 112
A641/A651	SEQ ID NO: 217	SEQ ID NO: 229
A641/A652	SEQ ID NO: 217	SEQ ID NO: 231
A641/A653	SEQ ID NO: 217	SEQ ID NO: 233
A641/A654	SEQ ID NO: 217	SEQ ID NO: 235
A641/A656	SEQ ID NO: 217	SEQ ID NO: 237
A642/A467	SEQ ID NO: 219	SEQ ID NO: 92
A642/A468	SEQ ID NO: 219	SEQ ID NO: 94
A642/A469	SEQ ID NO: 219	SEQ ID NO: 96
A642/A470	SEQ ID NO: 219	SEQ ID NO: 98
A642/A471	SEQ ID NO: 219	SEQ ID NO: 100
A642/A472	SEQ ID NO: 219	SEQ ID NO: 102
A642/A473	SEQ ID NO: 219	SEQ ID NO: 104
A642/A518	SEQ ID NO: 219	SEQ ID NO: 112
A642/A651	SEQ ID NO: 219	SEQ ID NO: 229
A642/A652	SEQ ID NO: 219	SEQ ID NO: 231
A642/A653	SEQ ID NO: 219	SEQ ID NO: 233
A642/A654	SEQ ID NO: 219	SEQ ID NO: 235
A642/A656	SEQ ID NO: 219	SEQ ID NO: 237
A643/A467	SEQ ID NO: 221	SEQ ID NO: 92
A643/A468	SEQ ID NO: 221	SEQ ID NO: 94
A643/A469	SEQ ID NO: 221	SEQ ID NO: 96
A643/A470	SEQ ID NO: 221	SEQ ID NO: 98
A643/A471	SEQ ID NO: 221	SEQ ID NO: 100
A643/A472	SEQ ID NO: 221	SEQ ID NO: 102
A643/A473	SEQ ID NO: 221	SEQ ID NO: 104
A643/A518	SEQ ID NO: 221	SEQ ID NO: 112
A643/A651	SEQ ID NO: 221	SEQ ID NO: 229
A643/A652	SEQ ID NO: 221	SEQ ID NO: 231
A643/A653	SEQ ID NO: 221	SEQ ID NO: 233
A643/A654	SEQ ID NO: 221	SEQ ID NO: 235
A643/A656	SEQ ID NO: 221	SEQ ID NO: 237
A645/A467	SEQ ID NO: 223	SEQ ID NO: 92
A645/A468	SEQ ID NO: 223	SEQ ID NO: 94
A645/A469	SEQ ID NO: 223	SEQ ID NO: 96
A645/A470	SEQ ID NO: 223	SEQ ID NO: 98
A645/A471	SEQ ID NO: 223	SEQ ID NO: 100
A645/A472	SEQ ID NO: 223	SEQ ID NO: 102
A645/A473	SEQ ID NO: 223	SEQ ID NO: 104
A645/A518	SEQ ID NO: 223	SEQ ID NO: 112
A645/A651	SEQ ID NO: 223	SEQ ID NO: 229
A645/A652	SEQ ID NO: 223	SEQ ID NO: 231
A645/A653	SEQ ID NO: 223	SEQ ID NO: 233
A645/A654	SEQ ID NO: 223	SEQ ID NO: 235
A645/A656	SEQ ID NO: 223	SEQ ID NO: 237
A648/A467	SEQ ID NO: 225	SEQ ID NO: 92
A648/A468	SEQ ID NO: 225	SEQ ID NO: 94
A648/A469	SEQ ID NO: 225	SEQ ID NO: 96
A648/A470	SEQ ID NO: 225	SEQ ID NO: 98
A648/A471	SEQ ID NO: 225	SEQ ID NO: 100
A648/A472	SEQ ID NO: 225	SEQ ID NO: 102
A648/A473	SEQ ID NO: 225	SEQ ID NO: 104
A648/A518	SEQ ID NO: 225	SEQ ID NO: 112
A648/A651	SEQ ID NO: 225	SEQ ID NO: 229
A648/A652	SEQ ID NO: 225	SEQ ID NO: 231
A648/A653	SEQ ID NO: 225	SEQ ID NO: 233
A648/A654	SEQ ID NO: 225	SEQ ID NO: 235
A648/A656	SEQ ID NO: 225	SEQ ID NO: 237
A650/A467	SEQ ID NO: 227	SEQ ID NO: 92
A650/A468	SEQ ID NO: 227	SEQ ID NO: 94
A650/A469	SEQ ID NO: 227	SEQ ID NO: 96
A650/A470	SEQ ID NO: 227	SEQ ID NO: 98
A650/A471	SEQ ID NO: 227	SEQ ID NO: 100
A650/A472	SEQ ID NO: 227	SEQ ID NO: 102
A650/A473	SEQ ID NO: 227	SEQ ID NO: 104
A650/A518	SEQ ID NO: 227	SEQ ID NO: 112
A650/A651	SEQ ID NO: 227	SEQ ID NO: 229
A650/A652	SEQ ID NO: 227	SEQ ID NO: 231
A650/A653	SEQ ID NO: 227	SEQ ID NO: 233
A650/A654	SEQ ID NO: 227	SEQ ID NO: 235
A650/A656	SEQ ID NO: 227	SEQ ID NO: 237

TABLE 36 — Polynucleotide sequences of exemplary mouse antibodies

Antibody Name	VH	VL
A291/A290	SEQ ID NO: 34	SEQ ID NO: 39
A291/A403	SEQ ID NO: 34	SEQ ID NO: 51
A291/A439	SEQ ID NO: 34	SEQ ID NO: 57
A291/A440	SEQ ID NO: 34	SEQ ID NO: 199
A402/A290	SEQ ID NO: 49	SEQ ID NO: 39
A402/A403	SEQ ID NO: 49	SEQ ID NO: 51
A402/A439	SEQ ID NO: 49	SEQ ID NO: 57
A402/A440	SEQ ID NO: 49	SEQ ID NO: 199
A448/A290	SEQ ID NO: 53	SEQ ID NO: 39
A448/A403	SEQ ID NO: 53	SEQ ID NO: 51
A448/A439	SEQ ID NO: 53	SEQ ID NO: 57
A448/A440	SEQ ID NO: 53	SEQ ID NO: 199
A490/A290	SEQ ID NO: 55	SEQ ID NO: 39
A490/A403	SEQ ID NO: 55	SEQ ID NO: 51
A490/A439	SEQ ID NO: 55	SEQ ID NO: 57
A490/A440	SEQ ID NO: 55	SEQ ID NO: 199
A486/A290	SEQ ID NO: 59	SEQ ID NO: 39
A486/A403	SEQ ID NO: 59	SEQ ID NO: 51
A486/A439	SEQ ID NO: 59	SEQ ID NO: 57
A486/A440	SEQ ID NO: 59	SEQ ID NO: 199
A437/A290	SEQ ID NO: 180	SEQ ID NO: 39
A437/A403	SEQ ID NO: 180	SEQ ID NO: 51
A437/A439	SEQ ID NO: 180	SEQ ID NO: 57
A437/A440	SEQ ID NO: 180	SEQ ID NO: 199
A428/A290	SEQ ID NO: 189	SEQ ID NO: 39
A428/A403	SEQ ID NO: 189	SEQ ID NO: 51
A428/A439	SEQ ID NO: 189	SEQ ID NO: 57
A428/A440	SEQ ID NO: 189	SEQ ID NO: 199
A435/A290	SEQ ID NO: 191	SEQ ID NO: 39
A435/A403	SEQ ID NO: 191	SEQ ID NO: 51
A435/A439	SEQ ID NO: 191	SEQ ID NO: 57
A435/A440	SEQ ID NO: 191	SEQ ID NO: 199
A436/A290	SEQ ID NO: 193	SEQ ID NO: 39
A436/A403	SEQ ID NO: 193	SEQ ID NO: 51
A436/A439	SEQ ID NO: 193	SEQ ID NO: 57
A436/A440	SEQ ID NO: 193	SEQ ID NO: 199
A438/A290	SEQ ID NO: 195	SEQ ID NO: 39
A438/A403	SEQ ID NO: 195	SEQ ID NO: 51
A438/A439	SEQ ID NO: 195	SEQ ID NO: 57
A438/A440	SEQ ID NO: 195	SEQ ID NO: 199
A450/A290	SEQ ID NO: 197	SEQ ID NO: 39
A450/A403	SEQ ID NO: 197	SEQ ID NO: 51
A450/A439	SEQ ID NO: 197	SEQ ID NO: 57
A450/A440	SEQ ID NO: 197	SEQ ID NO: 199

