Gp130 antigen-binding molecules

Abstract

Gp130 antigen-binding molecules are disclosed. Also disclosed are nucleic acids and expression vectors encoding, cells comprising, compositions comprising, and methods using, the Gp130 antigen-binding molecules.

Description

[0001] Gp130 Antigen-Binding Molecules

[0002] This application claims priority from GB 2408044.2 filed 6 June 2024, the contents and elements of which are herein incorporated by reference for all purposes.

[0003] Technical Field

[0004] The present disclosure relates to the fields of molecular biology, more specifically antibody technology. The present disclosure also relates to methods of medical treatment and prophylaxis.

[0005] Background

[0006] Gp130 is a constituent protein of receptors of a diversity of cytokines including IL-6, IL-11 , OSM, LIF, CNTF, CT-1 , CLC, IL-27 and IL-35, which are often referred to collectively as IL-6 family cytokines. Certain IL-6 family cytokines such as IL-6 and IL-11 are implicated in the pathology of a broad spectrum of diseases / conditions characterised by inflammation and / or fibrosis (see e.g. Rose-John, FI OOORes. (2020) 9:F1000 Faculty Rev-1013, Tanaka et al., Cold Spring Harb Perspect Biol. (2014) 6(10): a016295, Hirano et al. International Immunology (2021) 33(3): 127-148, Putoczki and Ernst, Immunotherapy (2015) 7(4): 441-453, Nguyen et al. Growth Factors (2019) 37(1-2):1 -11 , Cook and Schafer Annu. Rev. Med. (2020) 71 :263-276 and Fung et al., Cytokine (2022) 149:155750).

[0007] However, because gp130 is important for the signalling mediated by such a range of different cytokines, it has been considered to be an unattractive target for therapeutic intervention for such diseases / conditions. For example, it has been suggested that as a result of its role in promoting resistance to pathogens, therapies targeting gp130 might leave patients vulnerable to opportunistic infections. Moreover, because signalling mediated by some IL-6 family cytokines might be beneficial in certain settings, agents targeting gp130 may cause and / or exacerbate disease (see e.g. Silver and Hunter, J Leukoc Biol. (2010) 88(6):1145-1156).

[0008] Monoclonal antibodies that bind to gp130 and antagonise gp130-mediated signalling have previously been described, including mAb16673 which is reported in WO 2019 / 126071 A1 to inhibit signalling mediated by OSM, LIF and CNTF.

[0009] Summary

[0010] In a first aspect, the present disclosure provides an antigen-binding molecule, optionally isolated, which binds to gp130, wherein the antigen-binding molecule comprises:

[0011] (a)

[0012] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0013] HC-CDR1 having the amino acid sequence of SEQ ID NO:2 HC-CDR2 having the amino acid sequence of SEQ ID NO:245 HC-CDR3 having the amino acid sequence of SEQ ID NO:4; and

[0014] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0015] LC-CDR1 having the amino acid sequence of SEQ ID NO:10 LC-CDR2 having the amino acid sequence of SEQ ID NO:11 LC-CDR3 having the amino acid sequence of SEQ ID NO:281 ; or

[0016] (b)

[0017] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0018] HC-CDR1 having the amino acid sequence of SEQ ID NO:2 HC-CDR2 having the amino acid sequence of SEQ ID NO:3 HC-CDR3 having the amino acid sequence of SEQ ID NO:4; and

[0019] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0020] LC-CDR1 having the amino acid sequence of SEQ ID NQ:10 LC-CDR2 having the amino acid sequence of SEQ ID NO:11 LC-CDR3 having the amino acid sequence of SEQ ID NO:12; or

[0021] (c)

[0022] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0023] HC-CDR1 having the amino acid sequence of SEQ ID NO:401 HC-CDR2 having the amino acid sequence of SEQ ID NO:3 HC-CDR3 having the amino acid sequence of SEQ ID NO:4; and

[0024] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0025] LC-CDR1 having the amino acid sequence of SEQ ID NQ:10 LC-CDR2 having the amino acid sequence of SEQ ID NO:11 LC-CDR3 having the amino acid sequence of SEQ ID NO:12; or

[0026] (d)

[0027] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0028] HC-CDR1 having the amino acid sequence of SEQ ID NO:401 HC-CDR2 having the amino acid sequence of SEQ ID NO:245 HC-CDR3 having the amino acid sequence of SEQ ID NO:4; and