TABLE 37 — Polynucleotide sequences of humanized antibodies

Antibody Name	VH	VL
A454/A467	SEQ ID NO: 65	SEQ ID NO: 91
A454/A468	SEQ ID NO: 65	SEQ ID NO: 93
A454/A469	SEQ ID NO: 65	SEQ ID NO: 95
A454/A470	SEQ ID NO: 65	SEQ ID NO: 97
A454/A471	SEQ ID NO: 65	SEQ ID NO: 99
A454/A472	SEQ ID NO: 65	SEQ ID NO: 101
A454/A473	SEQ ID NO: 65	SEQ ID NO: 103
A454/A518	SEQ ID NO: 65	SEQ ID NO: 111
A454/A651	SEQ ID NO: 65	SEQ ID NO: 228
A454/A652	SEQ ID NO: 65	SEQ ID NO: 230
A454/A653	SEQ ID NO: 65	SEQ ID NO: 232
A454/A654	SEQ ID NO: 65	SEQ ID NO: 234
A454/A656	SEQ ID NO: 65	SEQ ID NO: 236
A455/A467	SEQ ID NO: 67	SEQ ID NO: 91
A455/A468	SEQ ID NO: 67	SEQ ID NO: 93
A455/A469	SEQ ID NO: 67	SEQ ID NO: 95
A455/A470	SEQ ID NO: 67	SEQ ID NO: 97
A455/A471	SEQ ID NO: 67	SEQ ID NO: 99
A455/A472	SEQ ID NO: 67	SEQ ID NO: 101
A455/A473	SEQ ID NO: 67	SEQ ID NO: 103
A455/A518	SEQ ID NO: 67	SEQ ID NO: 111
A455/A651	SEQ ID NO: 67	SEQ ID NO: 228
A455/A652	SEQ ID NO: 67	SEQ ID NO: 230
A455/A653	SEQ ID NO: 67	SEQ ID NO: 232
A455/A654	SEQ ID NO: 67	SEQ ID NO: 234
A455/A656	SEQ ID NO: 67	SEQ ID NO: 236
A456/A467	SEQ ID NO: 69	SEQ ID NO: 91
A456/A468	SEQ ID NO: 69	SEQ ID NO: 93
A456/A469	SEQ ID NO: 69	SEQ ID NO: 95
A456/A470	SEQ ID NO: 69	SEQ ID NO: 97
A456/A471	SEQ ID NO: 69	SEQ ID NO: 99
A456/A472	SEQ ID NO: 69	SEQ ID NO: 101
A456/A473	SEQ ID NO: 69	SEQ ID NO: 103
A456/A518	SEQ ID NO: 69	SEQ ID NO: 111
A456/A651	SEQ ID NO: 69	SEQ ID NO: 228
A456/A652	SEQ ID NO: 69	SEQ ID NO: 230
A456/A653	SEQ ID NO: 69	SEQ ID NO: 232
A456/A654	SEQ ID NO: 69	SEQ ID NO: 234
A456/A656	SEQ ID NO: 69	SEQ ID NO: 236
A457/A467	SEQ ID NO: 71	SEQ ID NO: 91
A457/A468	SEQ ID NO: 71	SEQ ID NO: 93
A457/A469	SEQ ID NO: 71	SEQ ID NO: 95
A457/A470	SEQ ID NO: 71	SEQ ID NO: 97
A457/A471	SEQ ID NO: 71	SEQ ID NO: 99
A457/A472	SEQ ID NO: 71	SEQ ID NO: 101
A457/A473	SEQ ID NO: 71	SEQ ID NO: 103
A457/A518	SEQ ID NO: 71	SEQ ID NO: 111
A457/A651	SEQ ID NO: 71	SEQ ID NO: 228
A457/A652	SEQ ID NO: 71	SEQ ID NO: 230
A457/A653	SEQ ID NO: 71	SEQ ID NO: 232
A457/A654	SEQ ID NO: 71	SEQ ID NO: 234
A457/A656	SEQ ID NO: 71	SEQ ID NO: 236
A458/A467	SEQ ID NO: 73	SEQ ID NO: 91
A458/A468	SEQ ID NO: 73	SEQ ID NO: 93
A458/A469	SEQ ID NO: 73	SEQ ID NO: 95
A458/A470	SEQ ID NO: 73	SEQ ID NO: 97
A458/A471	SEQ ID NO: 73	SEQ ID NO: 99
A458/A472	SEQ ID NO: 73	SEQ ID NO: 101
A458/A473	SEQ ID NO: 73	SEQ ID NO: 103
A458/A518	SEQ ID NO: 73	SEQ ID NO: 111
A458/A651	SEQ ID NO: 73	SEQ ID NO: 228
A458/A652	SEQ ID NO: 73	SEQ ID NO: 230
A458/A653	SEQ ID NO: 73	SEQ ID NO: 232
A458/A654	SEQ ID NO: 73	SEQ ID NO: 234
A458/A656	SEQ ID NO: 73	SEQ ID NO: 236
A459/A467	SEQ ID NO: 75	SEQ ID NO: 91
A459/A468	SEQ ID NO: 75	SEQ ID NO: 93
A459/A469	SEQ ID NO: 75	SEQ ID NO: 95
A459/A470	SEQ ID NO: 75	SEQ ID NO: 97
A459/A471	SEQ ID NO: 75	SEQ ID NO: 99
A459/A472	SEQ ID NO: 75	SEQ ID NO: 101
A459/A473	SEQ ID NO: 75	SEQ ID NO: 103
A459/A518	SEQ ID NO: 75	SEQ ID NO: 111
A459/A651	SEQ ID NO: 75	SEQ ID NO: 228
A459/A652	SEQ ID NO: 75	SEQ ID NO: 230
A459/A653	SEQ ID NO: 75	SEQ ID NO: 232
A459/A654	SEQ ID NO: 75	SEQ ID NO: 234
A459/A656	SEQ ID NO: 75	SEQ ID NO: 236
A460/A467	SEQ ID NO: 77	SEQ ID NO: 91
A460/A468	SEQ ID NO: 77	SEQ ID NO: 93
A460/A469	SEQ ID NO: 77	SEQ ID NO: 95
A460/A470	SEQ ID NO: 77	SEQ ID NO: 97
A460/A471	SEQ ID NO: 77	SEQ ID NO: 99
A460/A472	SEQ ID NO: 77	SEQ ID NO: 101
A460/A473	SEQ ID NO: 77	SEQ ID NO: 103
A460/A518	SEQ ID NO: 77	SEQ ID NO: 111
A460/A651	SEQ ID NO: 77	SEQ ID NO: 228
A460/A652	SEQ ID NO: 77	SEQ ID NO: 230
A460/A653	SEQ ID NO: 77	SEQ ID NO: 232
A460/A654	SEQ ID NO: 77	SEQ ID NO: 234
A460/A656	SEQ ID NO: 77	SEQ ID NO: 236
A461/A467	SEQ ID NO: 79	SEQ ID NO: 91
A461/A468	SEQ ID NO: 79	SEQ ID NO: 93
A461/A469	SEQ ID NO: 79	SEQ ID NO: 95
A461/A470	SEQ ID NO: 79	SEQ ID NO: 97
A461/A471	SEQ ID NO: 79	SEQ ID NO: 99
A461/A472	SEQ ID NO: 79	SEQ ID NO: 101
A461/A473	SEQ ID NO: 79	SEQ ID NO: 103
A461/A518	SEQ ID NO: 79	SEQ ID NO: 111
A461/A651	SEQ ID NO: 79	SEQ ID NO: 228
A461/A652	SEQ ID NO: 79	SEQ ID NO: 230
A461/A653	SEQ ID NO: 79	SEQ ID NO: 232
A461/A654	SEQ ID NO: 79	SEQ ID NO: 234
A461/A656	SEQ ID NO: 79	SEQ ID NO: 236
A462/A467	SEQ ID NO: 81	SEQ ID NO: 91
A462/A468	SEQ ID NO: 81	SEQ ID NO: 93
A462/A469	SEQ ID NO: 81	SEQ ID NO: 95
A462/A470	SEQ ID NO: 81	SEQ ID NO: 97
A462/A471	SEQ ID NO: 81	SEQ ID NO: 99
A462/A472	SEQ ID NO: 81	SEQ ID NO: 101
A462/A473	SEQ ID NO: 81	SEQ ID NO: 103
A462/A518	SEQ ID NO: 81	SEQ ID NO: 111
A462/A651	SEQ ID NO: 81	SEQ ID NO: 228
A462/A652	SEQ ID NO: 81	SEQ ID NO: 230
A462/A653	SEQ ID NO: 81	SEQ ID NO: 232
A462/A654	SEQ ID NO: 81	SEQ ID NO: 234
A462/A656	SEQ ID NO: 81	SEQ ID NO: 236
A463/A467	SEQ ID NO: 83	SEQ ID NO: 91
A463/A468	SEQ ID NO: 83	SEQ ID NO: 93
A463/A469	SEQ ID NO: 83	SEQ ID NO: 95
A463/A470	SEQ ID NO: 83	SEQ ID NO: 97
A463/A471	SEQ ID NO: 83	SEQ ID NO: 99
A463/A472	SEQ ID NO: 83	SEQ ID NO: 101
A463/A473	SEQ ID NO: 83	SEQ ID NO: 103
A463/A518	SEQ ID NO: 83	SEQ ID NO: 111
A463/A651	SEQ ID NO: 83	SEQ ID NO: 228
A463/A652	SEQ ID NO: 83	SEQ ID NO: 230
A463/A653	SEQ ID NO: 83	SEQ ID NO: 232
A463/A654	SEQ ID NO: 83	SEQ ID NO: 234
A463/A656	SEQ ID NO: 83	SEQ ID NO: 236
A464/A467	SEQ ID NO: 85	SEQ ID NO: 91
A464/A468	SEQ ID NO: 85	SEQ ID NO: 93
A464/A469	SEQ ID NO: 85	SEQ ID NO: 95
A464/A470	SEQ ID NO: 85	SEQ ID NO: 97
A464/A471	SEQ ID NO: 85	SEQ ID NO: 99
A464/A472	SEQ ID NO: 85	SEQ ID NO: 101
A464/A473	SEQ ID NO: 85	SEQ ID NO: 103
A464/A518	SEQ ID NO: 85	SEQ ID NO: 111
A464/A651	SEQ ID NO: 85	SEQ ID NO: 228
A464/A652	SEQ ID NO: 85	SEQ ID NO: 230
A464/A653	SEQ ID NO: 85	SEQ ID NO: 232
A464/A654	SEQ ID NO: 85	SEQ ID NO: 234
A464/A656	SEQ ID NO: 85	SEQ ID NO: 236
A465/A467	SEQ ID NO: 87	SEQ ID NO: 91
A465/A468	SEQ ID NO: 87	SEQ ID NO: 93
A465/A469	SEQ ID NO: 87	SEQ ID NO: 95
A465/A470	SEQ ID NO: 87	SEQ ID NO: 97
A465/A471	SEQ ID NO: 87	SEQ ID NO: 99
A465/A472	SEQ ID NO: 87	SEQ ID NO: 101
A465/A473	SEQ ID NO: 87	SEQ ID NO: 103
A465/A518	SEQ ID NO: 87	SEQ ID NO: 111
A465/A651	SEQ ID NO: 87	SEQ ID NO: 228
A465/A652	SEQ ID NO: 87	SEQ ID NO: 230
A465/A653	SEQ ID NO: 87	SEQ ID NO: 232
A465/A654	SEQ ID NO: 87	SEQ ID NO: 234
A465/A656	SEQ ID NO: 87	SEQ ID NO: 236
A466/A467	SEQ ID NO: 89	SEQ ID NO: 91
A466/A468	SEQ ID NO: 89	SEQ ID NO: 93
A466/A469	SEQ ID NO: 89	SEQ ID NO: 95
A466/A470	SEQ ID NO: 89	SEQ ID NO: 97
A466/A471	SEQ ID NO: 89	SEQ ID NO: 99
A466/A472	SEQ ID NO: 89	SEQ ID NO: 101
A466/A473	SEQ ID NO: 89	SEQ ID NO: 103
A466/A518	SEQ ID NO: 89	SEQ ID NO: 111
A466/A651	SEQ ID NO: 89	SEQ ID NO: 228
A466/A652	SEQ ID NO: 89	SEQ ID NO: 230
A466/A653	SEQ ID NO: 89	SEQ ID NO: 232
A466/A654	SEQ ID NO: 89	SEQ ID NO: 234
A466/A656	SEQ ID NO: 89	SEQ ID NO: 236
A512/A467	SEQ ID NO: 107	SEQ ID NO: 91
A512/A468	SEQ ID NO: 107	SEQ ID NO: 93
A512/A469	SEQ ID NO: 107	SEQ ID NO: 95
A512/A470	SEQ ID NO: 107	SEQ ID NO: 97
A512/A471	SEQ ID NO: 107	SEQ ID NO: 99
A512/A472	SEQ ID NO: 107	SEQ ID NO: 101
A512/A473	SEQ ID NO: 107	SEQ ID NO: 103
A512/A518	SEQ ID NO: 107	SEQ ID NO: 111
A512/A651	SEQ ID NO: 107	SEQ ID NO: 228
A512/A652	SEQ ID NO: 107	SEQ ID NO: 230
A512/A653	SEQ ID NO: 107	SEQ ID NO: 232
A512/A654	SEQ ID NO: 107	SEQ ID NO: 234
A512/A656	SEQ ID NO: 107	SEQ ID NO: 236
A515/A467	SEQ ID NO: 109	SEQ ID NO: 91
A515/A468	SEQ ID NO: 109	SEQ ID NO: 93
A515/A469	SEQ ID NO: 109	SEQ ID NO: 95
A515/A470	SEQ ID NO: 109	SEQ ID NO: 97
A515/A471	SEQ ID NO: 109	SEQ ID NO: 99
A515/A472	SEQ ID NO: 109	SEQ ID NO: 101
A515/A473	SEQ ID NO: 109	SEQ ID NO: 103
A515/A518	SEQ ID NO: 109	SEQ ID NO: 111
A515/A651	SEQ ID NO: 109	SEQ ID NO: 228
A515/A652	SEQ ID NO: 109	SEQ ID NO: 230
A515/A653	SEQ ID NO: 109	SEQ ID NO: 232
A515/A654	SEQ ID NO: 109	SEQ ID NO: 234
A515/A656	SEQ ID NO: 109	SEQ ID NO: 236
A553/A467	SEQ ID NO: 105	SEQ ID NO: 91
A553/A468	SEQ ID NO: 105	SEQ ID NO: 93
A553/A469	SEQ ID NO: 105	SEQ ID NO: 95
A553/A470	SEQ ID NO: 105	SEQ ID NO: 97
A553/A471	SEQ ID NO: 105	SEQ ID NO: 99
A553/A472	SEQ ID NO: 105	SEQ ID NO: 101
A553/A473	SEQ ID NO: 105	SEQ ID NO: 103
A553/A518	SEQ ID NO: 105	SEQ ID NO: 111
A553/A651	SEQ ID NO: 105	SEQ ID NO: 228
A553/A652	SEQ ID NO: 105	SEQ ID NO: 230
A553/A653	SEQ ID NO: 105	SEQ ID NO: 232
A553/A654	SEQ ID NO: 105	SEQ ID NO: 234
A553/A656	SEQ ID NO: 105	SEQ ID NO: 236
A631/A467	SEQ ID NO: 202	SEQ ID NO: 91
A631/A468	SEQ ID NO: 202	SEQ ID NO: 93
A631/A469	SEQ ID NO: 202	SEQ ID NO: 95
A631/A470	SEQ ID NO: 202	SEQ ID NO: 97
A631/A471	SEQ ID NO: 202	SEQ ID NO: 99
A631/A472	SEQ ID NO: 202	SEQ ID NO: 101
A631/A473	SEQ ID NO: 202	SEQ ID NO: 103
A631/A518	SEQ ID NO: 202	SEQ ID NO: 111
A631/A651	SEQ ID NO: 202	SEQ ID NO: 228
A631/A652	SEQ ID NO: 202	SEQ ID NO: 230
A631/A653	SEQ ID NO: 202	SEQ ID NO: 232
A631/A654	SEQ ID NO: 202	SEQ ID NO: 234
A631/A656	SEQ ID NO: 202	SEQ ID NO: 236
A632/A467	SEQ ID NO: 204	SEQ ID NO: 91
A632/A468	SEQ ID NO: 204	SEQ ID NO: 93
A632/A469	SEQ ID NO: 204	SEQ ID NO: 95
A632/A470	SEQ ID NO: 204	SEQ ID NO: 97
A632/A471	SEQ ID NO: 204	SEQ ID NO: 99
A632/A472	SEQ ID NO: 204	SEQ ID NO: 101
A632/A473	SEQ ID NO: 204	SEQ ID NO: 103
A632/A518	SEQ ID NO: 204	SEQ ID NO: 111
A632/A651	SEQ ID NO: 204	SEQ ID NO: 228
A632/A652	SEQ ID NO: 204	SEQ ID NO: 230
A632/A653	SEQ ID NO: 204	SEQ ID NO: 232
A632/A654	SEQ ID NO: 204	SEQ ID NO: 234
A632/A656	SEQ ID NO: 204	SEQ ID NO: 236
A633/A467	SEQ ID NO: 206	SEQ ID NO: 91
A633/A468	SEQ ID NO: 206	SEQ ID NO: 93
A633/A469	SEQ ID NO: 206	SEQ ID NO: 95
A633/A470	SEQ ID NO: 206	SEQ ID NO: 97
A633/A471	SEQ ID NO: 206	SEQ ID NO: 99
A633/A472	SEQ ID NO: 206	SEQ ID NO: 101
A633/A473	SEQ ID NO: 206	SEQ ID NO: 103
A633/A518	SEQ ID NO: 206	SEQ ID NO: 111
A633/A651	SEQ ID NO: 206	SEQ ID NO: 228
A633/A652	SEQ ID NO: 206	SEQ ID NO: 230
A633/A653	SEQ ID NO: 206	SEQ ID NO: 232
A633/A654	SEQ ID NO: 206	SEQ ID NO: 234
A633/A656	SEQ ID NO: 206	SEQ ID NO: 236
A634/A467	SEQ ID NO: 208	SEQ ID NO: 91
A634/A468	SEQ ID NO: 208	SEQ ID NO: 93
A634/A469	SEQ ID NO: 208	SEQ ID NO: 95
A634/A470	SEQ ID NO: 208	SEQ ID NO: 97
A634/A471	SEQ ID NO: 208	SEQ ID NO: 99
A634/A472	SEQ ID NO: 208	SEQ ID NO: 101
A634/A473	SEQ ID NO: 208	SEQ ID NO: 103
A634/A518	SEQ ID NO: 208	SEQ ID NO: 111
A634/A651	SEQ ID NO: 208	SEQ ID NO: 228
A634/A652	SEQ ID NO: 208	SEQ ID NO: 230
A634/A653	SEQ ID NO: 208	SEQ ID NO: 232
A634/A654	SEQ ID NO: 208	SEQ ID NO: 234
A634/A656	SEQ ID NO: 208	SEQ ID NO: 236
A636/A467	SEQ ID NO: 210	SEQ ID NO: 91
A636/A468	SEQ ID NO: 210	SEQ ID NO: 93
A636/A469	SEQ ID NO: 210	SEQ ID NO: 95
A636/A470	SEQ ID NO: 210	SEQ ID NO: 97
A636/A471	SEQ ID NO: 210	SEQ ID NO: 99
A636/A472	SEQ ID NO: 210	SEQ ID NO: 101
A636/A473	SEQ ID NO: 210	SEQ ID NO: 103
A636/A518	SEQ ID NO: 210	SEQ ID NO: 111
A636/A651	SEQ ID NO: 210	SEQ ID NO: 228
A636/A652	SEQ ID NO: 210	SEQ ID NO: 230
A636/A653	SEQ ID NO: 210	SEQ ID NO: 232
A636/A654	SEQ ID NO: 210	SEQ ID NO: 234
A636/A656	SEQ ID NO: 210	SEQ ID NO: 236
A638/A467	SEQ ID NO: 212	SEQ ID NO: 91
A638/A468	SEQ ID NO: 212	SEQ ID NO: 93
A638/A469	SEQ ID NO: 212	SEQ ID NO: 95
A638/A470	SEQ ID NO: 212	SEQ ID NO: 97
A638/A471	SEQ ID NO: 212	SEQ ID NO: 99
A638/A472	SEQ ID NO: 212	SEQ ID NO: 101
A638/A473	SEQ ID NO: 212	SEQ ID NO: 103
A638/A518	SEQ ID NO: 212	SEQ ID NO: 111
A638/A651	SEQ ID NO: 212	SEQ ID NO: 228
A638/A652	SEQ ID NO: 212	SEQ ID NO: 230
A638/A653	SEQ ID NO: 212	SEQ ID NO: 232
A638/A654	SEQ ID NO: 212	SEQ ID NO: 234
A638/A656	SEQ ID NO: 212	SEQ ID NO: 236
A639/A467	SEQ ID NO: 214	SEQ ID NO: 91
A639/A468	SEQ ID NO: 214	SEQ ID NO: 93
A639/A469	SEQ ID NO: 214	SEQ ID NO: 95
A639/A470	SEQ ID NO: 214	SEQ ID NO: 97
A639/A471	SEQ ID NO: 214	SEQ ID NO: 99
A639/A472	SEQ ID NO: 214	SEQ ID NO: 101
A639/A473	SEQ ID NO: 214	SEQ ID NO: 103
A639/A518	SEQ ID NO: 214	SEQ ID NO: 111
A639/A651	SEQ ID NO: 214	SEQ ID NO: 228
A639/A652	SEQ ID NO: 214	SEQ ID NO: 230
A639/A653	SEQ ID NO: 214	SEQ ID NO: 232
A639/A654	SEQ ID NO: 214	SEQ ID NO: 234
A639/A656	SEQ ID NO: 214	SEQ ID NO: 236
A641/A467	SEQ ID NO: 216	SEQ ID NO: 91
A641/A468	SEQ ID NO: 216	SEQ ID NO: 93
A641/A469	SEQ ID NO: 216	SEQ ID NO: 95
A641/A470	SEQ ID NO: 216	SEQ ID NO: 97
A641/A471	SEQ ID NO: 216	SEQ ID NO: 99
A641/A472	SEQ ID NO: 216	SEQ ID NO: 101
A641/A473	SEQ ID NO: 216	SEQ ID NO: 103
A641/A518	SEQ ID NO: 216	SEQ ID NO: 111
A641/A651	SEQ ID NO: 216	SEQ ID NO: 228
A641/A652	SEQ ID NO: 216	SEQ ID NO: 230
A641/A653	SEQ ID NO: 216	SEQ ID NO: 232
A641/A654	SEQ ID NO: 216	SEQ ID NO: 234
A641/A656	SEQ ID NO: 216	SEQ ID NO: 236
A642/A467	SEQ ID NO: 218	SEQ ID NO: 91
A642/A468	SEQ ID NO: 218	SEQ ID NO: 93
A642/A469	SEQ ID NO: 218	SEQ ID NO: 95
A642/A470	SEQ ID NO: 218	SEQ ID NO: 97
A642/A471	SEQ ID NO: 218	SEQ ID NO: 99
A642/A472	SEQ ID NO: 218	SEQ ID NO: 101
A642/A473	SEQ ID NO: 218	SEQ ID NO: 103
A642/A518	SEQ ID NO: 218	SEQ ID NO: 111
A642/A651	SEQ ID NO: 218	SEQ ID NO: 228
A642/A652	SEQ ID NO: 218	SEQ ID NO: 230
A642/A653	SEQ ID NO: 218	SEQ ID NO: 232
A642/A654	SEQ ID NO: 218	SEQ ID NO: 234
A642/A656	SEQ ID NO: 218	SEQ ID NO: 236
A643/A467	SEQ ID NO: 220	SEQ ID NO: 91
A643/A468	SEQ ID NO: 220	SEQ ID NO: 93
A643/A469	SEQ ID NO: 220	SEQ ID NO: 95
A643/A470	SEQ ID NO: 220	SEQ ID NO: 97
A643/A471	SEQ ID NO: 220	SEQ ID NO: 99
A643/A472	SEQ ID NO: 220	SEQ ID NO: 101
A643/A473	SEQ ID NO: 220	SEQ ID NO: 103
A643/A518	SEQ ID NO: 220	SEQ ID NO: 111
A643/A651	SEQ ID NO: 220	SEQ ID NO: 228
A643/A652	SEQ ID NO: 220	SEQ ID NO: 230
A643/A653	SEQ ID NO: 220	SEQ ID NO: 232
A643/A654	SEQ ID NO: 220	SEQ ID NO: 234
A643/A656	SEQ ID NO: 220	SEQ ID NO: 236
A645/A467	SEQ ID NO: 222	SEQ ID NO: 91
A645/A468	SEQ ID NO: 222	SEQ ID NO: 93
A645/A469	SEQ ID NO: 222	SEQ ID NO: 95
A645/A470	SEQ ID NO: 222	SEQ ID NO: 97
A645/A471	SEQ ID NO: 222	SEQ ID NO: 99
A645/A472	SEQ ID NO: 222	SEQ ID NO: 101
A645/A473	SEQ ID NO: 222	SEQ ID NO: 103
A645/A518	SEQ ID NO: 222	SEQ ID NO: 111
A645/A651	SEQ ID NO: 222	SEQ ID NO: 228
A645/A652	SEQ ID NO: 222	SEQ ID NO: 230
A645/A653	SEQ ID NO: 222	SEQ ID NO: 232
A645/A654	SEQ ID NO: 222	SEQ ID NO: 234
A645/A656	SEQ ID NO: 222	SEQ ID NO: 236
A648/A467	SEQ ID NO: 224	SEQ ID NO: 91
A648/A468	SEQ ID NO: 224	SEQ ID NO: 93
A648/A469	SEQ ID NO: 224	SEQ ID NO: 95
A648/A470	SEQ ID NO: 224	SEQ ID NO: 97
A648/A471	SEQ ID NO: 224	SEQ ID NO: 99
A648/A472	SEQ ID NO: 224	SEQ ID NO: 101
A648/A473	SEQ ID NO: 224	SEQ ID NO: 103
A648/A518	SEQ ID NO: 224	SEQ ID NO: 111
A648/A651	SEQ ID NO: 224	SEQ ID NO: 228
A648/A652	SEQ ID NO: 224	SEQ ID NO: 230
A648/A653	SEQ ID NO: 224	SEQ ID NO: 232
A648/A654	SEQ ID NO: 224	SEQ ID NO: 234
A648/A656	SEQ ID NO: 224	SEQ ID NO: 236
A650/A467	SEQ ID NO: 226	SEQ ID NO: 91
A650/A468	SEQ ID NO: 226	SEQ ID NO: 93
A650/A469	SEQ ID NO: 226	SEQ ID NO: 95
A650/A470	SEQ ID NO: 226	SEQ ID NO: 97
A650/A471	SEQ ID NO: 226	SEQ ID NO: 99
A650/A472	SEQ ID NO: 226	SEQ ID NO: 101
A650/A473	SEQ ID NO: 226	SEQ ID NO: 103
A650/A518	SEQ ID NO: 226	SEQ ID NO: 111
A650/A651	SEQ ID NO: 226	SEQ ID NO: 228
A650/A652	SEQ ID NO: 226	SEQ ID NO: 230
A650/A653	SEQ ID NO: 226	SEQ ID NO: 232
A650/A654	SEQ ID NO: 226	SEQ ID NO: 234
A650/A656	SEQ ID NO: 226	SEQ ID NO: 236

alanine	Ala	(A)
arginine	Arg	(R)
asparagine	Asn	(N)
aspartic acid	Asp	(D)
cysteine	Cys	(C)
glutamic acid	Glu	(E)
glutamine	Gln	(Q)
glycine	Gly	(G)
histidine	His	(H)
isoleucine	Ile	(I)
leucine	Leu	(L)
lysine	Lys	(K)
methionine	Met	(M)
phenylalanine	Phe	(F)
proline	Pro	(P)
serine	Ser	(S)
threonine	Thr	(T)
tryptophan	Trp	(W)
tyrosine	Tyr	(Y)
valine	Val	(V)

TABLE 13 — Nucleotide and amino acid sequences of Fn14 proteins

Description	Sequence (SEQ ID NO)
Human Fn14 (full	ATGGCTCGGGGCTCGCTGCGCCGGTTGCTGCGGCTCCTCGTG
length) nucleotide	CTGGGGCTCTGGCTGGCGTTGCTGCGCTCCGTGGCCGGGGAG
sequence	CAAGCGCCAGGCACCGCCCCCTGCTCCCGCGGCAGCTCCTGG
	AGCGCGGACCTGGACAAGTGCATGGACTGCGCGTCTTGCAG
	GGCGCGACCGCACAGCGACTTCTGCCTGGGCTGCGCTGCAG
	CACCTCCTGCCCCCTTCCGGCTGCTTTGGCCCATCCTTGGGG
	GCGCTCTGAGCCTGACCTTCGTGCTGGGGCTGCTTTCTGGCT
	TTTTGGTCTGGAGACGATGCCGCAGGAGAGAGAAGTTCACC
	ACCCCCATAGAGGAGACCGGCGGAGAGGGCTGCCCAGCTGT
	GGCGCTGATCCAG (SEQ ID NO: 1)
Human Fn14 (full	MARGSLRRLLRLLVLGLWLALLRSVAGEQAPGTAPCSRGSSWS
length) amino acid	ADLDKCMDCASCRARPHSDFCLGCAAAPPAPFRLLWPILGGAL
sequence	SLTFVLGLLSGFLVWRRCRRREKFTTPIEETGGEGCPAVALIQ
	(SEQ ID NO: 2)
human Fn14 mature,	GAGCAAGCGCCAGGCACCGCCCCCTGCTCCCGCGGCAGCTC
extracellular domain	CTGGAGCGCGGACCTGGACAAGTGCATGGACTGCGCGTCTT
(aa28-75) (nucleotide	GCAGGGCGCGACCGCACAGCGACTTCTGCCTGGGCTGCGCT
sequence)	GCAGCACCTCCTGCCCCCTTC (SEQ ID NO: 3)
human Fn14 mature,	EQAPGTAPCSRGSSWSADLDKCMDCASCRARPHSDFCLGCAA
extracellular domain	APPAPF (SEQ ID NO: 4)
(aa28-75) (amino acid
sequence)
mouse Fn14 (full	ATGGCTTCGGCTTGGCCGCGGTCTCTGCCGCAGATCCTCGTG
length) nucleotide	TTGGGATTCGGCTTGGTGTTGATGCGCGCCGCGGCCGGGGAG
sequence	CAAGCACCAGGCACCTCCCCATGCTCTAGCGGCAGCTCCTGG
	AGCGCGGACCTCGACAAGTGCATGGACTGCGCTTCTTGTCCA
	GCGCGACCACACAGCGACTTCTGCCTGGGATGCGCCGCAGC
	ACCTCCTGCCCACTTCAGGCTACTGTGGCCCATTCTGGGGGG
	CGCTCTTAGTCTGGTCCTGGTTTTGGCGCTGGTTTCTAGTTTC
	CTGGTCTGGAGAAGATGCCGCCGGAGAGAAAAGTTTACTAC
	CCCCATAGAGGAGACTGGTGGAGAGGGCTGCCCAGGTGTGG
	CACTGATCCAG (SEQ ID NO: 5)
mouse Fn14 (full	MASAWPRSLPQILVLGFGLVLMRAAAGEQAPGTSPCSSGSSWS
length) amino acid	ADLDKCMDCASCPARPHSDFCLGCAAAPPAHFRLLWPILGGAL
sequence	SLVLVLALVSSFLVWRRCRRREKFTTPIEETGGEGCPGVALIQ
	(SEQ ID NO: 6)
rat Fn14 (full length)	ATGGCTCCGGGTTGGCCGCGGCCTCTGCCGCAGCTCCTCGTG
nucleotide sequence	TTGGGATTCGGGTTGGTGTTGATACGCGCCACGGCCGGGGA
	GCAAGCACCAGGCAACGCCCCATGCTCAAGCGGCAGCTCCT
	GGAGCGCGGACCTCGACAAGTGCATGGACTGCGCTTCTTGTC
	CAGCGCGACCACACAGCGACTTCTGCCTGGGATGCGCAGCA
	GCACCTCCTGCCCACTTCAGGATGCTATGGCCCATTCTGGGA
	GGCGCTCTTAGTCTGGCCCTGGTTTTGGCGCTGGTTTCTGGTT
	TCCTGGTCTGGAGACGATGCCGCCGGAGAGAAAAGTTTACT
	ACCCCCATAGAGGAGACTGGTGGAGAAGGCTGCCCAGGTGT
	GGCACTGATCCAG (SEQ ID NO: 7)
rat Fn14 (full length)	MAPGWPRPLPQLLVLGFGLVLIRATAGEQAPGNAPCSSGSSWS
amino acid sequence	ADLDKCMDCASCPARPHSDFCLGCAAAPPAHFRMLWPILGGA
	LSLALVLALVSGFLVWRRCRRREKFTTPIEETGGEGCPGVALIQ
	(SEQ ID NO: 8)
cynomolgus macaque	ATGGCTCGGGGTTCGCTGCGCCGGTTGCTGCGGCTCCTCGTG
( Macaca fascicularis )	CTGGGGCTCTGGCTGGCGTTGCTGCGCTCCGTGGCTGGGGAG
Fn14 (full length)	CAAGCGCCAGGCACCGCCCCCTGCTCCCACGGCAGTTCCTGG
nucleotide sequence	AGCGCGGACCTGGACAAGTGCATGGACTGCGCGTCTTGCAG
	GGCGCGACCGCACAGCGACTTCTGCCTGGGCTGCTCTGCGGC
	ACCTCCTGCCCCCTTCCGGCTGCTTTGGCCCATCCTTGGGGG
	CGCTCTGAGTCTGACCTTCGTGCTGGGGCTGCTTTCTGGCTTT
	CTGGTCTGGAGACGATGCCGCAGGAGAGAGAAGTTCACCAC
	CCCCATAGAGGAGACCGGCGGAGAGGGCTGCCCAGCTGTGG
	CGCTGATCCAGTGA (SEQ ID NO: 9)
cynomolgus macaque	MARGSLRRLLRLLVLGLWLALLRSVAGEQAPGTAPCSHGSSWS
( Macaca fascicularis )	ADLDKCMDCASCRARPHSDFCLGCSAAPPAPFRLLWPILGGAL
Fn14 (full length)	SLTFVLGLLSGFLVWRRCRRREKFTTPIEETGGEGCPAVALIQ
amino acid sequence	(SEQ ID NO: 10)

TABLE 15 — VH and VL nucleotide and amino acid sequences of antibodies KO41c and KO42d.

Description	Sequences (SEQ ID NO)
41C-VH	ATGGGATGGAGCTGGATCTTTCTCTTTCTCCTGTCAGAAACTGCAGGTGTCC
(with signal peptide)	TCTCTGAGGTCCAGCTGCAACAGTCTGGACCTGAGCTGGTGAAGCCTGGGGC
(not codon optimized)	TTCAGTGAAGATGTCCTGCAAGGCTTCTGGATACACATTCACTGACTACAAC
	ATGCACTGGGTGAAGCAGAGCCATGGAAAGAGCCTTGAATGGATTGGATATA
	TTAACCCTAACAATGGTGGTACTAACTACAACCAGAAGTTCAAGGGCAAGGC
	CACATTGACTGTAAACAAGTCCTCCAGGTCAGCCTACATGGAGTTCCGCAGC
	CTGACATCGGAGGATTCTGCAGTCTATTACTGTGCCTCGTCGGGATGGTTTA
	CTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA
	(SEQ ID NO: 31)
41C-VH	MGWSWIFLFLLSETAGVLSEVQLQQSGPELVKPGASVKMSCKASGYTFTDYN
(with signal peptide)	MHWVKQSHGKSLEWIGYINPNNGGTNYNQKFKGKATLTVNKSSRSAYMEFRS
	LTSEDSAVYYCASSGWFTYWGQGTLVTVSA
	(SEQ ID NO: 32)
41C-VH	GAGGTCCAGCTGCTCCAGTCTGGACCTGAGCTGGTGAAGCCTGTGGCTTCAG
(no signal peptide)	TGAAGATGTCCTGCAAGGCTTCTGGATACACATTCACTGACTACAACATTCA
(not codon optimized)	CTGGGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGATATATTAAC
	CCTAACAATGGTGTTACTGGCTACAACCAGAAGTTCAGGGGCAAGGCCACAT
	TGACTGTTAACAGGTCCTCCAACACAGCCTACATGGACCTCCGCAGCCTGAC
	ATCGGAGGATTCTGCAGTCTATTACTGTACAAGACGCTATGGTGACTACGTC
	CATGCTATGGACTGCTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA
	(SEQ ID NO: 33)
41C-VH	GAAGTGCAGCTGCAGCAGTCTGGCCCCGAGCTCGTGAAACCTGGCGCCTCCG
(no signal peptide)	TGAAGATGTCCTGCAAGGCCTCCGGCTACACCTTCACCGACTACAACATGCA
(codon optimized)	CTGGGTCAAGCAGTCCCACGGCAAGTCCCTGGAATGGATCGGCTACATCAAC
	CCCAACAACGGCGGCACCAACTACAACCAGAAGTTCAAGGGCAAGGCTACCC
	TGACCGTGAACAAGTCCTCCAGATCCGCCTACATGGAATTTCGGTCCCTGAC
	CTCCGAGGACTCCGCCGTGTACTACTGCGCCTCCTCTGGCTGGTTCACCTAC
	TGGGGCCAGGGCACCCTCGTGACCGTGTCTGCT
	(SEQ ID NO: 34)
41C-VH	EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLEWIGYIN
(no signal peptide)	PNNGGTNYNQKFKGKATLTVNKSSRSAYMEFRSLTSEDSAVYYCASSGWFTY
	WGQGTLVTVSA
	(SEQ ID NO: 35)
41C-VL	ATGATGAGTCCTGCCCAGTTCCTGTTTCTGTTAGTGCTCTGGATTCGGGAAA
(with signal peptide)	CCAACGGTGATGTTGTGATGACCCAGACTCCACTCACTTTGTCGGTTGCCAT
(not codon optimized)	TGGACAACCAGCCTCCATCTCTTGCAAGTCAAGTCAGAGCCTCTTAAATAGT
	GCTGGAAAGACATATTTGAATTGGTTGTTACAGAGGCCAGGCCAGTCTCCAA
	AGCGCCTAATTTATCTGGTGTCTCAACTGGACTCTGGAGTCCCTGACAGGTT
	CACTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAG
	GCTGAGGATTTGGGAGTTTATTATTGCTGGCAAGGTACACATTTTCCGTGGA
	CGTTCGGTGGAGGCACCAAGCTGGAAATCAAA
	(SEQ ID NO: 36)
41C-VL	MMSPAQFLFLLVLWIRETNGDVVMTQTPLTLSVAIGQPASISCKSSQSLLNS
(with signal peptide)	AGKTYLNWLLQRPGQSPKRLIYLVSQLDSGVPDRFTGSGSGTDFTLKISRVE
	AEDLGVYYCWQGTHFPWTFGGGTKLEIK
	(SEQ ID NO: 37)
41C-VL	GATGTTGTGATGACCCAGACTCCACTCACTTTGTCGGTTGCCATTGGACAAC
(no signal peptide)	CAGCCTCCATCTCTTGCAAGTCAAGTCAGAGCCTCTTAAATAGTGCTGGAAA
(not codon optimized)	GACATATTTGAATTGGTTGTTACAGAGGCCAGGCCAGTCTCCAAAGCGCCTA
	ATTTATCTGGTGTCTCAACTGGACTCTGGAGTCCCTGACAGGTTCACTGGCA
	GTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGA
	TTTGGGAGTTTATTATTGCTGGCAAGGTACACATTTTCCGTGGACGTTCGGT
	GGAGGCACCAAGCTGGAAATCAAA
	(SEQ ID NO: 38)
41C-VL	GACGTCGTGATGACCCAGACCCCCCTGACACTGTCTGTGGCCATCGGCCAGC
(no signal peptide)	CTGCCTCCATCTCCTGCAAGTCCTCCCAGTCCCTGCTGAACTCCGCCGGCAA
(codon optimized)	GACCTACCTGAACTGGCTGCTGCAGCGGCCTGGCCAGTCCCCCAAGAGACTG
	ATCTACCTGGTGTCCCAGCTGGACTCCGGCGTGCCCGATAGATTCACCGGCT
	CTGGCTCTGGCACCGACTTCACCCTGAAGATCAGCCGGGTGGAAGCCGAGGA
	CCTGGGCGTGTACTACTGCTGGCAGGGCACCCACTTCCCTTGGACCTTTGGC
	GGAGGCACCAAGCTGGAAATCAAG
	(SEQ ID NO: 39)
41C-VL	DVVMTQTPLTLSVAIGQPASISCKSSQSLLNSAGKTYLNWLLQRPGQSPKRL
(no signal peptide)	IYLVSQLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTHFPWTFG
	GGTKLEIK
	(SEQ ID NO: 40)
42d-VH	ATGGGATGGAGCTGGATCTTTCTCTTTCTCCTGTCAGAAACTGCAGGTGTCC
(with signal peptide)	TCTCTGAGGTCCAGCTGCTCCAGTCTGGACCTGAGCTGGTGAAGCCTGTGGC
	TTCAGTGAAGATGTCCTGCAAGGCTTCTGGATACACATTCACTGACTACAAC
	ATTCACTGGGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGATATA
	TTAACCCTAACAATGGTGTTACTGGCTACAACCAGAAGTTCAGGGGCAAGGC
	CACATTGACTGTTAACAGGTCCTCCAACACAGCCTACATGGACCTCCGCAGC
	CTGACATCGGAGGATTCTGCAGTCTATTACTGTACAAGACGCTATGGTGACT
	ACGTCCATGCTATGGACTGCTGGGGTCAAGGAACCTCAGTCACCGTCTCCTC
	A
	(SEQ ID NO: 41)
42d-VH	MGWSWIFLFLLSETAGVLSEVQLLQSGPELVKPVASVKMSCKASGYTFTDYN
(with signal peptide)	IHWVKQSHGKSLEWIGYINPNNGVTGYNQKFRGKATLTVNRSSNTAYMDLRS
	LTSEDSAVYYCTRRYGDYVHAMDCWGQGTSVTVSS
	(SEQ ID NO: 42)
42d-VH	GAGGTCCAGCTGCTCCAGTCTGGACCTGAGCTGGTGAAGCCTGTGGCTTCAG
(no signal peptide)	TGAAGATGTCCTGCAAGGCTTCTGGATACACATTCACTGACTACAACATTCA
	CTGGGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGATATATTAAC
	CCTAACAATGGTGTTACTGGCTACAACCAGAAGTTCAGGGGCAAGGCCACAT
	TGACTGTTAACAGGTCCTCCAACACAGCCTACATGGACCTCCGCAGCCTGAC
	ATCGGAGGATTCTGCAGTCTATTACTGTACAAGACGCTATGGTGACTACGTC
	CATGCTATGGACTGCTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCA
	(SEQ ID NO: 43)
42d-VH	EVQLLQSGPELVKPVASVKMSCKASGYTFTDYNIHWVKQSHGKSLEWIGYIN
(no signal peptide)	PNNGVTGYNQKFRGKATLTVNRSSNTAYMDLRSLTSEDSAVYYCTRRYGDYV
	HAMDCWGQGTSVTVSS
	(SEQ ID NO: 44)
42d-VL	ATGGACATGAGGGCTCCTGCACAGATTTTTGGCTTCTTGTTGCTCTTGTTTC
(with signal peptide)	CAGGTACCAGATGTGACATCCAGATGACCCAGTCTCCATCCTCCTTATCTGC
	CTCTCTGGGAGAAAGAGTCAGTCTCACTTGTCGGGCAAGTCAGGACATTGGT
	AGTAGGTTAAACTGGCTTCAGCAGGAACCAGATGGAACTATTAAACGCCTGA
	TCTACGCCACATCCAGTTTAGATTCTGGTGTCCCCAAAAGGTTCAGTGGCAG
	TAGGTCTGGGTCAGATTATTCTCTCACCATCAGCAGCCTTGAGTCTGAAGAT
	TTTGTAGACTATTACTGTCTACAATATGCTAGTTCTCCGTACACATTCGGAG
	GGGGGACCAAGCTGGAAATAAAA
	(SEQ ID NO: 45)
42d-VL	MDMRAPAQIFGFLLLLFPGTRCDIQMTQSPSSLSASLGERVSLTCRASQDIG
(with signal peptide)	SRLNWLQQEPDGTIKRLIYATSSLDSGVPKRFSGSRSGSDYSLTISSLESED
	FVDYYCLQYASSPYTFGGGTKLEIK
	(SEQ ID NO: 46)
42d-VL	GACATCCAGATGACCCAGTCTCCATCCTCCTTATCTGCCTCTCTGGGAGAAA
(no signal peptide)	GAGTCAGTCTCACTTGTCGGGCAAGTCAGGACATTGGTAGTAGGTTAAACTG
	GCTTCAGCAGGAACCAGATGGAACTATTAAACGCCTGATCTACGCCACATCC
	AGTTTAGATTCTGGTGTCCCCAAAAGGTTCAGTGGCAGTAGGTCTGGGTCAG
	ATTATTCTCTCACCATCAGCAGCCTTGAGTCTGAAGATTTTGTAGACTATTA
	CTGTCTACAATATGCTAGTTCTCCGTACACATTCGGAGGGGGGACCAAGCTG
	GAAATAAAA
	(SEQ ID NO: 47)
42d-VL	DIQMTQSPSSLSASLGERVSLTCRASQDIGSRLNWLQQEPDGTIKRLIYATS
(no signal peptide)	SLDSGVPKRFSGSRSGSDYSLTISSLESEDFVDYYCLQYASSPYTFGGGTKL
	EIK
	(SEQ ID NO: 48)

TABLE 18 — Amino acid sequences of VH, VL and CDRs of R35B9

VH	EVQLQQSGPELVKPGASVKMSCKASGYIF	VL	DVVMTQTPLTLSVAIGQPASISCKSSQSLL
	QDYNMHWVKQSHGKSLEWIGSINPRNGWT		NSAGKTYLNWLLQRPGQSPKRLIYLVSQLD
	NYNQKFKGKATLTVNKSSRSAYMEFRSLT		SGVPDRFTGSGSGTDFTLKISRVEAEDLGV
	SEDSAVYYCASSGWFTYWGQGTLVTVSA		YYCWQGTFYPWTFGGGTKLEIK
	(SEQ ID NO: 50)		(SEQ ID NO: 52)
HCDR1	GYIFQDYNMH	LCDR1	KSSQSLLNSAGKTYLN
	(SEQ ID NO: 122)		(SEQ ID NO: 127)
HCDR2	SINPRNGWTNYNQKFKG	LCDR2	LVSQLDS
	(SEQ ID NO: 123)		(SEQ ID NO: 128)
HCDR3	SGWFTY	LCDR3	WQGTFYPWT
	(SEQ ID NO: 121)		(SEQ ID NO: 130)

TABLE 19 — Comparison of 41c and R35B9

		Heavy	Light
Name	Purpose	Vector ID	Vector ID	HCDR1	HCDR2	LCDR3
41c	parental	A291	A290	--T-T-----	Y---N--G---------	----HF---
(mouse)
R35B9	affinity	A402	A403	--I-Q-----	S---R--W---------	----FY---
(mouse)	matured

TABLE 20 — Nucleotide and amino acid sequences of R35B9 VH and VL and variants.