[0029] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0030] LC-CDR1 having the amino acid sequence of SEQ ID NQ:10 LC-CDR2 having the amino acid sequence of SEQ ID NO:11 LC-CDR3 having the amino acid sequence of SEQ ID NO:281 ; or

[0031] (e)

[0032] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0033] HC-CDR1 having the amino acid sequence of SEQ ID NO:37 HC-CDR2 having the amino acid sequence of SEQ ID NO:38 HC-CDR3 having the amino acid sequence of SEQ ID NO:39; and

[0034] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0035] LC-CDR1 having the amino acid sequence of SEQ ID NO:45 LC-CDR2 having the amino acid sequence of SEQ ID NO:46 LC-CDR3 having the amino acid sequence of SEQ ID NO:47; or (D

[0036] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0037] HC-CDR1 having the amino acid sequence of SEQ ID NO:37 HC-CDR2 having the amino acid sequence of SEQ ID NO:38 HC-CDR3 having the amino acid sequence of SEQ ID NO:39; and

[0038] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0039] LC-CDR1 having the amino acid sequence of SEQ ID NO:45 LC-CDR2 having the amino acid sequence of SEQ ID NO:46 LC-CDR3 having the amino acid sequence of SEQ ID NO:457; or

[0040] (g)

[0041] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0042] HC-CDR1 having the amino acid sequence of SEQ ID NO:37 HC-CDR2 having the amino acid sequence of SEQ ID NO:38 HC-CDR3 having the amino acid sequence of SEQ ID NO:39; and

[0043] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0044] LC-CDR1 having the amino acid sequence of SEQ ID NO:45 LC-CDR2 having the amino acid sequence of SEQ ID NO:46 LC-CDR3 having the amino acid sequence of SEQ ID NO:458; or

[0045] (h)

[0046] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0047] HC-CDR1 having the amino acid sequence of SEQ ID NO:37 HC-CDR2 having the amino acid sequence of SEQ ID NO:38 HC-CDR3 having the amino acid sequence of SEQ ID NO:39; and

[0048] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0049] LC-CDR1 having the amino acid sequence of SEQ ID NO:45 LC-CDR2 having the amino acid sequence of SEQ ID NO:46 LC-CDR3 having the amino acid sequence of SEQ ID NO:459.

[0050] In some embodiments, the antigen-binding molecule comprises: a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:1 , 36, 106, 220, 240, 398, 399, 400, 485, 406, 407, 408, 486, 412, 413, 414, 487, 389, 392, 393, 394, 488, 418, 419, 420, 439; and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:9, 44, 110, 271 , 475, 430, 431 , 445, 448, 449, 450, 478, 479, 480, 451 , 452, 453, 454, 455, 456, 469, 470, or 471 .

[0051] In some embodiments, the antigen-binding molecule comprises:

[0052] (a) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:1 , and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:9; or

[0053] (b) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:106, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:110; or

[0054] (c) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:220, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or

[0055] (d) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:240, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or

[0056] (e) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:398, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:9; or

[0057] (f) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:399, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:9; or

[0058] (g) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:400, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:9; or

[0059] (h) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:485, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:9; or

[0060] (i) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:406, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or

[0061] (j) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:407, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or

[0062] (k) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:408, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or (l) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:486, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or

[0063] (m) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:412, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or

[0064] (n) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:413, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or

[0065] (o) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:414, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or

[0066] (p) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:487, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or

[0067] (q) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:389, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or

[0068] (r) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:392, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or

[0069] (s) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:393, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or

[0070] (t) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:394, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or

[0071] (u) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:488, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or

[0072] (v) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:36, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:44; or

[0073] (w) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:475; or

[0074] (x) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:430; or

[0075] (y) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:431 ; or

[0076] (z) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:475; or

[0077] (aa) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:430; or

[0078] (ab) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:431 ; or

[0079] (ac) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:475; or

[0080] (ad) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:430; or

[0081] (ae) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:431 ; or

[0082] (at) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:36, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:475; or (ag) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:36, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:430; or

[0083] (ah) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:36, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:431 ; or