Description	Sequence (SEQ ID NO)
R35B9-VH	GAGGTGCAGCTGCAGCAAAGCGGCCCGGAGCTGGTGAAACCGGGTGCGAGCGTTA
	AAATGAGCTGCAAGGCGAGCGGTTACATTTTTCAGGATTATAATATGCATTGGGT
	TAAACAGAGCCACGGTAAAAGCCTGGAGTGGATCGGCTCTATTAATCCGCGTAAT
	GGTTGGACCAACTATAACCAAAAGTTCAAAGGCAAGGCGACCCTGACCGTGAACA
	AGAGCAGCCGTAGCGCGTACATGGAGTTTCGTAGCCTGACCAGCGAAGATAGCGC
	GGTTTACTATTGCGCGTCTTCGGGGTGGTTCACGTATTGGGGTCAAGGCACCCTG
	GTGACCGTTAGCGCG (SEQ ID NO: 49)
R35B9-VH	EVQLQQSGPELVKPGASVKMSCKASGYIFQDYNMHWVKQSHGKSLEWIGSINPRN
	GWTNYNQKFKGKATLTVNKSSRSAYMEFRSLTSEDSAVYYCASSGWFTYWGQGTL
	VTVSA (SEQ ID NO: 50)
R35B9-VL	GACGTGGTTATGACCCAAACCCCGCTGACCCTGAGCGTGGCGATTGGTCAGCCGG
	CGAGCATTAGCTGCAAGAGCAGCCAAAGCCTGCTGAACAGCGCGGGTAAAACCTA
	CCTGAACTGGCTGCTGCAGCGTCCGGGTCAAAGCCCGAAGCGTCTGATCTATCTG
	GTGAGCCAGCTGGACAGCGGTGTGCCGGACCGTTTCACCGGTAGCGGTAGCGGCA
	CCGACTTTACCCTGAAAATTAGCCGTGTGGAGGCGGAAGATCTGGGTGTTTACTA
	TTGCTGGCAAGGTACTTTTTATCCGTGGACCTTTGGTGGCGGTACCAAGCTGGAG
	ATCAAA (SEQ ID NO: 51)
R35B9-VL	DVVMTQTPLTLSVAIGQPASISCKSSQSLLNSAGKTYLNWLLQRPGQSPKRLIYL
	VSQLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTFYPWTFGGGTKLE
	IK (SEQ ID NO: 52)
R35B9(Y50G57)-VH	GAGGTGCAGCTGCAGCAAAGCGGCCCGGAGCTGGTGAAACCGGGTGCGAGCGTTA
	AAATGAGCTGCAAGGCGAGCGGTTACATTTTTCAGGATTATAATATGCATTGGGT
	TAAACAGAGCCACGGTAAAAGCCTGGAGTGGATCGGCTaTATTAATCCGCGTAAT
	GGTgGGACCAACTATAACCAAAAGTTCAAAGGCAAGGCGACCCTGACCGTGAACA
	AGAGCAGCCGTAGCGCGTACATGGAGTTTCGTAGCCTGACCAGCGAAGATAGCGC
	GGTTTACTATTGCGCGTCTTCGGGGTGGTTCACGTATTGGGGTCAAGGCACCCTG
	GTGACCGTTAGCGCG (SEQ ID NO: 53)
R35B9(Y50G57)-VH	EVQLQQSGPELVKPGASVKMSCKASGYIFQDYYNMHWVKQSHGKSLEWIGYINPR
	NGGTNYNQKFKGKATLTVNKSSRSAYMEFRSLTSEDSAVYYCASSGWFTYWGQGT
	LVTVSA (SEQ ID NO: 54)
R35B9(Y50A56G57)-VH	GAGGTGCAGCTGCAGCAAAGCGGCCCGGAGCTGGTGAAACCGGGTGCGAGCGTTA
	AAATGAGCTGCAAGGCGAGCGGTTACATTTTTCAGGATTATAATATGCATTGGGT
	TAAACAGAGCCACGGTAAAAGCCTGGAGTGGATCGGCTaTATTAATCCGCGTAAT
	gccGGGACCAACTATAACCAAAAGTTCAAAGGCAAGGCGACCCTGACCGTGAACA
	AGAGCAGCCGTAGCGCGTACATGGAGTTTCGTAGCCTGACCAGCGAAGATAGCGC
	GGTTTACTATTGCGCGTCTTCGGGGTGGTTCACGTATTGGGGTCAAGGCACCCTG
	GTGACCGTTAGCGCG (SEQ ID NO: 55)
R35B9(Y50A56G57)-VH	EVQLQQSGPELVKPGASVKMSCKASGYIFQDYNNHWVKQSHGKSLEWIGYINPRN
	AGTNYNQKFKGKATLTVNKSSRSAYMEFRSLTSEDSAVYYCASSGWFTYWGQGTL
	VTVSA (SEQ ID NO: 56)
R35B9(H98)-VL	GACGTGGTTATGACCCAAACCCCGCTGACCCTGAGCGTGGCGATTGGTCAGCCGG
	CGAGCATTAGCTGCAAGAGCAGCCAAAGCCTGCTGAACAGCGCGGGTAAAACCTA
	CCTGAACTGGCTGCTGCAGCGTCCGGGTCAAAGCCCGAAGCGTCTGATCTATCTG
	GTGAGCCAGCTGGACAGCGGTGTGCCGGACCGTTTCACCGGTAGCGGTAGCGGCA
	CCGACTTTACCCTGAAAATTAGCCGTGTGGAGGCGGAAGATCTGGGTGTTTACTA
	TTGCTGGCAAGGTACTcaTTATCCGTGGACCTTTGGTGGCGGTACCAAGCTGGAG
	ATCAAA (SEQ ID NO: 57)
R35B9(H98)-VL	DVVIVITQTPLTLSVAIGQPASISCKSSQSLLNSAGKTYLNWLLQRPGQSPKRLI
	YLVSQLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTHYPWTFGGGTK
	LEIK (SEQ ID NO: 58)
R35B9(A56)-VH	GAGGTGCAGCTGCAGCAAAGCGGCCCGGAGCTGGTGAAACCGGGTGCGAGCGTTA
	AAATGAGCTGCAAGGCGAGCGGTTACATTTTTCAGGATTATAATATGCATTGGGT
	TAAACAGAGCCACGGTAAAAGCCTGGAGTGGATCGGCTCTATTAATCCGCGTAAT
	GcTTGGACCAACTATAACCAAAAGTTCAAAGGCAAGGCGACCCTGACCGTGAACA
	AGAGCAGCCGTAGCGCGTACATGGAGTTTCGTAGCCTGACCAGCGAAGATAGCGC
	GGTTTACTATTGCGCGTCTTCGGGGTGGTTCACGTATTGGGGTCAAGGCACCCTG
	GTGACCGTTAGCGCG (SEQ ID NO: 59)
R35B9(A56)-VH	EVQLQQSGPELVKPGASVKMSCKASGYIFQDYNNHWVKQSHGKSLEWIGSINPRN
	AWTNYNQKFKGKATLTVNKSRSAYMEFRSLTSEDSAVYYCASSGWFTYWGQGTLV
	TVSA (SEQ ID NO: 60)
R35B9(Y50)-VH	GAGGTGCAGCTGCAGCAAAGCGGCCCGGAGCTGGTGAAACCGGGTGCGAGCGTTA
	AAATGAGCTGCAAGGCGAGCGGTTACATTTTTCAGGATTATAATATGCATTGGGT
	TAAACAGAGCCACGGTAAAAGCCTGGAGTGGATCGGCTaTATTAATCCGCGTAAT
	GGTTGGACCAACTATAACCAAAAGTTCAAAGGCAAGGCGACCCTGACCGTGAACA
	AGAGCAGCCGTAGCGCGTACATGGAGTTTCGTAGCCTGACCAGCGAAGATAGCGC
	GGTTTACTATTGCGCGTCTTCGGGGTGGTTCACGTATTGGGGTCAAGGCACCCTG
	GTGACCGTTAGCGCG (SEQ ID NO: 180)
R35B9(Y50)-VH	EVQLQQSGPELVKPGASVKMSCKASGYIFQDYNMHWVKQSHGKSLEWIGYINPRN
	GWTNYNQKFKGKATLTVNKSSRSAYMEFRSLTSEDSAVYYCASSGWFTYWGQGTL
	VTVSA (SEQ ID NO: 181)
R35B9(F99)-VL	GACGTGGTTATGACCCAAACCCCGCTGACCCTGAGCGTGGCGATTGGTCAGCCGG
	CGAGCATTAGCTGCAAGAGCAGCCAAAGCCTGCTGAACAGCGCGGGTAAAACCTA
	CCTGAACTGGCTGCTGCAGCGTCCGGGTCAAAGCCCGAAGCGTCTGATCTATCTG
	GTGAGCCAGCTGGACAGCGGTGTGCCGGACCGTTTCACCGGTAGCGGTAGCGGCA
	CCGACTTTACCCTGAAAATTAGCCGTGTGGAGGCGGAAGATCTGGGTGTTTACTA
	TTGCTGGCAAGGTACTTTTTtTCCGTGGACCTTTGGTGGCGGTACCAAGCTGGAG
	ATCAAA (SEQ ID NO: 199)
R35B9(F99)-VL	DVVIVITQTPLTLSVAIGQPASISCKSSQSLLNSAGKTYLNWLLQRPGQSPKRLI
	YLVSQLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTFFPWTFGGGTK
	LEIK (SEQ ID NO: 200)

TABLE 1 — Mouse VH and VL amino acid sequences of Fn14 antagonist monoclonal antibodies

VH Name	Variable Sequence
(Heavy Vector ID)	(SEQ ID NO)
41c	EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLEWIG
(A291)	YINPNNGGTNYNQKFKGKATLTVNKSSRSAYMEFRSLTSEDSAVYYCAS
	SGWFTYWGQGTLVTVSA (SEQ ID NO: 35)
42d	EVQLLQSGPELVKPVASVKMSCKASGYTFTDYNIHWVKQSHGKSLEWIG
	YINPNNGVTGYNQKFRGKATLTVNRSSNTAYMDLRSLTSEDSAVYYCTR
	RYGDYVHAMDCWGQGTSVTVSS (SEQ ID NO: 44)
R35B9	EVQLQQSGPELVKPGASVKMSCKASGYIFQDYNMHWVKQSHGKSLEWIG
(A402, A451)	SINPRNGWTNYNQKFKGKATLTVNKSSRSAYMEFRSLTSEDSAVYYCAS
	SGWFTYWGQGTLVTVSA (SEQ ID NO: 50)
R35B9(Y50G57)	EVQLQQSGPELVKPGASVKMSCKASGYIFQDYNMHWVKQSHGKSLEWIG
(A448, A474)	YINPRNGGTNYNQKFKGKATLTVNKSSRSAYMEFRSLTSEDSAVYYCAS
	SGWFTYWGQGTLVTVSA (SEQ ID NO: 54)
R35B9(A56)	EVQLQQSGPELVKPGASVKMSCKASGYIFQDYNMHWVKQSKGKSLEWIG
(A486)	SINPRNAWTNYNQKFKGKATLTVNKSSRSAYMEFRSLTSEDSAVYYCAS
	SGWFTYWGQGLTVTVSA (SEQ ID NO: 60)
R35B9(Y50A56G57)	EVQLQQSGPELVKPGASVKMSCKASGYIFQDYNMHWVKQSHGKSLEWIG
(A490)	YINPRNAGTNYNQKFKGKATLTVNKSSRSAYMEFRSLTSEDSAVYYCAS
	SGWFTYWGQGTLVTVSA (SEQ ID NO: 56)
R35B9(Y50)	EVQLQQSGPELVKPGASVKMSCKASGYIFQDYNMHWVKQSHGKSLEWIG
(A437)	YINPRNGWTNYNQKFKGKATLTVNKSSRSAYMEFRSLTSEDSAVYYCAS
	SGWGTYWGQGTLVTVSA (SEQ ID NO: 181)
VL Name	Variable Sequence
(Light Vector ID)	(SEQ ID NO)
41c	DVVMTQTPLTLSVAIGQPASISCKSSQSLLNSAGKTYLNWLLQRPGQSP
(A290)	KRLIYLVSQLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTH
	FPWTFGGGTKLEIK (SEQ ID NO: 40)
42d	DIQMTQSPSSLSASLGERVSLTCRASQDIGSRLNWLQQEPDGTIKRLIY
	ATSSLDSGVPKRFSGSRSGSDYSLTISSLESEDFVDYYCLQYASSPYTF
	GGGTKLEIK (SEQ ID NO: 48)
R35B9	DVVMTQTPLTLSVAIGQPASISCKSSQSLLNSAGKTYLNWLLQRPGQSP
(A403, A452)	KRLIYLVSQLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTF
	YPWTFGGGTKLEIK (SEQ ID NO: 52)
R35B9(H98)	DVVMTQTPLTLSVAIGQPASISCKSSQSLLNSAGKTYLNWLLQRPGQSP
(A439)	KRLIYLVSQLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTH
	YPWTFGGGTKLEIK(SEQ ID NO: 58)

TABLE 2 — VL amino acid sequences broken down into framework and CDR sequences with corresponding SEQ ID NOs. Light

Name		LCDR1		LCDR2		LCDR3
Vector ID)	L-FR1	(Kabat)	L-FR2	(Kabat)	L-FR3	(Kabat)	L-FR4
41c VL	DVVMTQTPLTL	KSSQSLLLSAG	WLLQRPGQSPK	LVSQLDS	GVPDRFTGSGS	WQGTHPWT	FGGGTKLEIK
(A290, A370)	SVAIGQPASIS	KTYLN	RLIY	(SEQ ID	GTDFTLKISRV	(SEQ ID	(SEQ ID
Mouse	C	(SEQ ID	(SEQ ID	NO: 128)	EAEDLGVYYC	NO: 129)	NO: 171)
	(SEQ ID	NO: 127)	NO: 163)		(SEQ ID
	NO: 160)				NO: 169)
R35B9 VL	DVVMTQTPLTL	KSSQSLLLSAG	WLLQRPGQSPK	LVSQLDS	GVPDRFTGSGS	WGQGTFYPWT	FGGGTKLEIK
(A403, A452)	SVAIGQPASIS	KTYLN	RLIY	(SEQ ID	GTDFTLKISRV	(SEQ ID	(SEQ ID
Mouse	C	(SEQ ID	(SEQ ID	NO: 128)	EAEDLGVYYC	NO: 130)	NO: 171)
	(SEQ ID	NO: 127)	NO: 163)		(SEQ ID
	NO: 160)				NO: 169)
AA102700.1	DVVMTQSPLSL	—	WFQQRPGQSPR	—	GVPDRFSGSGS	—	FGGGTKVEIK
(N/A)	PVTLGQPASIS		RLIY		GTDFTLKISRV		(SEQ ID
Human	C		(SEQ ID		EAEDVGVYYC		NO: 172)
	(SEQ ID		NO: 164)		(SEQ ID
	NO: 161)				NO: 170)
hzR35B9-LV0	DVVMTQSPLSL	KSSQSLLLSAG	WFQQRPGQSPR	LVSQLDS	GVPDRFSGSGS	WGQGTFYPWT	FGGGTKVEIK
(A467)	PVTLGQPASIS	KTYLN	RLIY	(SEQ ID	GTDFTLKISRV	(SEQ ID	(SEQ ID
Humanized	C	(SEQ ID	(SEQ ID	NO: 128)	EAEDVGVYYC	NO: 130)	NO: 172)
	(SEQ ID	NO: 127)	NO: 164)		(SEQ ID
	NO: 161)				NO: 170)
hzR35B9-LV1a	DVVMTQSPLSL	KSSQSLLLSAG	WLQQRPGQSPR	LVSQLDS	GVPDRFSGSGS	WGQGTFYPWT	FGGGTKVEIK
(A468)	PVTLGQPASIS	KTYLN	RLIY	(SEQ ID	GTDFTLKISRV	(SEQ ID	(SEQ ID
Humanized	C	(SEQ ID	(SEQ ID	NO: 128)	EAEDVGVYYC	NO: 130)	NO: 172)
	(SEQ ID	NO: 127)	NO: 165)		(SEQ ID
	NO: 161)				NO: 170)
hzR35B9-LV1b	DVVMTQSPLSL	KSSQSLLLSAG	WFLQRPGQSPR	LVSQLDS	GVPDRFSGSGS	WGQGTFYPWT	FGGGTKVEIK
(A469)	PVTLGQPASIS	KTYLN	RLIY	(SEQ ID	GTDFTLKISRV	(SEQ ID	(SEQ ID
Humanized	C	(SEQ ID	(SEQ ID	NO: 128)	EAEDVGVYYC	NO: 130)	NO: 172)
	(SEQ ID	NO: 127)	NO: 166)		(SEQ ID
	NO: 161)				NO: 170)
hzR35B9-LV3a	DVVMTQSPLSL	KSSQSLLLSAG	WFLQRPGQSPK	LVSQLDS	GVPDRFSGSGS	WGQGTFYPWT	FGGGTKVEIK
(A470)	PVTIGQPASIS	KTYLN	RLIY	(SEQ ID	GTDFTLKISRV	(SEQ ID	(SEQ ID
Humanized	C	(SEQ ID	(SEQ ID	NO: 128)	EAEDVGVYYC	NO: 130)	NO: 172)
	(SEQ ID	NO: 127)	NO: 167)		(SEQ ID
	NO: 162)				NO: 170)
hzR35B9-LV3b	DVVMTQSPLSL	KSSQSLLLSAG	WLLQRPGQSPR	LVSQLDS	GVPDRFSGSGS	WGQGTFYPWT	FGGGTKVEIK
(A471)	PVTIGQPASIS	KTYLN	RLIY	(SEQ ID	GTDFTLKISRV	(SEQ ID	(SEQ ID
Humanized	C	(SEQ ID	(SEQ ID	NO: 128)	EAEDVGVYYC	NO: 130)	NO: 172)
	(SEQ ID	NO: 127)	NO: 168)		(SEQ ID
	NO: 162)				NO: 170)
hzR35B9-LV4	DVVMTQSPLSL	KSSQSLLLSAG	WLLQRPGQSPK	LVSQLDS	GVPDRFSGSGS	WGQGTFYPWT	FGGGTKVEIK
(A472)	PVTIGQPASIS	KTYLN	RLIY	(SEQ ID	GTDFTLKISRV	(SEQ ID	(SEQ ID
Humanized	C	(SEQ ID	(SEQ ID	NO: 128)	EAEDVGVYYC	NO: 130)	NO: 172)
	(SEQ ID	NO: 127)	NO: 163)		(SEQ ID
	NO: 162)				NO: 170)
hzR35B9-LV5	DVVMTQSPLSL	KSSQSLLLSAG	WLLQRPGQSPK	LVSQLDS	GVPDRFSGSGS	WGQGTFYPWT	FGGGTKLEIK
(A473)	PVTIGQPASIS	KTYLN	RLIY	(SEQ ID	GTDFTLKISRV	(SEQ ID	(SEQ ID
Humanized	C	(SEQ ID	(SEQ ID	NO: 128)	EAEDVGVYYC	NO: 130)	NO: 171)
	(SEQ ID	NO: 127)	NO: 163)		(SEQ ID
	NO: 162)				NO: 170)
hzR35B9(H98)-	DVVMTQSPLSL	KSSQSLLLSAG	WLQQRPGQSPR	LVSQLDS	GVPDRFSGSGS	WQGTHYPWT	FGGGTKVEIK
LV1a	PVTLGQPASIS	KTYLN	RLIY	(SEQ ID	GTDFTLKISRV	(SEQ ID	(SEQ ID
(A518)	C	(SEQ ID	(SEQ ID	NO: 128)	EAEDVGVYYC	NO: 131)	NO: 172)
Humanized	(SEQ ID	NO: 127)	NO: 165)		(SEQ ID
	NO: 161)				NO: 170)
hzR35B9(A56)-	DVVMTQSPLSL	KSSQSLLLSAG	WLQQRPGQSPR	LVSQLDS	GVPDRFSGSGS	WGQGTFYPWT	FGGGTKVEIK
LV2a	PVTLGQPASIS	KTYLN	RGIY	(SEQ ID	GTDFTLKISRV	(SEQ ID	(SEQ ID
(A651)	C	(SEQ ID	(SEQ ID	NO: 128)	EAEDVGVYYC	NO: 130)	NO: 172)
Humanized	(SEQ ID	NO: 127)	NO: 252)		(SEQ ID
	NO: 161)				NO: 170)
hzR35B9(A56)-	DVVMTQSPLSL	KSSQSLLLSAG	WLQQRPGQSPR	LVSQLDS	GVPDRFSGSGS	WGQGTFYPWT	FGGGTKVEIK
LV2b	PVTLGQPASIS	KTYLN	RLAY	(SEQ ID	GTDFTLKISRV	(SEQ ID	(SEQ ID
(A652)	C	(SEQ ID	(SEQ ID	NO: 128)	EAEDVGVYYC	NO: 130)	NO: 172)
Humanized	(SEQ ID	NO: 127)	NO: 253)		(SEQ ID
	NO: 161)				NO: 170)
hzR35B9(A56)-	DVVMTQSPLSL	KSSQSLLLSAG	WLQQRPGQSPR	LVSELDS	GVPDRFSGSGS	WGQGTFYPWT	FGGGTKVEIK
LV2c	PVTLGQPASIS	KTYLN	RLIY	(SEQ ID	GTDFTLKISRV	(SEQ ID	(SEQ ID
(A653)	C	(SEQ ID	(SEQ ID	NO: 255)	EAEDVGVYYC	NO: 130)	NO: 172)
Humanized	(SEQ ID	NO: 127)	NO: 165)		(SEQ ID
	NO: 161)				NO: 170)
hzR35B9(A56)-	DVVMTQSPLSL	KSSQSLLLSAG	WLQQRPGQSPR	LVSQLDD	GVPDRFSGSGS	WGQGTFYPWT	FGGGTKVEIK
LV2d	PVTLGQPASIS	KTYLN	RLIY	(SEQ ID	GTDFTLKISRV	(SEQ ID	(SEQ ID
(A654)	C	(SEQ ID	(SEQ ID	NO: 254)	EAEDVGVYYC	NO: 130)	NO: 172)
Humanized	(SEQ ID	NO: 127)	NO: 165)		(SEQ ID
	NO: 161)				NO: 170)
hzR35B9(A56)-	DVVMTQSPLSL	KSSQSLLLSAG	WLQQRPGQSPR	LVAQLDS	GVPDRFSGSGS	WGQGTFYPWT	FGGGTKVEIK
LV2f	PVTLGQPASIS	KTYLN	RLIY	(SEQ ID	GTDFTLKISRV	(SEQ ID	(SEQ ID
(A656)	C	(SEQ ID	(SEQ ID	NO: 256)	EAEDVGVYYC	NO: 130)	NO: 172)
Humanized	(SEQ ID	NO: 127)	NO: 165)		(SEQ ID
	NO: 161)				NO: 170)

TABLE 3 — VH amino acid sequences broken down into framework and CDR sequences with corresponding SEQ ID NOs Name (Heavy

Vector ID)		H-CDR1		H-CDR2		H-CDR3
Species	H-FR1	(Chothia)	H-FR2	(Kabat)	H-FR3	(Kabat)	H-FR4
41c VH	EVQLQQSGP	GYTFTDYNMH	WVKQSHGKSL	YINPNNGGTN	KATLTVNKSS	SGWFTY	WGQGTLVTV
(A291, A369)	ELVKPGASV	(SEQ ID	EWIG	YNQKFKG	RSAYMEFRSL	(SEQ ID	SA
Mouse	KMSCKAS	NO: 119)	(SEQ ID	(SEQ ID	TSEDSAVYYC	NO: 121)	(SEQ ID
	(SEQ ID		NO: 138)	NO: 120)	AS		NO: 158)
	NO: 132)				(SEQ ID
					NO: 145)
R35B9 VH	EVQLQQSGP	GYIFQDYNMH	WVKQSHGKSL	SINPRNGWTN	KATLTVNKSS	SGWFTY	WGQGTLVTV
(A402)	ELVKPGASV	(SEQ ID	EWIG	YNQKFKG	RSAYMEFRSL	(SEQ ID	SA
Mouse	KMSCKAS	NO: 122)	(SEQ ID	(SEQ ID	TSEDSAVYYC	NO: 121)	(SEQ ID
	(SEQ ID		NO: 138)	NO: 123)	AS		NO: 158)
	NO: 132)				(SEQ ID
					NO: 145)
R35B9(Y50) VH	EVQLQQSGP	GYIFQDYNMH	WVKQSHGKSL	YINPRNGWTN	KATLTVNKSS	SGWFTY	WGQGTLVTV
(A437)	ELVKPGASV	(SEQ ID	EWIG	YNQKFKG	RSAYMEFRSL	(SEQ ID	SA
Mouse	KMSCKAS	NO: 122)	(SEQ ID	(SEQ ID	TSEDSAVYYC	NO: 121)	(SEQ ID
	(SEQ ID		NO: 138)	NO: 149)	AS		NO: 158)
	NO: 132)				(SEQ ID
					NO: 145)
R35B9(Y50G57)	EVQLQQSGP	GYIFQDYNMH	WVKQSHGKSL	YINPRNGGTN	KATLTVNKSS	SGWFTY	WGQGTLVTV
VH	ELVKPGASV	(SEQ ID	EWIG	YNQKFKG	RSAYMEFRSL	(SEQ ID	SA
(A447, A474)	KMSCKAS	NO: 122)	(SEQ ID	(SEQ ID	TSEDSAVYYC	NO: 121)	(SEQ ID
Mouse	(SEQ ID		NO: 138)	NO: 125)	AS		NO: 158)
	NO: 132)				(SEQ ID
					NO: 145)
hSGHI(1)	QVQLVQSGA	—	WVRQAPGQGL	—	RVTITADTST	—	WGQGTLVTV
(N/A)	EVKKPGASV		EWMG		STAYMELSSL		SS
Human Template	KVSCKAS		(SEQ ID		RSEDTAVYYC		(SEQ ID
	(SEQ ID		NO: 173)		AR		NO: 159)
	NO: 133)				(SEQ ID
					NO: 174)
hzR35B9-HV0	QVQLVQSGA	GYIFQDYNMH	WVRQAPGQGL	SINPRNGWTN	RVTITADTST	SGWFTY	WGQGTLVTV
(A700)	EVKKPGASV	(SEQ ID	EWMG	YNQKFKG	STAYMELSSL	(SEQ ID	SS
Humanized	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
	(SEQ ID		NO: 173)	NO: 123)	AR		NO: 159)
	NO: 133)				(SEQ ID
					NO: 174)
hzR35B9-HV5a	QVQLVQSGA	GYIFQDYNMH	WVRQAPGQGL	SINPRNGWTN	RATITADTST	SGWFTY	WGQGTLVTV
(A454)	EVKKPGASV	(SEQ ID	EWIG	YNQKFKG	STAYMELSSL	(SEQ ID	SS
Humanized	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
	(SEQ ID		NO: 139)	NO: 123)	AS		NO: 159)
	NO: 133)				(SEQ ID
					NO: 146)
hzR35B9-HV5b	QVQLVQSGA	GYIFQDYNMH	WVRQAHGQG	SINPRNGWTN	RVTITADTST	SGWFTY	WGQGTLVTV
(A455)	EVVKPGASV	(SEQ ID	LEWMG	YNQKFKG	STAYMELSSL	(SEQ ID	SS
Humanized	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
	(SEQ ID		NO: 140)	NO: 123)	AS		NO: 159)
	NO: 134)				(SEQ ID
					NO: 147)
hzR35B9-HV6b	QVQLVQSGA	GYIFQDYNMH	WVRQAHGQS	SINPRNGWTN	RVTITADTST	SGWFTY	WGQGTLVTV
(A456)	EVVKPGASV	(SEQ ID	LEWMG	YNQKFKG	STAYMELSSL	(SEQ ID	SS
Humanized	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
	(SEQ ID		NO: 141)	NO: 123)	AS		NO: 159)
	NO: 134)				(SEQ ID
					NO: 147)
hzR35B9-HV6b	QVQLVQSGA	GYIFQDYNMH	WVRQAHGQG	SINPRNGWTN	RATITADKST	SGWFTY	WGQGTLVTV
(A457)	EVKGPGASV	(SEQ ID	LEWIG	YNQKFKG	STAYMELSSL	(SEQ ID	SS
Humanized	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
	(SEQ ID		NO: 142)	NO: 123)	AR		NO: 159)
	NO: 133)				(SEQ ID
					NO: 148)
hzR35B9-HV6c	QVQLVQSGA	GYIFQDYNMH	WVRQAHGQG	SINPRNGWTN	RATITADTST	SGWFTY	WGQGTLVTV
(A458)	EVKGPGASV	(SEQ ID	LEWIG	YNQKFKG	STAYMELSSL	(SEQ ID	SS
Humanized	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
	(SEQ ID		NO: 142)	NO: 123)	AS		NO: 159)
	NO: 133)				(SEQ ID
					NO: 146)
hzR35B9-HV7a	QVQLVQSGA	GYIFQDYNMH	WVRQAHGQS	SINPRNGWTN	RVTITADTST	SGWFTY	WGQGTLVTV
(A459)	EVVKPGASV	(SEQ ID	LEWMG	YNQKFKG	RTAYMELSSL	(SEQ ID	SS
Humanized	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
	(SEQ ID		NO: 141)	NO: 123)	AS		NO: 159)
	NO: 134)				(SEQ ID
					NO: 150)
hzR35B9-HV7b	QVQLVQSGA	GYIFQDYNMH	WVRQAHGQG	SINPRNGWTN	RVTITADKST	SGWFTY	WGQGTLVTV
(A460)	EVVKPGASV	(SEQ ID	LEWMG	YNQKFKG	RTAYMELSSL	(SEQ ID	SS
Humanized	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
	(SEQ ID		NO: 140)	NO: 123)	AS		NO: 159)
	NO: 134)				(SEQ ID
					NO: 151)
hzR35B9-HV7c	QVQLVQSGA	GYIFQDYNMH	WVKQAPGGQ	SINPRNGWTN	KATITADTST	SGWFTY	WGQGTLVTV
(A461)	EVKGPGASV	(SEQ ID	LEWIG	YNQKFKG	STAYMELSSL	(SEQ ID	SS
Humanized	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
	(SEQ ID		NO: 143)	NO: 123)	AS		NO: 159)
	NO: 133)				(SEQ ID
					NO: 152)
hzR35B9-HV9a	QVQLVQSGA	GYIFQDYNMH	WVRQAPGQG	SINPRNGWTN	RATLTVDTST	SGWFTY	WGQGTLVTV
(A462)	EVKKPGASV	(SEQ ID	LEWIG	YNQKFKG	STAYMEFSSL	(SEQ ID	SS
Humanized	KMSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
	(SEQ ID		NO: 139)	NO: 123)	AS		NO: 159)
	NO: 135)				(SEQ ID
					NO: 153)
hzR35B9-HV9b	QVQLVQSGA	GYIFQDYNMH	WVKQAHGQS	SINPRNGWTN	RATITADTST	SGWFTY	WGQGTLVTV
(A463)	EVKGPGASV	(SEQ ID	LEWIG	YNQKFKG	STAYMEFSSL	(SEQ ID	SS
Humanized	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
	(SEQ ID		NO: 144)	NO: 123)	AS		NO: 159)
	NO: 133)				(SEQ ID
					NO: 154)
hzR35B9-HV10	QVQLVQSGA	GYIFQDYNMH	WVRQAHGQG	SINPRNGWTN	KATITADKST	SGWFTY	WGQGTLVTV
(A464)	EVKGPGASV	(SEQ ID	LEWIG	YNQKFKG	RTAYMEFSSL	(SEQ ID	SS
Humanized	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
	(SEQ ID		NO: 142)	NO: 123)	AS		NO: 159)
	NO: 133)				(SEQ ID
					NO: 155)
hzR35B9-HV11	QVQLVQSGP	GYIFQDYNMH	WVRQAHGQS	SINPRNGWTN	RATITVDKST	SGWFTY	WGQGTLVTV
(A465)	EVVKPGASV	(SEQ ID	LEWMG	YNQKFKG	RTAYMELSSL	(SEQ ID	SS
Humanized	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
	(SEQ ID		NO: 141)	NO: 123)	AS		NO: 159)
	NO: 136)				(SEQ ID
					NO: 156)
hzR35B9-HV18	EVQLVQSGP	GYIFQDYNMH	WVKQAHGQS	SINPRNGWTN	KATLTVDKST	SGWFTY	WGQGTLVTV
(A466)	EVVKPGASV	(SEQ ID	LEWIG	YNQKFKG	RTAYMEFSSL	(SEQ ID	SS
Humanized	KMSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
	(SEQ ID		NO: 144)	NO: 123)	AS		NO: 159)
	NO: 137)				(SEQ ID
					NO: 157)
hzR35B9(A56)-	QVQLVQSGP	GYIFQDYNMH	WVRQAHGQS	SINPRNAWTN	RATITVDKST	SGWFTY	WGQGTLVTV
HV11	EVVKPGASV	(SEQ ID	LEWMG	YNQKFKG	RTAYMELSSL	(SEQ ID	SS
(A512)	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
Humanized	(SEQ ID		NO: 141)	NO: 124)	AS		NO: 159)
	NO: 136)				(SEQ ID
					NO: 156)
hzR35B9	QVQLVQSGA	GYIFQDYNMH	WVRQAHGQG	YINPRNAGTN	RVTITADKST	SGWFTY	WGQGTLVTV
(Y50A56G57)-	EVVKPGASV	(SEQ ID	LEWMG	YNQKFKG	RTAYMELSSL	(SEQ ID	SS
VH7b	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
(A515)	(SEQ ID		NO: 140)	NO: 126)	AS		NO: 159)
Humanized	NO: 134)				(SEQ ID
					NO: 151)
hzR35B9(A56)-	QVQLVQSGA	GYIFQDYNMH	WVKQAPGGQ	SINPRNAWTN	KATITADTST	SGWFTY	WGQGTLVTV
HV7c	EVKGPGASV	(SEQ ID	LEWIG	YNQKFKG	STAYMELSSL	(SEQ ID	SS
(A553)	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
Humanized	(SEQ ID		NO: 143)	NO: 124)	AS		NO: 159)
	NO: 133)				(SEQ ID
					NO: 152)
hzR35B9(A56)-	QVQLVQSGP	GYIFQDYNMH	WVRQADGQS	SINPRNAWTN	RATITVDKST	SGWFTY	WGQGTLVTV
HV12a	EVVKPGASV	(SEQ ID	LEWMG	YNQKFKG	RTAYMELSSL	(SEQ ID	SS
(A631)	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
Humanized	(SEQ ID		NO: 240)	NO: 124)	AS		NO: 159)
	NO: 136)				(SEQ ID
					NO: 156)
hzR35B9(A56)-	QVQLVQSGP	GYIFQDYNMH	WVRQAPGQS	SINPRNAWTN	RATITVDKST	SGWFTY	WGQGTLVTV
HV12b	EVVKPGASV	(SEQ ID	LEWMG	YNQKFKG	RTAYMELSSL	(SEQ ID	SS
(A632)	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
Humamized	(SEQ ID		NO: 241)	NO: 124)	AS		NO: 159)
	NO: 136)				(SEQ ID
					NO: 156)
hzR35B9(A56)-	QVQLVQSGP	GYIFQDYNMH	WVREAHGQS	SINPRNAWTN	RATITVDKST	SGWFTY	WGQGTLVTV
HV13a	EVVKPGASV	(SEQ ID	LEWMG	YNQKFKG	RTAYMELSSL	(SEQ ID	SS
(A633)	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
Humamized	(SEQ ID		NO: 242)	NO: 124)	AS		NO: 159)
	NO: 136)				(SEQ ID
					NO: 156)
hzR35B9(A56)-	QVQLVQSGP	GYIFQDYNMH	WVRQAHGQS	SINPRNAWTN	RATITVDKST	SGWFTY	WGQGTLVTV
HV13b	EVVKPGASV	(SEQ ID	LEWMG	YNQKFGG	RTAYMELSSL	(SEQ ID	SS
(A634)	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
Humamized	(SEQ ID		NO: 141)	NO: 247)	AS		NO: 159)
	NO: 136)				(SEQ ID
					NO: 156)
hzR35B9(A56)-	QVQLVQSGP	GYIFQDYNMH	WGRQAGGQS	SINPRNAWTN	RATITVDKST	SGWFTY	WGQGTLVTV
HV13d	EVVKPGASV	(SEQ ID	KEWMG	YNQKFKG	RTAYMELSSL	(SEQ ID	SS
(A636)	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
Humamized	(SEQ ID		NO: 243)	NO: 124)	AS		NO: 159)
	NO: 136)				(SEQ ID
					NO: 156)
hzR35B9(A56)-	QVQLVQSGP	GYIFQDYNMH	WVRQAHGQS	SINPRNAWTN	RATITVDKST	SGWFTY	WGQGTLVTV
HV13f	EVVKPGASV	(SEQ ID	LEWMG	YNDKFKG	RTAYMELSSL	(SEQ ID	SS
(A638)	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
Humamized	(SEQ ID		NO: 141)	NO: 249)	AS		NO: 159)
	NO: 136)				(SEQ ID
					NO: 156)
hzR35B9(A56)-	QVQLVQSGP	GYIFQDYNMH	WVRQAHGDS	SINPRNAWTN	RATITVDKST	SGWFTY	WGQGTLVTV
HV13g	EVVKPGASV	(SEQ ID	LEWMG	YNQKFKG	RTAYMELSSL	(SEQ ID	SS
(A639)	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
Humamized	(SEQ ID		NO: 244)	NO: 124)	AS		NO: 159)
	NO: 136)				(SEQ ID
					NO: 156)
hzR35B9(A56)-	QVQLQQSGP	GYIFQDYNMH	WVKQAHGQS	SINPRNAWTN	KATLTVDKST	SGWFTY	WGQGTLVTV
HV16	EVVKPGASV	(SEQ ID	LEWMG	YNQKFKG	RTAYMELSSL	(SEQ ID	SS
(A641)	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
Humamized	(SEQ ID		NO: 245)	NO: 124)	AS		NO: 159)
	NO: 238)				(SEQ ID
					NO: 251)
hzR35B9(A56)-	QVQLQQSGP	GYIFQDYNMH	WVKQGHGQS	SINPRNAWTN	KATLTVDKST	SGWFTY	WGQGTLVTV
HV167a	EVVKPGASV	(SEQ ID	LEWMG	YNQKFKG	RTAYMELSSL	(SEQ ID	SS
(A642)	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
Humamized	(SEQ ID		NO: 246)	NO: 124)	AS		NO: 159)
	NO: 238)				(SEQ ID
					NO: 251)
hzR35B9(A56)-	QVQLQQSGP	GYIFQDYNMH	WVKQAHGQS	SINPRNAWTN	KATLTVDKST	SGWFTY	WGQGTLVTV
HV17b	EVVKPGASV	(SEQ ID	LEWMG	YNQKFHG	RTAYMELSSL	(SEQ ID	SS
(A643)	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
Humamized	(SEQ ID		NO: 245)	NO: 250)	AS		NO: 159)
	NO: 238)				(SEQ ID
					NO: 251)
hzR35B9(A56)-	QVQLQQSGP	GYIFQDYNMH	WVKQAHGQS	SINPRNAWTN	KATLTVDKST	SGWFTY	WGQGTLVTV
HV17d	EVVKPGASV	(SEQ ID	LEWMG	YNQKFDG	RTAYMELSSL	(SEQ ID	SS
(A645)	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
Humamized	(SEQ ID		NO: 245)	NO: 248)	AS		NO: 159)
	NO: 238)				(SEQ ID
					NO: 251)
hzR35B9(A56)-	QVQLQQSGP	GYIFQDYNMH	WVKQAHGQS	SINPRNAWTN	KATLTVDKST	SGWFTY	WGQGTLVTV
HV17g	EVVKPGASV	(SEQ ID	LEWMG	YNDKFKG	RTAYMELSSL	(SEQ ID	SS
(A648)	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
Humamized	(SEQ ID		NO: 245)	NO: 249)	AS		NO: 159)
	NO: 238)				(SEQ ID
					NO: 251)
hzR35B9(A56)-	QVQLQQSGP	GYIFQDYNMH	WVKQAHGQS	SINPRNAWTN	KATLTVDKST	SGWFTY	WGQGTLVTV
HV17i	EVAKPGASV	(SEQ ID	LEWMG	YNQKFKG	RTAYMELSSL	(SEQ ID	SS
(A650)	KVSCKAS	NO: 122)	(SEQ ID	(SEQ ID	RSEDTAVYYC	NO: 121)	(SEQ ID
Humamized	(SEQ ID		NO: 245)	NO: 124)	AS		NO: 159)
	NO: 239)				(SEQ ID
					NO: 251)

TABLE 21 — R35B39 Variants

		Heavy	Light
Name	Purpose	Vector ID	Vector ID	CDR-H	CDR-L
41c (mouse)	parental	A291	A290	41c	41c
R35B9 (mouse)	affinity matured	A402	A403	R35B9	R35B9
A448/A403	variant(mo)	A448	A403	R35B9(Y50G57)	R35B9
A428/A403	variant(mo)	A428	A403	R35B9(G57)	R35B9
A437/A403	variant(mo)	A437	A403	R35B9(Y50)	R35B9
A402/A440	variant(mo)	A402	A440	R35B9	R35B9(F99)
A402/A439	variant(mo)	A402	A439	R35B9	R35B9(H98)
A402/A290	variant(mo)	A402	A290	R35B9	41c
A448/A439	variant(mo)	A448	A439	R35B9(Y50G57)	R35B9(H98)
A437/A290	variant(mo)	A437	A290	R35B9(Y50)	41c
A448/A290	variant(mo)	A448	A290	R35B9(Y50G57)	41c
A428/A290	variant(mo)	A428	A290	R35B9(G57)	41c
A291/A403	variant(mo)	A291	A403	41c	R35B9
A436/A403	variant(mo)	A436	A403	R35B9(T30)	R35B9
A438/A403	variant(mo)	A438	A403	R35B9(N54)	R35B9
A291/A449	variant(mo)	A291	A449	41c	41C(R101)
A435/A403	variant(mo)	A435	A403	R35B9(T28)	R35B9
A450/A290	variant(mo)	A450	A290	41C(R28Q30R54)	41c

TABLE 12 — Anti-Fn14 R35B9 optimized clones antagonize TWEAK-induced ICAM-1 expression on HRMC

	mAb (0.1 μg/mL)	ICAM-1 MFI*
250 ng/mL	41c	13,107
rhTWEAK	R35B9	5,828
	A437/A290	5,112
	A448/A290	6,429
	A448/A439	5,484
	ITEM-4	9,620
	CRCBT	11,785
	mIgG1	33,254
	mIgG2b	34,696
(MFI* = mean fluorescence intensity.)