[0084] (ai) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:478; or

[0085] (aj) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:479; or

[0086] (ak) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:480; or

[0087] (al) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:451 ; or

[0088] (am) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:452; or

[0089] (an) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:453; or

[0090] (ao) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:454; or

[0091] (ap) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:455; or

[0092] (aq) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:456; or

[0093] (ar) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID

[0094] NO:478; or

[0095] (as) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID

[0096] NO:479; or

[0097] (at) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID

[0098] NQ:480; or

[0099] (au) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID

[0100] NO:451 ; or

[0101] (av) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID

[0102] NO:452; or

[0103] (aw) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID

[0104] NO:453; or

[0105] (ax) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID

[0106] NO:454; or

[0107] (ay) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID

[0108] NO:455; or

[0109] (az) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID

[0110] NO:456; or

[0111] (ba) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:478; or (bb) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:479; or

[0112] (be) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:480; or

[0113] (bd) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:451 ; or

[0114] (be) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:452; or

[0115] (bf) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:453; or

[0116] (bg) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:454; or

[0117] (bh) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:455; or

[0118] (bi) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:456; or

[0119] (bj) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:439, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:445; or

[0120] (bk) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:439, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:469; or

[0121] (bl) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:439, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:470; or

[0122] (bm) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:439, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:471.

[0123] In some embodiments, the antigen-binding molecule is a multispecific antigen-binding molecule, and wherein the antigen-binding molecule further comprises an antigen-binding domain which binds to an antigen other than gp130.

[0124] The present disclosure also provides a chimeric antigen receptor (CAR) comprising an antigen-binding molecule according to the present disclosure.

[0125] The present disclosure also provides a nucleic acid, or a plurality of nucleic acids, optionally isolated, encoding an antigen-binding molecule or a CAR according to the present disclosure.

[0126] The present disclosure also provides an expression vector, or a plurality of expression vectors, comprising a nucleic acid or a plurality of nucleic acids according to the present disclosure.

[0127] The present disclosure also provides a cell comprising an antigen-binding molecule, a CAR, a nucleic acid or a plurality of nucleic acids, or an expression vector or a plurality of expression vectors according to the present disclosure.

[0128] The present disclosure also provides a method comprising culturing a cell according to the present disclosure under conditions suitable for expression of an antigen-binding molecule or CAR by the cell.

[0129] The present disclosure also provides a composition comprising an antigen-binding molecule, a CAR, a nucleic acid or a plurality of nucleic acids, an expression vector or a plurality of expression vectors, or a cell according to the present disclosure, and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

[0130] The present disclosure also provides an antigen-binding molecule, a CAR, a nucleic acid or a plurality of nucleic acids, an expression vector or a plurality of expression vectors, a cell , or a composition according to the present disclosure, for use in a method of medical treatment or prophylaxis.

[0131] The present disclosure also provides an antigen-binding molecule, a CAR, a nucleic acid or a plurality of nucleic acids, an expression vector or a plurality of expression vectors, a cell , or a composition according to the present disclosure, for use in a method of treatment or prevention of: pathological inflammation, fibrosis, a disease / condition characterised by inflammation, a disease / condition characterised by fibrosis, a disease / condition characterised by inflammation and fibrosis, a disease / condition in which signalling through a gp130-containing complex is pathologically-implicated, a disease / condition in which a cytokine that signals through a gp130-containing complex is pathologically-implicated, an autoimmune disease, metabolic syndrome, a neurodegenerative disease, a chronic inflammatory disease, arthritis, rheumatoid arthritis, juvenile arthritis, systemic juvenile idiopathic arthritis, lupus, systemic lupus erythematosus, pancreatitis, thyroiditis, periodontitis, rhinitis, allergic rhinitis, dermatitis, dermatitis, atopic dermatitis, psoriasis, Hermansky-Pudlak syndrome, Graves' disease, obesity, insulin resistance, diabetes, type 1 diabetes, type 2 diabetes, pregnancy-associated hyperglycemia, multiple sclerosis, giant cell arteritis, Takayasu arteritis, cardiovascular disease, atherosclerosis, atrial fibrillation, ventricular fibrillation, cardiac hypertrophy, hypertrophic cardiomyopathy, dilated cardiomyopathy, myocarditis, cardiogenic shock, heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, ischemic heart disease, myocardial infarction, Marfan syndrome, systemic sclerosis, keloid, scleroderma, Alzheimer’s disease, Parkinson's disease, Huntington’s disease, amyotrophic lateral sclerosis, hippocampal atrophy, pulmonary disease, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, hepatitis, liver fibrosis, cirrhosis, hepatotoxicity, acetaminophen-induced hepatotoxicity, alcoholic liver disease, pancreatitis, steatosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, cholestasis, primary biliary cholangitis, primary sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, colitis, ulcerative colitis, endometriosis, stroke, ischemic stroke, nephropathy, kidney injury, acute kidney injury, nephrotoxicity, glomerulonephritis, chronic kidney disease, kidney fibrosis, Alport syndrome, adult-onset Still’s disease, Castleman’s disease, cytokine release syndrome, sepsis, septic shock, a retinal disorder, retinal fibrosis, age-related macular degeneration, wet age-related macular degeneration, retinitis pigmentosa, dry eye syndrome, COVID-19, Peutz-Jeghers syndrome, a skeletal muscle disorder, muscular dystrophy, amyotrophy, cachexia, an endocrine disorder, polycystic ovary syndrome, a cancer, a hematologic malignancy, leukemia, plasmacytoma, Hodgkin’s lymphoma, lung cancer, colorectal cancer, intestinal cancer, urinary cancer, bladder cancer, vulvar cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, bone cancer, glioblastoma, breast cancer, stomach cancer, renal cancer, metastatic renal cell cancer, prostate cancer, skin cancer, melanoma, liver cancer, hepatocellular carcinoma, frailty, age-related increase in fat mass, sarcopenia, age-related hyperlipidaemia, age-related hypertriglyceridemia, age- related hypercholesterolemia, age-related liver steatosis, age-related non-alcoholic fatty liver disease, age-related non-alcoholic fatty liver, age-related non-alcoholic steatohepatitis, age-related cardiovascular disease, age-related hypertension, age-related renal disease, age-related skin disease, an infectious disease, a viral disease, viral hepatitis, hepatitis B, HIV infection, influenza infection, malaria, tuberculosis, an allergic disease, transplant rejection and graft-versus-host disease.