TABLE 4 — Binding kinetics of deamidation fixed R35B9(A56) mAb to human Fn14 His-Sumo-huFn14 Concentration Range 0.111 nM-9 nM

Anti-Fn14 mAbs	kd (1/s)	ka (1/Ms)	(KD)	Rmax
R35B9 (A451/A452)	9.938E−04	7525000	0.1321 nM	31.85
R35B9 (A56)	3.541E−04	4961000	71.38 pM	61.16
(A486/A452)

TABLE 6 — Humanized VH and VL amino acid sequences with corresponding SEQ ID NOs Heavy

Vector		Humanized
ID	VH Name	framework	Variable sequence
A700	hzR35B9-	HV0	QVQLVQSGAEVKKPGASVKVSCKASGYIFQDY
	HV0		NMHWVRQAPGQGLEWMGSINPRNGWTNYNQKF
			KGRVTITADTSTSTAYMELSSLRSEDTAVYYC
			ARSGWFTYWGQGTLVTVSS (SEQ ID NO:
			179)
A454	hzR35B9-	HV5a	QVQLVQSGAEVKKPGASVKVSCKASGYIFQDY
	HV5a		NMHWVRQAPGQGLEWIGSINPRNGWTNYNQKF
			KGRATITADTSTSTAYMELSSLRSEDTAVYYC
			ASSGWFTYWGQGTLVTVSS (SEQ ID NO:
			66)
A455	hzR35B9-	HV5b	QVQLVQSGAEVVKPGASVKVSCKASGYIFQDY
	HV5b		NMHWVRQAHGQGLEWMGSINPRNGWTNYNQKF
			KGRVTITADTSTSTAYMELSSLRSEDTAVYYC
			ASSGWFTYWGQGTLVTVSS (SEQ ID NO:
			68)
A456	hzR35B9-	HV6a	QVQLVQSGAEVVKPGASVKVSCKASGYIFQDY
	HV6a		NMHWVRQAHGQSLEWMGSINPRNGWTNYNQKF
			KGRVTITADTSTSTAYMELSSLRSEDTAVYYC
			ASSGWFTYWGQGTIVTVSS (SEQ ID NO:
			70)
A457	hzR35B9-	HV6b	QVQLVQSGAEVKKPGASVKVSCKASGYIFQDY
	HV6b		NMHWVRQAHGQGLEWIGSINPRNGWTNYNQKF
			KGRATITADKSTSTAYMELSSLRSEDTAVYYC
			ARSGWFTYWGQGTLVTVSS (SEQ ID NO:
			72)
A458	hzR35B9-	HV6c	QVQLVQSGAEVKKPGASVKVSCKASGYIFQDY
	HV6c		NMHWVRQAHGQGLEWIGSINPRNGWTNYNQKF
			KGRATITADTSTSTAYMELSSLRSEDTAVYYC
			ASSGWFTYWGQGTLVTVSS (SEQ ID NO:
			74)
A459	hzR35B9-	HV7a	QVQLVQSGAEVVKPGASVKVSCKASGYIFQDY
	HV7a		NMHWVRQAHGQSLEWMGSINPRNGWTNYNQKF
			KGRVTITADTSTRTAYMELSSLRSEDTAVYYC
			ASSGWFTYWGQGTLVTVSS (SEQ ID NO:
			76)
A460	hzR35B9-	HV7b	QVQLVQSGAEVVKPGASVKVSCKASGYIFQDY
	HV7b		NMHWVRQAHGQGLEWMGSINPRNGWTNYNQKF
			KGRVTITADKSTRTAYMELSSLRSEDTAVYYC
			ASSGWFTYWGQGTLVTVSS (SEQ ID NO:
			78)
A461	hzR35B9-	HV7c	QVQLVQSGAEVKKPGASVKVSCKASGYIFQDY
	HV7c		NMHWVKQAPGQGLEWIGSINPRNGWTNYNQKF
			KGKATITADTSTSTAYMELSSLRSEDTAVYYC
			ASSGWFTYWGQGTLVTVSS (SEQ ID NO:
			80)
A462	hzR35B9-	HV9a	QVQLVQSGAEVKKPGASVKMSCKASGYIFQDY
	HV9a		NMHWVRQAPGQGLEWIGSINPRNGWTNYNQKF
			KGRATLTVDTSTSTAYMEFSSLRSEDTAVYYC
			ASSGWFTYWGQGTLVTVSS (SEQ ID NO:
			82)
A463	hzR35B9-	HV9b	QVQLVQSGAEVKKPGASVKVSCKASGYIFQDY
	HV9b		NMHWVKQAHGQSLEWIGSINPRNGWTNYNQKF
			KGRATITADTSTSTAYMEFSSLRSEDTAVYYC
			ASSGWFTYWGQGTLVTVSS (SEQ ID NO:
			84)
A464	hzR35B9-	HV10	QVQLVQSGAEVKKPGASVKVSCKASGYIFQDY
	HV10		NMHWVRQAHGQGLEWIGSINPRNGWTNYNQKF
			KGKATITADKSTRTAYMEFSSLRSEDTAVYYC
			ASSGWFTYWGQGTLVTVSS (SEQ ID NO:
			86)
A465	hzR35B9-	HV11	QVQLVQSGPEVVKPGASVKVSCKASGYIFQDY
	HV11		NMHWVRQAHGQSLEWMGSINPRNGWTNYNQKF
			KGRATITVDKSTRTAYMELSSLRSEDTAVYYC
			ASSGWFTYWGQGTLVTVSS (SEQ ID NO:
			88)
A466	hzR35B9-	HV18	EVQLVQSGPEVVKPGASVKMSCKASGYIFQDY
	HV18		NMHWVKQAHGQSLEWIGSINPRNGWTNYNQKF
			KGKATLTVDKSTRTAYMEFSSLRSEDTAVYYC
			ASSGWFTYWGQGTLVTVSS (SEQ ID NO:
			90)
A512	hzR35B9	HV11	QVQLVQSGPEVVKPGASVKVSCKASGYIFQDY
	(A56)-HV11		NMHWVRQAHGQSLEWMGSINPRNAWTNYNQKF
			KGRATITVDKSTRTAYMELSSLRSEDTAVYYC
			ASSGWFTYWGQGTLVTVSS (SEQ ID NO:
			108)
A515	hzR35B9	HV7b	QVQLVQSGAEVVKPGASVKVSCKASGYIFQDY
	(Y50A56G57)-		NMHWVRQAHGQGLEWMGYINPRNAGTNYNQKF
	HV7b		KGRVTITADKSTRTAYMELSSLRSEDTAVYYC
			ASSGWFTYWGQGTLVTVSS (SEQ ID NO:
			110)
A553	hzR35B9	HV7c	QVQLVQSGAEVKKPGASVKVSCKASGYIFQDY
	(A56)-HV7c		NMHWVKQAPGQGLEWIGSINPRNAWTNYNQKF
			KGKATITADTSTSTAYMELSSLRSEDTAVYYC
			ASSGWFTYWGQGTLVTVSS (SEQ ID NO:
			106)
A467	hzR35B9-	LV0	DVVMTQSPLSLPVTLGQPASISCKSSQSLLNS
	LV0		AGKTYLNWFQQRPGQSPRRLIYLVSQLDSGVP
			DRFSGSGSGTDFTLKISRVEAEDVGVYYCWQG
			TFYPWTFGGGTKVEIK (SEQ ID NO: 92)
A468	hzR35B9-	LV1a	DVVMTQSPLSLPVTLGQPASISCKSSQSLLNS
	LV1a		AGKTYLNWLQQRPGQSPRRLIYLVSQLDSGVP
			DRFSGSGSGTDFTLKISRVEAEDVGVYYCWQG
			TFYPWTFGGGTKVEIK (SEQ ID NO: 94)
A469	hzR35B9-	LV1b	DVVMTQSPLSLPVTLGQPASISCKSSQSLLNS
	LV1b		AGKTYLNWFLQRPGQSPRRLIYLVSQLDSGVP
			DRFSGSGSGTDFTLKISRVEAEDVGVYYCWQG
			TFYPWTFGGGTKVEIK (SEQ ID NO: 96)
A470	hzR35B9-	LV3a	DVVMTQSPLSLPVTIGQPASISCKSSQSLLNS
	LV3a		AGKTYLNWFLQRPGQSPKRLIYLVSQLDSGVP
			DRFSGSGSGTDFTLKISRVEAEDVGVYYCWQG
			TFYPWTFGGGTKVEIK (SEQ ID NO: 98)
A471	hzK35B9-	LV3b	DVVMIQSPLSLPVTIGQPASISCKSSQSLLNS
	LV3b		AGKTYLNWLLQRPGQSPRRLIYLVSQLDSGVP
			DRFSGSGSGTDFTLKISRVEAEDVGVYYCWQG
			TFYPWTFGGGTKVEIK (SEQ ID NO:
			100)
A472	hzR35B9-	LV4	DVVMTQSPLSLPVTIGQPASISCKSSQSLLNS
	LV4		AGKTYLNWLLQRPGQSPKRLIYLVSQLDSGVP
			DRFSGSGSGTDFTLKISRVEAEDVGVYYCWQG
			TFYPWTFGGGTKVEIK (SEQ ID NO:
			102)
A473	hzR35B9-	LV5	DVVMTQSPLSLPVTIGQPASISCKSSQSLLNS
	LV5		AGKTYLNWLLQRPGQSPKRLIYLVSQLDSGVP
			DRFSGSGSGTDFTLKISRVEAEDVGVYYCWQG
			TFYPWTFGGGTKLEIK (SEQ ID NO:
			104)
A518	hzR35B9	LV1a	DVVMTQSPLSLPVTLGQPASISCKSSQSLLNS
	(H98)-LV1a		AGKTYLNWLQQRPGQSPRRLIYLVSQLDSGVP
			DRFSGSGSGTDFTLKISRVEAEDVGVYYCWQG
			THYPWTFGGGTKVEIK (SEQ ID NO:
			112)

TABLE 22 — Humanized VH and VL nucleotide sequences with corresponding SEQ ID NOs Sequence (SEQ ID NO) VH Name