[0132] The present disclosure also provides an in vitro complex, optionally isolated, comprising an antigenbinding molecule according to the present disclosure bound to gp130.

[0133] The present disclosure also provides a method for detecting gp130 in a sample, comprising contacting a sample containing, or suspected to contain, gp130 with an antigen-binding molecule according to the present disclosure, and detecting the formation of a complex of the antigen-binding molecule with gp130.

[0134] The present disclosure also provides a method of selecting or stratifying a subject for treatment with a gp130-targeted agent, the method comprising contacting, in vitro, a sample from the subject with an antigen-binding molecule according to the present disclosure, and detecting the formation of a complex of the antigen-binding molecule with gp130.

[0135] The present disclosure also provides use of an antigen-binding molecule according to the present disclosure as an in vitro or in vivo diagnostic or prognostic agent.

[0136] Description

[0137] The present disclosure provides antigen-binding molecules that bind to gp130, having novel biophysical and / or functional properties as compared to antigen-binding molecules disclosed in the prior art.

[0138] In particular, the present disclosure is concerned with gp130-binding antigen-binding molecules that inhibit signalling mediated by IL-6 / gp130:IL-6Ra and IL-11 / gp130:IL-11 Ra, but which do not inhibit signalling mediated by other IL-6 family cytokines or other cytokine receptor complexes comprising gp130. That is, the present disclosure is concerned in particular with gp130-binding antigen-binding molecules that inhibit signalling mediated by IL-6 / gp130:IL-6Ra and IL-11 / gp130:IL-11 Ra only.

[0139] The antigen-binding molecules of the present disclosure are useful to inhibit signalling mediated by the pro-fibroinflammatory IL-6 / gp130:IL-6Ra and IL-11 / gp130: IL-11 Ra signalling axes, without substantial inhibition of signalling mediated by other IL-6 family cytokines.

[0140] The gp130-containing receptor complexes responsible for transducing IL-11- and IL-6-mediated signalling are formed of a heteromer comprising gp130 and IL-11 Ra or IL-6Ra molecules. By contrast, the gp130- containing receptor complexes responsible for transducing signalling mediated by OSM, LIF, CNTF, CT- 1 , CLC, IL-27 and IL-35 comprise a single gp130 molecule. Without wishing to be bound by any particular theory, the antigen-binding molecules of the present disclosure may selectively inhibit signalling mediated by IL-6 / gp130:IL-6Ra and I L-11 Zg p130:l L-11 Ra through inhibiting formation of a gp130-containing receptor complex comprising more than one gp130 molecule.

[0141] The gp130-binding antigen-binding molecules that inhibit signalling mediated by IL-6 / gp130:IL-6Ra and IL-11 / gp130:IL-11Ra according to the present disclosure are moreover shown to bind to the membrane- proximal region of gp130.