hzR35B9-	CAAGTGCAACTGGTGCAAAGCGGAGCTGAAGTAAAGAAGCCTGGAGCATCC
VH_HV5a	GTCAAGGTAAGTTGCAAGGCTAGTGGCTATATCTTCCAGGACTATAATATG
	CATTGGGTACGCCAGGCTCCCGGACAAGGGCTGGAGTGGATAGGGAGCATC
	AATCCACGCAACGGATGGACCAACTACAATCAGAAGTTCAAAGGACGAGCA
	ACTATCACTGCAGATACATCAACCTCCACTGCTTACATGGAATTGAGTTCC
	CTGCGTTCCGAAGACACCGCAGTGTACTATTGTGCCAGTTCAGGGTGGTTT
	ACTTACTGGGGACAAGGCACACTGGTGACCGTTTCTAGC (SEQ ID NO:
	65)
hzR35B9-	CAAGTTCAGCTTGTCCAGAGCGGTGCTGAAGTGGTCAAACCAGGCGCAAGT
VH_HV5b	GTTAAAGTTTCTTGCAAGGCATCTGGATATATTTTTCAGGACTACAACATG
	CACTGGGTACGACAAGCCCACGGTCAGGGATTGGAATGGATGGGATCCATC
	AACCCAAGAAACGGTTGGACAAATTACAATCAAAAGTTCAAAGGCAGGGTA
	ACAATCACCGCAGACACAAGCACCAGTACCGCTTACATGGAGCTGAGCTCT
	TTGAGATCAGAGGACACTGCTGTGTACTATTGCGCATCTAGCGGGTGGTTC
	ACTTACTGGGGACAGGGCACTCTTGTGACTGTGAGCTCT (SEQ ID NO:
	67)
hzR35B9-	CAAGTTCAACTTGTTCAATCAGGCGCAGAAGTAGTGAAACCTGGTGCTTCT
VH_HV6a	GTGAAGGTGTCATGTAAGGCCAGCGGTTATATCTTTCAGGACTACAATATG
	CATTGGGTTCGCCAAGCACATGGGCAGTCCCTGGAGTGGATGGGGTCTATC
	AATCCTCGCAATGGCTGGACCAACTATAACCAAAAGTTCAAGGGTAGGGTC
	ACTATCACTGCTGACACATCCACCTCTACCGCCTACATGGAATTGTCATCT
	TTGCGCTCTGAGGACACTGCTGTGTACTATTGCGCTTCATCAGGCTGGTTC
	ACCTATTGGGGACAGGGCACATTGGTGACTGTGTCTTCC (SEQ ID NO:
	69)
hzR35B9-	CAAGTCCAACTGGTGCAAAGCGGAGCTGAAGTGAAGAAGCCAGGTGCCAGT
VH_HV6b	GTCAAGGTATCCTGCAAGGCAAGTGGTTATATTTTCCAGGACTATAATATG
	CATTGGGTTAGGCAGGCACATGGACAGGGGCTCGAATGGATCGGGAGTATT
	AACCCACGTAATGGGTGGACTAATTACAACCAGAAGTTCAAAGGAAGGGCC
	ACCATTACAGCCGACAAATCAACCTCAACTGCTTATATGGAGCTTAGCAGC
	CTGCGTTCTGAGGACACTGCTGTATACTATTGTGCCCGTTCAGGTTGGTTC
	ACCTACTGGGGACAGGGCACTCTTGTTACAGTCAGTTCT (SEQ ID NO:
	71)
hzR35B9-	CAGGTACAGCTCGTTCAAAGCGGTGCCGAGGTAAAAAAGCCTGGGGCCTCT
VH_HV6c	GTTAAAGTTTCATGCAAGGCCTCAGGATATATCTTTCAAGACTACAACATG
	CATTGGGTGCGTCAGGCACATGGCCAGGGCCTCGAATGGATCGGCAGCATA
	AATCCACGGAACGGTTGGACCAACTACAACCAGAAATTCAAAGGAAGGGCC
	ACTATAACCGCCGACACATCTACTTCTACCGCATACATGGAACTCTCCAGT
	CTCAGGTCAGAAGATACAGCCGTCTACTATTGCGCCAGTAGCGGTTGGTTT
	ACATACTGGGGGCAAGGAACTCTCGTTACCGTGTCCAGC (SEQ ID NO:
	73)
hzR35B9-	CAGGTACAACTGGTACAGTCTGGAGCTGAGGTGGTTAAGCCAGGGGCCAGC
VH_HV7a	GTCAAAGTATCCTGTAAGGCTTCCGGATATATATTCCAGGACTACAATATG
	CACTGGGTTCGGCAAGCCCACGGACAATCTCTGGAGTGGATGGGCTCCATC
	AATCCCAGGAATGGATGGACCAATTACAATCAGAAGTTCAAGGGGCGAGTC
	ACAATCACAGCTGATACAAGTACTAGAACCGCTTACATGGAGCTTTCTTCA
	TTGAGGTCCGAGGATACAGCTGTCTACTACTGCGCTTCCTCAGGATGGTTT
	ACTTATTGGGGTCAAGGAACTCTGGTGACAGTTAGCAGC (SEQ ID NO:
	75)
hzR35B9-	CAAGTGCAGCTCGTTCAGTCTGGAGCCGAGGTAGTCAAGCCCGGCGCATCT
VH_HV7b	GTTAAAGTCAGTTGCAAAGCTTCCGGCTATATCTTCCAGGATTACAACATG
	CACTGGGTCAGACAGGCTCACGGTCAAGGGCTCGAATGGATGGGAAGTATT
	AACCCTCGTAATGGATGGACTAACTATAACCAAAAGTTTAAGGGGAGGGTG
	ACTATTACAGCAGATAAGTCTACTCGCACTGCCTATATGGAGCTTAGCTCA
	CTCCGCTCCGAAGACACCGCTGTGTATTACTGTGCTAGTTCCGGGTGGTTC
	ACCTATTGGGGGCAAGGAACTCTTGTAACAGTTTCCTCT (SEQ ID NO:
	77)
hzR35B9-	CAAGTTCAACTGGTGCAGTCTGGCGCTGAGGTAAAAAAACCCGGCGCCTCT
VH_HV7c	GTTAAAGTAAGTTGTAAAGCATCTGGGTATATCTTTCAAGATTACAACATG
	CACTGGGTTAAGCAGGCTCCCGGACAGGGTCTTGAGTGGATAGGGTCCATA
	AATCCCCGCAATGGCTGGACTAATTATAACCAAAAGTTCAAAGGAAAAGCC
	ACCATCACAGCAGACACCAGTACATCTACCGCCTACATGGAATTGAGTTCT
	CTGCGGAGCGAGGATACCGCAGTCTATTACTGCGCCTCATCTGGATGGTTT
	ACTTACTGGGGTCAGGGCACTCTGGTGACTGTTTCAAGT (SEQ ID NO:
	79)
hzR35B9-	CAAGTTCAGCTCGTGCAGTCTGGAGCAGAGGTAAAGAAACCCGGCGCATCA
VH_HV9a	GTGAAGATGAGTTGTAAGGCTAGTGGTTATATATTCCAGGATTATAATATG
	CACTGGGTACGACAGGCTCCAGGCCAAGGGCTTGAATGGATAGGCAGCATT
	AACCCCCGAAACGGCTGGACTAATTACAACCAGAAATTCAAGGGACGCGCA
	ACCCTCACTGTGGATACTTCCACATCTACTGCTTACATGGAGTTTTCATCA
	CTCAGGTCAGAAGACACAGCAGTGTACTACTGTGCCTCCTCTGGGTGGTTC
	ACATATTGGGGACAAGGCACATTGGTGACAGTCTCCTCT (SEQ ID NO:
	81)
hzR35B9-	CAGGTCCAACTGGTACAGTCCGGCGCTGAAGTAAAAAAACCAGGCGCTAGT
VH_HV9b	GTCAAGGTATCATGCAAAGCAAGTGGGTATATCTTTCAGGATTATAATATG
	CACTGGGTAAAACAGGCTCACGGCCAATCCCTGGAGTGGATCGGTTCCATC
	AATCCACGGAACGGCTGGACCAACTACAACCAGAAGTTTAAGGGCCGTGCT
	ACCATTACAGCCGACACTAGCACTAGCACAGCTTACATGGAATTCTCCTCC
	CTGCGAAGCGAAGACACCGCAGTGTATTACTGCGCTAGTTCCGGTTGGTTC
	ACTTACTGGGGCCAGGGCACACTCGTCACTGTCTCAAGC (SEQ ID NO:
	83)
hzR35B9-	CAGGTGCAACTGGTGCAATCTGGGGCAGAAGTTAAAAAACCAGGCGCTAGC
VH_HV10	GTAAAAGTTTCTTGCAAAGCAAGTGGGTACATATTCCAAGATTACAATATG
	CATTGGGTCAGGCAGGCCCACGGTCAGGGATTGGAGTGGATCGGCTCTATC
	AACCCTAGAAATGGTTGGACTAACTACAACCAGAAGTTCAAAGGAAAAGCC
	ACCATTACCGCCGATAAATCCACCAGGACAGCCTATATGGAGTTTTCTAGC
	CTTCGTAGCGAAGACACCGCTGTGTATTATTGCGCTTCTAGTGGATGGTTC
	ACTTATTGGGGTCAGGGGACCTTGGTCACTGTTAGTTCT (SEQ ID NO:
	85)
hzR35B9-	CAAGTTCAACTTGTCCAATCCGGTCCAGAAGTCGTAAAACCAGGTGCTAGT
VH_HV11	GTGAAAGTCTCATGCAAGGCTTCAGGCTACATATTTCAAGACTATAATATG
	CATTGGGTTAGACAGGCACACGGTCAGTCACTGGAATGGATGGGGTCAATC
	AACCCTCGCAACGGATGGACAAATTACAACCAAAAGTTCAAAGGGAGAGCT
	ACTATCACTGTCGATAAATCTACCAGAACAGCTTACATGGAGCTGAGTAGT
	CTGAGATCAGAGGACACCGCCGTCTACTATTGTGCTTCTTCTGGGTGGTTT
	ACATACTGGGGGCAGGGGACACTGGTGACTGTGAGTTCT (SEQ ID NO:
	87)
hzR35B9-	GAGGTCCAACTGGTTCAAAGTGGACCAGAGGTGGTGAAACCAGGAGCTAGC
VH_HV18	GTAAAAATGAGCTGTAAGGCTTCAGGTTATATCTTTCAGGATTACAACATG
	CACTGGGTAAAACAAGCCCACGGCCAGTCTCTCGAATGGATTGGGTCAATC
	AATCCCCGAAACGGTTGGACAAACTATAATCAGAAATTCAAAGGTAAAGCA
	ACATTGACTGTTGACAAATCAACCAGGACCGCATACATGGAGTTTTCATCC
	CTGCGTAGTGAAGACACTGCTGTTTACTACTGTGCTAGTTCTGGGTGGTTC
	ACTTACTGGGGGCAGGGAACTCTTGTCACTGTTTCTTCA (SEQ ID NO:
	89)
VL Name
hzR35B9-	GACGTAGTGATGACTCAGAGCCCTCTGTCACTCCCCGTCACACTGGGACAA
VL_LV0	CCAGCTTCCATCTCCTGCAAGTCATCTCAATCTTTGTTGAATAGCGCAGGA
	AAGACATACCTGAACTGGTTCCAACAACGCCCTGGTCAAAGCCCACGCAGG
	CTGATCTATTTGGTAAGTCAACTGGATAGCGGAGTACCTGACCGTTTCTCT
	GGAAGTGGAAGTGGTACTGACTTCACCTTGAAAATCTCCAGGGTTGAAGCC
	GAGGACGTGGGGGTGTATTACTGTTGGCAAGGTACTTTCTACCCTTGGACT
	TTCGGCGGCGGTACCAAGGTAGAGATTAAA (SEQ ID NO: 91)
hzR35B9-	GATGTAGTAATGACCCAGTCCCCACTTAGCTTGCCCGTTACACTCGGCCAA
VL_LV1a	CCCGCAAGCATATCTTGCAAATCCAGTCAGAGCCTCCTGAACTCTGCTGGA
	AAGACCTATCTGAATTGGCTTCAACAACGTCCCGGTCAATCCCCCAGACGA
	CTTATCTACTTGGTAAGTCAGCTTGACTCCGGGGTTCCAGACAGGTTTTCC
	GGATCTGGAAGTGGAACTGATTTTACACTCAAAATTAGTCGAGTCGAGGCC
	GAAGACGTGGGTGTCTATTATTGCTGGCAAGGCACCTTTTATCCATGGACT
	TTTGGTGGGGGCACCAAGGTTGAAATTAAG (SEQ ID NO: 93)
hzR35B9-	GATGTTGTGATGACACAAAGTCCTCTGAGCCTTCCAGTCACATTGGGTCAG
VL_LV1b	CCTGCATCTATTAGTTGTAAGAGCAGTCAATCACTGCTGAATAGTGCCGGA
	AAAACATACTTGAATTGGTTCCTTCAGCGCCCAGGCCAGTCTCCTCGGCGG
	TTGATTTATCTTGTGTCTCAACTGGATTCTGGTGTCCCCGATAGATTTTCA
	GGTTCAGGGTCAGGGACCGATTTTACACTGAAGATTTCTCGCGTCGAGGCA
	GAGGACGTTGGGGTTTATTACTGTTGGCAGGGAACATTTTATCCATGGACA
	TTCGGGGGAGGAACCAAGGTAGAGATTAAA (SEQ ID NO: 95)
hzR35B9-	GACGTAGTTATGACTCAGTCTCCACTCTCTCTCCCCGTGACCATTGGACAG
VL_LV3a	CCTGCATCAATATCCTGCAAAAGTAGCCAGTCCTTGCTCAACTCAGCCGGT
	AAAACCTACCTCAACTGGTTCCTTCAGCGCCCCGGTCAGTCTCCAAAGCGT
	TTGATATACCTGGTGAGTCAACTCGACTCAGGTGTCCCCGATCGCTTCTCT
	GGGAGCGGTTCAGGCACAGATTTTACTCTCAAAATATCCAGAGTTGAAGCT
	GAAGACGTTGGGGTTTACTATTGCTGGCAGGGAACATTCTATCCTTGGACT
	TTTGGAGGAGGCACAAAGGTTGAGATCAAG (SEQ ID NO: 97)
hzR35B9-	GACGTTGTAATGACCCAAAGTCCACTGTCACTTCCCGTAACCATAGGGCAA
VL_LV3b	CCCGCCAGCATCTCCTGCAAATCATCCCAAAGTCTTCTTAACAGTGCCGGA
	AAAACATACTTGAACTGGCTCTTGCAGAGGCCAGGGCAATCTCCTCGACGA
	CTGATATACCTTGTATCCCAGTTGGATTCTGGCGTGCCCGACAGATTCAGT
	GGAAGCGGATCTGGCACAGACTTTACCCTTAAAATCAGCCGCGTGGAGGCC
	GAGGATGTTGGAGTGTACTACTGTTGGCAAGGAACATTTTACCCTTGGACC
	TTTGGCGGGGGGACCAAAGTCGAGATAAAG (SEQ ID NO: 99)
hzR35B9-	GATGTCGTGATGACACAAAGTCCCCTGAGCTTGCCCGTAACTATTGGGCAA
VL_LV4	CCAGCCTCTATCTCTTGTAAATCATCACAATCTTTGCTCAATTCTGCTGGC
	AAGACATACCTTAACTGGCTTTTGCAACGCCCTGGTCAAAGCCCTAAGAGA
	TTGATTTATCTCGTCAGCCAGCTGGACTCTGGGGTCCCAGATCGCTTTAGT
	GGGTCAGGCTCTGGAACCGACTTCACACTGAAGATCTCCAGGGTTGAAGCC
	GAGGATGTAGGGGTTTATTACTGTTGGCAAGGCACCTTTTATCCCTGGACT
	TTTGGGGGCGGCACCAAGGTCGAAATAAAG (SEQ ID NO: 101)
hzR35B9-	GATGTTGTCATGACTCAATCACCATTGAGCCTCCCCGTGACAATAGGCCAG
VL_LV5	CCTGCTTCCATTTCCTGTAAGTCAAGCCAGAGTCTGCTTAATAGTGCCGGG
	AAGACCTATCTGAACTGGCTCTTGCAGAGACCAGGACAATCTCCAAAACGG
	TTGATCTACCTGGTCAGCCAGTTGGACAGCGGCGTTCCAGATCGATTCAGT
	GGCAGTGGATCTGGAACTGATTTTACCTTGAAGATTAGTAGAGTAGAGGCA
	GAGGACGTGGGAGTATATTACTGCTGGCAGGGAACCTTCTACCCCTGGACC
	TTTGGCGGCGGCACCAAGCTCGAGATCAAA (SEQ ID NO: 103)
hzR35B9	CAAGTTCAACTGGTGCAGTCTGGCGCTGAGGTAAAAAAACCCGGCGCCTCT
(A56)-	GTTAAAGTAAGTTGTAAAGCATCTGGGTATATCTTTCAAGATTACAACATG
VH_HV7c	CACTGGGTTAAGCAGGCTCCCGGACAGGGTCTTGAGTGGATAGGGTCCATA
	AATCCCCGCAATGcCTGGACTAATTATAACCAAAAGTTCAAAGGAAAAGCC
	ACCATCACAGCAGACACCAGTACATCTACCGCCTACATGGAATTGAGTTCT
	CTGCGGAGCGAGGATACCGCAGTCTATTACTGCGCCTCATCTGGATGGTTT
	ACTTACTGGGGTCAGGGCACTCTGGTGACTGTTTCAAGT (SEQ ID NO:
	105)
hzR35B9	CAAGTTCAACTTGTCCAATCCGGTCCAGAAGTCGTAAAACCAGGTGCTAGT
(A56)-	GTGAAAGTCTCATGCAAGGCTTCAGGCTACATATTTCAAGACTATAATATG
VH_HV11	CATTGGGTTAGACAGGCACACGGTCAGTCACTGGAATGGATGGGGTCAATC
	AACCCTCGCAACGCCTGGACAAATTACAACCAAAAGTTCAAAGGGAGAGCT
	ACTATCACTGTCGATAAATCTACCAGAACAGCTTACATGGAGCTGAGTAGT
	CTGAGATCAGAGGACACCGCCGTCTACTATTGTGCTTCTTCTGGGTGGTTT
	ACATACTGGGGGCAGGGGACACTGGTGACTGTGAGTTCT (SEQ ID NO:
	107)
hzR35B9	CAAGTGCAGCTCGTTCAGTCTGGAGCCGAGGTAGTCAAGCCCGGCGCATCT
(Y50A56G57)-	GTTAAAGTCAGTTGCAAAGCTTCCGGCTATATCTTCCAGGATTACAACATG
VH_HV7b	CACTGGGTCAGACAGGCTCACGGTCAAGGGCTCGAATGGATGGGAtaTATT
	AACCCTCGTAATGCCGGGACTAACTATAACCAAAAGTTTAAGGGGAGGGTG
	ACTATTACAGCAGATAAGTCTACTCGCACTGCCTATATGGAGCTTAGCTCA
	CTCCGCTCCGAAGACACCGCTGTGTATTACTGTGCTAGTTCCGGGTGGTTC
	ACCTATTGGGGGCAAGGAACTCTTGTAACAGTTTCCTCT (SEQ ID NO:
	109)
hzR35B9	GATGTAGTAATGACCCAGTCCCCACTTAGCTTGCCCGTTACACTCGGCCAA
(H98)-	CCCGCAAGCATATCTTGCAAATCCAGTCAGAGCCTCCTGAACTCTGCTGGA
VL_LV1a	AAGACCTATCTGAATTGGCTTCAACAACGTCCCGGTCAATCCCCCAGACGA
	CTTATCTACTTGGTAAGTCAGCTTGACTCCGGGGTTCCAGACAGGTTTTCC
	GGATCTGGAAGTGGAACTGATTTTACACTCAAAATTAGTCGAGTCGAGGCC
	GAAGACGTGGGTGTCTATTATTGCTGGCAAGGCACCcaTTATCCATGGACT
	TTTGGTGGGGGCACCAAGGTTGAAATTAAG (SEQ ID NO: 111)

TABLE 5 — Nucleotide and amino acid sequences of variant VH sequences based on A512

VH Name	Sequence (SEQ ID NO)
hzR35B9(A56)-HV12a	CAAGTTCAACTTGTCCAATCCGGTCCAGAAGTCGTAAAACCA
(A631)	GGTGCTAGTGTGAAAGTCTCATGCAAGGCTTCAGGCTACATA
	TTTCAAGACTATAATATGCATTGGGTTAGACAGGCAGACGGT
	CAGTCACTGGAATGGATGGGGTCAATCAACCCTCGCAACGCC
	TGGACAAATTACAACCAAAAGTTCAAAGGGAGAGCTACTATC
	ACTGTCGATAAATCTACCAGAACAGCTTACATGGAGCTGAGT
	AGTCTGAGATCAGAGGACACCGCCGTCTACTATTGTGCTTCT
	TCTGGGTGGTTTACATACTGGGGGCAGGGGACACTGGTGACT
	GTGAGTTCT (SEQ ID NO: 202)
hzR35B9(A56)-HV12a	QVQLVQSGPEVVKPGASVKVSCKASGYIFQDYNMHWVRQADG
(A631)	QSLEWMGSINPRNAWTNYNQKFKGRATITVDKSTRTAYMELS
	SLRSEDTAVYYCASSGWFTYWGQGTLVTVSS (SEQ ID
	NO: 203)
hzR35B9(A56)-HV12b	CAAGTTCAACTTGTCCAATCCGGTCCAGAAGTCGTAAAACCA
(A632)	GGTGCTAGTGTGAAAGTCTCATGCAAGGCTTCAGGCTACATA
	TTTCAAGACTATAATATGCATTGGGTTAGACAGGCACCCGGT
	CAGTCACTGGAATGGATGGGGTCAATCAACCCTCGCAACGCC
	TGGACAAATTACAACCAAAAGTTCAAAGGGAGAGCTACTATC
	ACTGTCGATAAATCTACCAGAACAGCTTACATGGAGCTGAGT
	AGTCTGAGATCAGAGGACACCGCCGTCTACTATTGTGCTTCT
	TCTGGGTGGTTTACATACTGGGGGCAGGGGACACTGGTGACT
	GTGAGTTCT (SEQ ID NO: 204)
hzR35B9(A56)-HV12b	QVQLVQSGPEVVKPGASVKVSCKASGYIFQDYNMHWVRQAPG
(A632)	QSLEWMGSINPRNAWTNYNQKFKGRATITVDKSTRTAYMELS
	SLRSEDTAVYYCASSGWFTYWGQGTLVTVSS (SEQ ID
	NO: 205)
hzR35B9(A56)-HV13a	CAAGTTCAACTTGTCCAATCCGGTCCAGAAGTCGTAAAACCA
(A633)	GGTGCTAGTGTGAAAGTCTCATGCAAGGCTTCAGGCTACATA
	TTTCAAGACTATAATATGCATTGGGTTAGAGAAGCACACGGT
	CAGTCACTGGAATGGATGGGGTCAATCAACCCTCGCAACGCC
	TGGACAAATTACAACCAAAAGTTCAAAGGGAGAGCTACTATC
	ACTGTCGATAAATCTACCAGAACAGCTTACATGGAGCTGAGT
	AGTCTGAGATCAGAGGACACCGCCGTCTACTATTGTGCTTCT
	TCTGGGTGGTTTACATACTGGGGGCAGGGGACACTGGTGACT
	GTGAGTTCT (SEQ ID NO: 206)
hzR35B9(A56)-HV13a	QVQLVQSGPEVVKPGASVKVSCKASGYIFQDYNMHWVREAHG
(A633)	QSLEWMGSINPRNAWTNYNQKFKGRATITVDKSTRTAYMELS
	SLRSEDTAVYYCASSGWFTYWGQGTLVTVSS (SEQ ID
	NO: 207)
hzR35B9(A56)-HV13b	CAAGTTCAACTTGTCCAATCCGGTCCAGAAGTCGTAAAACCA
(A634)	GGTGCTAGTGTGAAAGTCTCATGCAAGGCTTCAGGCTACATA
	TTTCAAGACTATAATATGCATTGGGTTAGACAGGCACACGGT
	CAGTCACTGGAATGGATGGGGTCAATCAACCCTCGCAACGCC
	TGGACAAATTACAACCAAAAGTTCGGAGGGAGAGCTACTATC
	ACTGTCGATAAATCTACCAGAACAGCTTACATGGAGCTGAGT
	AGTCTGAGATCAGAGGACACCGCCGTCTACTATTGTGCTTCT
	TCTGGGTGGTTTACATACTGGGGGCAGGGGACACTGGTGACT
	GTGAGTTCT (SEQ ID NO: 208)
hzR35B9(A56)-HV13b	QVQLVQSGPEVVKPGASVKVSCKASGYIFQDYNMHWVRQAHG
(A634)	QSLEWMGSINPRNAWTNYNQKFGGRATITVDKSTRTAYMELS
	SLRSEDTAVYYCASSGWFTYWGQGTLVTVSS (SEQ ID
	NO: 209)
hzR35B9(A56)-HV13d	CAAGTTCAACTTGTCCAATCCGGTCCAGAAGTCGTAAAACCA
(A636)	GGTGCTAGTGTGAAAGTCTCATGCAAGGCTTCAGGCTACATA
	TTTCAAGACTATAATATGCATTGGGGCAGACAGGCACACGGT
	CAGTCACTGGAATGGATGGGGTCAATCAACCCTCGCAACGCC
	TGGACAAATTACAACCAAAAGTTCAAAGGGAGAGCTACTATC
	ACTGTCGATAAATCTACCAGAACAGCTTACATGGAGCTGAGT
	AGTCTGAGATCAGAGGACACCGCCGTCTACTATTGTGCTTCT
	TCTGGGTGGTTTACATACTGGGGGCAGGGGACACTGGTGACT
	GTGAGTTCT (SEQ ID NO: 210)
hzR35B9(A56)-HV13d	QVQLVQSGPEVVKPGASVKVSCKASGYIFQDYNMHWGRQAHG
(A636)	QSLEWMGSINPRNAWTNYNQKFKGRATITVDKSTRTAYMELS
	SLRSEDTAVYYCASSGWFTYWGQGTLVTVSS (SEQ ID
	NO: 211)
hzR35B9(A56)-HV13f	CAAGTTCAACTTGTCCAATCCGGTCCAGAAGTCGTAAAACCA
(A638)	GGTGCTAGTGTGAAAGTCTCATGCAAGGCTTCAGGCTACATA
	TTTCAAGACTATAATATGCATTGGGTTAGACAGGCACACGGT
	CAGTCACTGGAATGGATGGGGTCAATCAACCCTCGCAACGCC
	TGGACAAATTACAACGATAAGTTCAAAGGGAGAGCTACTATC
	ACTGTCGATAAATCTACCAGAACAGCTTACATGGAGCTGAGT
	AGTCTGAGATCAGAGGACACCGCCGTCTACTATTGTGCTTCT
	TCTGGGTGGTTTACATACTGGGGGCAGGGGACACTGGTGACT
	GTGAGTTCT (SEQ ID NO: 212)
hzR35B9(A56)-HV13f	QVQLVQSGPEVVKPGASVKVSCKASGYIFQDYNMHWVRQAHG
(A638)	QSLEWMGSINPRNAWTNYNDKFKGRATITVDKSTRTAYMELS
	SLRSEDTAVYYCASSGWFTYWGQGTLVTVSS (SEQ ID
	NO: 213)
hzR35B9(A56)-HV13g	CAAGTTCAACTTGTCCAATCCGGTCCAGAAGTCGTAAAACCA
(A639)	GGTGCTAGTGTGAAAGTCTCATGCAAGGCTTCAGGCTACATA
	TTTCAAGACTATAATATGCATTGGGTTAGACAGGCACACGGT
	GACTCACTGGAATGGATGGGGTCAATCAACCCTCGCAACGCC
	TGGACAAATTACAACCAAAAGTTCAAAGGGAGAGCTACTATC
	ACTGTCGATAAATCTACCAGAACAGCTTACATGGAGCTGAGT
	AGTCTGAGATCAGAGGACACCGCCGTCTACTATTGTGCTTCT
	TCTGGGTGGTTTACATACTGGGGGCAGGGGACACTGGTGACT
	GTGAGTTCT (SEQ ID NO: 214)
hzR35B9(A56)-HV13g	QVQLVQSGPEVVKPGASVKVSCKASGYIFQDYNMHWVRQAHG
(A639)	DSLEWMGSINPRNAWTNYNQKFKGRATITVDKSTRTAYMELS
	SLRSEDTAVYYCASSGWFTYWGQGTLVTVSS (SEQ ID
	NO: 215)
hzR35B9(A56)-HV16	CAAGTTCAACTTCAGCAATCCGGTCCAGAAGTCGTAAAACCA
(A641)	GGTGCTAGTGTGAAAGTCTCATGCAAGGCTTCAGGCTACATA
	TTTCAAGACTATAATATGCATTGGGTTAAACAGGCACACGGT
	CAGTCACTGGAATGGATGGGGTCAATCAACCCTCGCAACGCC
	TGGACAAATTACAACCAAAAGTTCAAAGGGAAAGCTACTCTG
	ACTGTCGATAAATCTACCAGAACAGCTTACATGGAGCTGAGT
	AGTCTGAGATCAGAGGACACCGCCGTCTACTATTGTGCTTCT
	TCTGGGTGGTTTACATACTGGGGGCAGGGGACACTGGTGACT
	GTGAGTTCT (SEQ ID NO: 216)
hzR35B9(A56)-HV16	QVQLQQSGPEVVKPGASVKVSCKASGYIFQDYNMHWVKQAHG
(A641)	QSLEWMGSINPRNAWTNYNQKFKGKATLTVDKSTRTAYMELS
	SLRSEDTAVYYCASSGWFTYWGQGTLVTVSS (SEQ ID
	NO: 217)
hzR35B9(A56)-HV17a	CAAGTTCAACTTCAGCAATCCGGTCCAGAAGTCGTAAAACCA
(A642)	GGTGCTAGTGTGAAAGTCTCATGCAAGGCTTCAGGCTACATA
	TTTCAAGACTATAATATGCATTGGGTTAAACAGGGACACGGT
	CAGTCACTGGAATGGATGGGGTCAATCAACCCTCGCAACGCC
	TGGACAAATTACAACCAAAAGTTCAAAGGGAAAGCTACTCTG
	ACTGTCGATAAATCTACCAGAACAGCTTACATGGAGCTGAGT
	AGTCTGAGATCAGAGGACACCGCCGTCTACTATTGTGCTTCT
	TCTGGGTGGTTTACATACTGGGGGCAGGGGACACTGGTGACT
	GTGAGTTCT (SEQ ID NO: 218)
hzR35B9(A56)-HV17a	QVQLQQSGPEVVKPGASVKVSCKASGYIFQDYNMHWVKQGHG
(A642)	QSLEWMGSINPRNAWTNYNQKFKGKATLTVDKSTRTAYMELS
	SLRSEDTAVYYCASSGWFTYWGQGTLVTVSS (SEQ ID
	NO: 219)
hzR35B9(A56)-HV17b	CAAGTTCAACTTCAGCAATCCGGTCCAGAAGTCGTAAAACCA
(A643)	GGTGCTAGTGTGAAAGTCTCATGCAAGGCTTCAGGCTACATA
	TTTCAAGACTATAATATGCATTGGGTTAAACAGGCACACGGT
	CAGTCACTGGAATGGATGGGGTCAATCAACCCTCGCAACGCC
	TGGACAAATTACAACCAAAAGTTCCACGGGAAAGCTACTCTG
	ACTGTCGATAAATCTACCAGAACAGCTTACATGGAGCTGAGT
	AGTCTGAGATCAGAGGACACCGCCGTCTACTATTGTGCTTCT
	TCTGGGTGGTTTACATACTGGGGGCAGGGGACACTGGTGACT
	GTGAGTTCT (SEQ ID NO: 220)
hzR35B9(A56)-HV17b	QVQLQQSGPEVVKPGASVKVSCKASGYIFQDYNMHWVKQAHG
(A643)	QSLEWMGSINPRNAWTNYNQKFHGKATLTVDKSTRTAYMELS
	SLRSEDTAVYYCASSGWFTYWGQGTLVTVSS (SEQ ID
	NO: 221)
hzR35B9(A56)-HV17d	CAAGTTCAACTTCAGCAATCCGGTCCAGAAGTCGTAAAACCA
(A645)	GGTGCTAGTGTGAAAGTCTCATGCAAGGCTTCAGGCTACATA
	TTTCAAGACTATAATATGCATTGGGTTAAACAGGCACACGGT
	CAGTCACTGGAATGGATGGGGTCAATCAACCCTCGCAACGCC
	TGGACAAATTACAACCAAAAGTTCGACGGGAAAGCTACTCTG
	ACTGTCGATAAATCTACCAGAACAGCTTACATGGAGCTGAGT
	AGTCTGAGATCAGAGGACACCGCCGTCTACTATTGTGCTTCT
	TCTGGGTGGTTTACATACTGGGGGCAGGGGACACTGGTGACT
	GTGAGTTCT (SEQ ID NO: 222)
hzR35B9(A56)-HV17d	QVQLQQSGPEVVKPGASVKVSCKASGYIFQDYNMHWVKQAHG
(A645)	QSLEWMGSINPRNAWTNYNQKFDGKATLTVDKSTRTAYMELS
	SLRSEDTAVYYCASSGWFTYWGQGTLVTVSS (SEQ ID
	NO: 223)
hzR35B9(A56)-HV17g	CAAGTTCAACTTCAGCAATCCGGTCCAGAAGTCGTAAAACCA
(A648)	GGTGCTAGTGTGAAAGTCTCATGCAAGGCTTCAGGCTACATA
	TTTCAAGACTATAATATGCATTGGGTTAAACAGGCACACGGT
	CAGTCACTGGAATGGATGGGGTCAATCAACCCTCGCAACGCC
	TGGACAAATTACAACGACAAGTTCAAAGGGAAAGCTACTCTG
	ACTGTCGATAAATCTACCAGAACAGCTTACATGGAGCTGAGT
	AGTCTGAGATCAGAGGACACCGCCGTCTACTATTGTGCTTCT
	TCTGGGTGGTTTACATACTGGGGGCAGGGGACACTGGTGACT
	GTGAGTTCT (SEQ ID NO: 224)
hzR35B9(A56)-HV17g	QVQLQQSGPEVVKPGASVKVSCKASGYIFQDYNMHWVKQAHG
(A648)	QSLEWMGSINPRNAWTNYNDKFKGKATLTVDKSTRTAYMELS
	SLRSEDTAVYYCASSGWFTYWGQGTLVTVSS (SEQ ID
	NO: 225)
hzR35B9(A56)-HV17i	CAAGTTCAACTTCAGCAATCCGGTCCAGAAGTCGCCAAACCA
(A650)	GGTGCTAGTGTGAAAGTCTCATGCAAGGCTTCAGGCTACATA
	TTTCAAGACTATAATATGCATTGGGTTAAACAGGCACACGGT
	CAGTCACTGGAATGGATGGGGTCAATCAACCCTCGCAACGCC
	TGGACAAATTACAACCAAAAGTTCAAAGGGAAAGCTACTCTG
	ACTGTCGATAAATCTACCAGAACAGCTTACATGGAGCTGAGT
	AGTCTGAGATCAGAGGACACCGCCGTCTACTATTGTGCTTCT
	TCTGGGTGGTTTACATACTGGGGGCAGGGGACACTGGTGACT
	GTGAGTTCT (SEQ ID NO: 226)
hzR35B9(A56)-HV17i	QVQLQQSGPEVAKPGASVKVSCKASGYIFQDYNMHWVKQAHG
(A650)	QSLEWMGSINPRNAWTNYNQKFKGKATLTVDKSTRTAYMELS
	SLRSEDTAVYYCASSGWFTYWGQGTLVTVSS (SEQ ID
	NO: 227)

TABLE 17 — Nucleotide and amino acid sequences of variant VL sequences based on A468

hzR35B9	GATGTAGTAATGACCCAGTCCCCACTTAGCTTGCCCGTTA
(A56)-	CACTCGGCCAACCCGCAAGCATATCTTGCAAATCCAGTCA
LV2a	GAGCCTCCTGAACTCTGCTGGAAAGACCTATCTGAATTGG
(A651)	CTTCAACAACGTCCCGGTCAATCCCCCAGACGAGGTATCT
	ACTTGGTAAGTCAGCTTGACTCCGGGGTTCCAGACAGGTT
	TTCCGGATCTGGAAGTGGAACTGATTTTACACTCAAAATT
	AGTCGAGTCGAGGCCGAAGACGTGGGTGTCTATTATTGCT
	GGCAAGGCACCTTTTATCCATGGACTTTTGGTGGGGGCAC
	CAAGGTTGAAATTAAG (SEQ ID NO: 228)
hzR35B9	DVVMTQSPLSLPVTLGQPASISCKSSQSLLNSAGKTYLNW
(A56)-	LQQRPGQSPRRGIYLVSQLDSGVPDRFSGSGSGTDFTLKI
LV2a	SRVEAEDVGVYYCWQGTFYPWTFGGGTKVEIK (SEQ ID
(A651)	NO: 229)
hzR35B9	GATGTAGTAATGACCCAGTCCCCACTTAGCTTGCCCGTTA
(A56)-	CACTCGGCCAACCCGCAAGCATATCTTGCAAATCCAGTCA
LV2b	GAGCCTCCTGAACTCTGCTGGAAAGACCTATCTGAATTGG
(A652)	CTTCAACAACGTCCCGGTCAATCCCCCAGACGACTTGCCT
	ACTTGGTAAGTCAGCTTGACTCCGGGGTTCCAGACAGGTT
	TTCCGGATCTGGAAGTGGAACTGATTTTACACTCAAAATT
	AGTCGAGTCGAGGCCGAAGACGTGGGTGTCTATTATTGCT
	GGCAAGGCACCTTTTATCCATGGACTTTTGGTGGGGGCAC
	CAAGGTTGAAATTAAG (SEQ ID NO: 230)
hzR35B9	DVVMTQSPLSLPVTLGQPASISCKSSQSLLNSAGKTYLNW
(A56)-	LQQRPGQSPRRLAYLVSQLDSGVPDRFSGSGSGTDFTLKI
LV2b	SRVEAEDVGVYYCWQGTFYPWTFGGGTKVEIK (SEQ ID
(A652)	NO: 231)
hzR35B9	GATGTAGTAATGACCCAGTCCCCACTTAGCTTGCCCGTTA
(A56)-	CACTCGGCCAACCCGCAAGCATATCTTGCAAATCCAGTCA
LV2c	GAGCCTCCTGAACTCTGCTGGAAAGACCTATCTGAATTGG
(A653)	CTTCAACAACGTCCCGGTCAATCCCCCAGACGACTTATCT
	ACTTGGTAAGTGAGCTTGACTCCGGGGTTCCAGACAGGTT
	TTCCGGATCTGGAAGTGGAACTGATTTTACACTCAAAATT
	AGTCGAGTCGAGGCCGAAGACGTGGGTGTCTATTATTGCT
	GGCAAGGCACCTTTTATCCATGGACTTTTGGTGGGGGCAC
	CAAGGTTGAAATTAAG (SEQ ID NO: 232)
hzR35B9	DVVMTQSPLSLPVTLGQPASISCKSSQSLLNSAGKTYLNW
(A56)-	LQQRPGQSPRRLIYLVSELDSGVPDRFSGSGSGTDFTLKI
LV2c	SRVEAEDVGVYYCWQGTFYPWTFGGGTKVEIK (SEQ ID
(A653)	NO: 233)
hzR35B9	GATGTAGTAATGACCCAGTCCCCACTTAGCTTGCCCGTTA
(A56)-	CACTCGGCCAACCCGCAAGCATATCTTGCAAATCCAGTCA
LV2d	GAGCCTCCTGAACTCTGCTGGAAAGACCTATCTGAATTGG
(A654)	CTTCAACAACGTCCCGGTCAATCCCCCAGACGACTTATCT
	ACTTGGTAAGTCAGCTTGACGACGGGGTTCCAGACAGGTT
	TTCCGGATCTGGAAGTGGAACTGATTTTACACTCAAAATT
	AGTCGAGTCGAGGCCGAAGACGTGGGTGTCTATTATTGCT
	GGCAAGGCACCTTTTATCCATGGACTTTTGGTGGGGGCAC
	CAAGGTTGAAATTAAG (SEQ ID NO: 234)
hzR35B9	DVVMTQSPLSLPVTLGQPASISCKSSQSLLNSAGKTYLNW
(A56)-	LQQRPGQSPRRLIYLVSQLDDGVPDRFSGSGSGTDFTLKI
LV2d	SRVEAEDVGVYYCWQGTFYPWTFGGGTKVEIK (SEQ ID
(A654)	NO: 235)
hzR35B9	GATGTAGTAATGACCCAGTCCCCACTTAGCTTGCCCGTTA
(A56)-	CACTCGGCCAACCCGCAAGCATATCTTGCAAATCCAGTCA
LV2f	GAGCCTCCTGAACTCTGCTGGAAAGACCTATCTGAATTGG
(A656)	CTTCAACAACGTCCCGGTCAATCCCCCAGACGACTTATCT
	ACTTGGTAGCCCAGCTTGACTCCGGGGTTCCAGACAGGTT
	TTCCGGATCTGGAAGTGGAACTGATTTTACACTCAAAATT
	AGTCGAGTCGAGGCCGAAGACGTGGGTGTCTATTATTGCT
	GGCAAGGCACCTTTTATCCATGGACTTTTGGTGGGGGCAC
	CAAGGTTGAAATTAAG (SEQ ID NO: 236)
hzR35B9	DVVMTQSPLSLPVTLGQPASISCKSSQSLLNSAGKTYLNW
(A56)-	LQQRPGQSPRRLIYLVAQLDSGVPDRFSGSGSGTDFTLKI
LV2f	SRVEAEDVGVYYCWQGTFYPWTFGGGTKVEIK (SEQ
(A656)	ID NO: 237)

TABLE 8 — Binding kinetics of Fn14 Fabs to human Fn14 KD (nM)

	Amine		ka	kd	KD	Average
Analyte	Coupled	Fitting Model	(1/Ms)	(1/s)	(nM)	(Std Dev)
R35B9 Fab	His-	1:1 Binding	3067000	6.302E−04	0.2055	0.208
LM042817	Sumo-	1:1 Binding	2030000	4.271E−04	0.2104	(+/0.00347)
	huFn14
CRCBT-06-	His-	1:1 Binding	887600	4.930E−04	0.8589	0.7654
002 Fab	Sumo-	1:1 Binding	806500	5.418E−04	0.6719	(+/−0.1322)
LM111816	huFn14
41C Fab	His-	1:1 Binding	1128000	2.423E−03	2.148	1.978
LM101416	Sumo-	1:1 Binding	1472000	2.661E−03	1.808	(+/−0.2404)
	huFn14
Item 4 Fab	His-	1:1 Binding	1682000	3.037E−03	1.805	1.6195
LM021617	Sumo-	1:1 Binding	1942000	2.785E−03	1.434	(+/−0.2623)
	huFn14

TABLE 9 — Binding kinetics of Fn14 Fabs to cynomolgus macaque Fn14

	Captured					KD (nM)
	by	Fitting	ka	kd	KD	Average
Analyte	antiGST	Model	(1/Ms)	(1/s)	(nM)	(Std Dev)
R35B9 Fab	CynoFn14	1:1 Binding	1457000	3.424E−04	0.235	0.2285
LM042817						(+/−0.00926)
		1:1 Binding	1714000	3.804E−04	0.2219
CRCBT-06-	CynoFn14	1:1 Binding	486200	4.017E−04	0.8262	0.76205
002 Fab						(+/−0.0907
LM111816
		1:1 Binding	554500	3.869E−04	0.6979
41C Fab	CynoFn14	1:1 Binding	441200	1.534E−03	3.476	3.38
LM101416						(+/−0.1386)
		1:1 Binding	678400	2.226E−03	3.280
Item 4 Fab	CynoFn14	1:1 Binding	1308000	1.1819E−03	1.390	1.298
LM021617						(+/−0.1308)
		1:1 Binding	1680000	2.024E−03	1.205

TABLE 24 — Binding kinetics of Fn14 mAbs to human Fn14 KD (nM)

	Fitting	ka	kd	KD	Average
Ligand	Model	(1/Ms)	(1/s)	(nM)	(Std Dev)
A512/	1:1 Binding	3.003e6	6.794e−4	2.262e−10	2.06E−10
A468	1:1 Binding	3.432e6	6.643e−4	1.936e−10	(1.77E−11)
	1:1 Binding	3.307e6	6.523e−4	1.973e−10
A515/	1:1 Binding	3.113e6	1.435e−3	4.611e−10	4.70E−10
A518	1:1 Binding	3.248e6	1.537e−3	4.734e−10	(8.33E−12)
	1:1 Binding	3.15e6	1.501e−3	4.766e−10
A553/	1:1 Binding	2.150e6	8.036e−4	3.738e−10	3.58E−10
A472	1:1 Binding	2.342e6	8.119e−4	3.466e−10	(1.40E−11)
	1:1 Binding	2.26e6	7.989e−4	3.535e−10
A641/	1:1 Binding	2.889e6	7.556e−4	2.615e−10	2.56E−10
A468	1:1 Binding	3.108e6	7.734e−4	2.489e−10	(6.56E−12)
	1:1 Binding	2.97e6	7.639e−4	2.573e−10
A648/	1:1 Binding	2.776e6	5.312e−4	1.914e−10	2.22E−10
A468	1:1 Binding	3.193e6	7.556e−4	2.367e−10	(2.66E−11)
	1:1 Binding	3.128e6	7.42e−4	2.372e−10
A650/	1:1 Binding	3.304e6	8.712e−4	2.636e−10	2.78E−10
A468	1:1 Binding	2.936e6	8.43e−4	2.871e−10	(1.21E−11)
	1:1 Binding	2.923e6	8.249e−4	2.822e−10

TABLE 10 — Interactions between Fn14 and heavy chain/light chain regions of 41c-His Fab

Antigen residues	Antibody residues	Hydrogen bonding
(Fn14)	(41c Fab)	distance (Å)
Polar interactions of Fn14 with heavy chain region of 41c Fab
CYS 49 [N]	ASP 31 [O]	2.82
LYS 48 [NZ]	TYR 32 [OH]	3.00
GLY 32 [N]	ASN 54 [O]	3.67
PRO 35 [O]	ASN 52 [ND2]	2.88
PRO 35 [O]	ASN 54 [ND2]	2.80
THR 33 [O]	ASN 55 [ND2]	2.72
ASP 47 [OD2]	GLY 100 [N]	3.07
ASP 47 [O]	GLY 100 [N]	2.75
ASP 47 [OD2]	TRP 101 [N]	2.91
ASP 45 [O]	TRP 101 [NE1]	2.86
ASP 47 [O]	SER 99 [OH]	2.80
Polar interactions of Fn14 with light chain region of 41c Fab
ASP 45 [OD1]	TYR 37 [OH]	2.63
ASP 45 [OD2]	LYS 35 [NZ]	2.69
		Salt bridge distance (Å)
ASP 45 [OD1]	LYS 35 [NZ]	3.08
ASP 45 [OD2]	LYS 35 [NZ]	2.69
Vander Waal contacts between Fn14 and 41c Fab
TRP 42	ASN 33 (HC)	4.21
ALA 44	TRP 101 (HC)	3.34
LEU 46	LEU 55 (LC)	4.40

TABLE 11 — Interactions between Fn14 and heavy chain/light chain regions of R35B9-His Fab

Antigen residues	Antibody residues	Hydrogen bonding
(Fn14)	(R35B9 Fab)	distance (Å)
Polar interactions of Fn14 with heavy chain region of R35B9 Fab
CYS 49 [N]	ASP 31 [O]	2.95
LYS 48 [NZ]	TYR 32 [OH]	3.30
LYS 48 [NZ]	TYR 27 [OH]	3.56
PRO 35 [O]	ASN 52 [ND2]	3.58
PRO 35 [O]	ARG 54 [NH2]	2.85
CYS 49 [SG]	ARG 54 [NH2]	3.00
THR 33 [O]	ASN 55 [ND2]	3.33
ALA 34 [O]	ASN 55 [ND2]	3.78
ASP 47 [OD2]	GLY 100 [N]	2.96
ASP 47 [OD2]	TRP 101 [N]	2.99
ASP 47 [O]	GLY 100 [N]	2.71
ASP 45 [O]	TRP 101 [NE1]	2.97
ASP 47 [O]	SER 99 [OG]	2.80
Polar interactions of Fn14 with light chain region of R35B9 Fab
ASP 45 [OD1]	TYR 37 [OH]	2.55
ASP 45 [OD1]	LYS 35 [NZ]	3.45
ASP 45 [OD2]	LYS 35 [NZ]	3.14
Ala 44 (O)	TYR 37 [OH]	3.58
Ala 44 (N)	TYR 37 [OH]	3.42
		Salt bridge distance (Å)
ASP 45 [OD1]	LYS 35 [NZ]	3.45
ASP 45 [OD2]	LYS 35 [NZ]	3.14

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IPC · International Patent Classification

Section A — Human necessities

A61P37/00
A61P35/00

Section C — Chemistry; metallurgy

C07K16/28

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