[0142] Prior to the present disclosure, it was not appreciated that it would be possible to obtain antigen-binding molecules that are able to inhibit signalling mediated by IL-6 / gp130:IL-6Ra and IL-11 / gp130JL-11 Ra (and that do not inhibit signalling mediated by other IL-6 family cytokines or other cytokine receptor complexes comprising gp130). Certainly, it was not clear that it would be possible to selectively inhibit signalling mediated by IL-6 / gp130:IL-6Ra and IL-11 / gp130:IL-11 Ra through targeting the membrane-proximal region of gp130. qp130

[0143] Human gp130 (also known as IL6ST, CD130) is the protein identified by UniProt P40189. The structure and function of gp130 is described e.g. in Silver and Hunter, J Leukoc Biol. (2010) 88(6):1145-1156 and Rose-John, Cold Spring Harb Perspect Biol. (2018) 10(2):a028415, which are hereby incorporated by reference in their entirety.

[0144] The canonical isoform of human gp130 (isoform 1) has the amino acid sequence shown in SEQ ID NO:129. Alternative splicing of mRNA encoded by the human IL6ST gene yields three main gp130 isoforms: isoform 1 (SEQ ID NO:129), isoform 2 (also known as gp130-RAPS; SEQ ID NQ:130) and isoform 3 (SEQ ID NO:131). Isoform 2 differs from isoform 1 in that positions 325 to 329 of SEQ ID NO:129 are different, and positions 330-918 are absent. Positions 423 to 483 of SEQ ID NO:129 are absent from isoform 3.

[0145] The canonical isoform of human gp130 comprises an N-terminal signal peptide (SEQ ID NO:132), followed by an extracellular domain (SEQ ID NO:134), a single-pass transmembrane domain (SEQ ID NO: 135) and a cytoplasmic domain (SEQ ID NO: 136) at the C-terminus. The mature form of human gp130 isoform 1 is shown in SEQ ID NO:133.

[0146] The extracellular domain comprises an N-terminal Ig-like C2-type domain (SEQ ID NO:137), followed by five fibronectin type III (FNIII) domains (shown in SEQ ID NOs:138, 139, 141 , 142 and 143, respectively). The cytokine-binding module (CBM) of gp130 is formed by the Ig-like C2-type domain, and FNIII domains 1 and 2 (SEQ ID NO:144). FNIII domain 2 comprises the WSXWS motif shown in SEQ ID NO:140.

[0147] WSXWS motifs are conserved among type I cytokine receptor polypeptides, and the WSXWS motif of gp130 is thought to be important for cytokine binding. gp130 is a constituent polypeptide of all receptors in the IL-6 receptor family, providing for signal transduction. Two gp130 polypeptides associate with two IL-6Ra polypeptides to form the receptor for IL- 6, and similarly two gp130 polypeptides associate with two IL-11 Ra polypeptides to form the receptor for IL-11. gp130 associates with OSMRp to form the type II receptor for OSM, or with LIFRp to form the type I receptor for OSM, which also serves as a receptor for LIF and CT-1 . gp130 also associates with LIFRp and CNTFRa to form the receptor for CNTF and CLC. gp130 associates with IL-27Ra to form the receptor for IL-27, and associates with I L-12Rp2 to form the receptor for IL-35.

[0148] Following the formation of complexes with its receptor interaction partner(s) and cognate ligand, gp130 is phosphorylated at tyrosine residues in its cytoplasmic domain (particularly Y767, Y814, Y905 and Y915), triggering downstream signalling through the JAK / STAT and MAPK / ERK signal transduction pathways. gp130 can also trigger signalling through PI3K / AKT. Receptor engagement leads to phosphorylation and activation of JAK1 and JAK2, which then phosphorylate STAT1 , STAT3 and STAT5. Phosphorylation of gp130 tyrosine residues also results in the recruitment and activation of SHP2, which in turn activates signalling through the Ras-ERK1 / ERK2 MAPK and PI3K / AKT signalling pathways.

[0149] In this specification ‘gp130’ refers to gp130 from any species, and includes isoforms, fragments, variants or homologues from any species. In some embodiments gp130 is gp130 from a mammal (e.g. a therian, placental, epitherian, preptotheria, archontan, primate (rhesus, cynomolgous, non-human primate or human)). In some embodiments, the gp130 is human gp130, rhesus gp130, mouse gp130, rat gp130 or canine gp130. In some embodiments, the gp130 is human gp130 or mouse gp130.

[0150] As used herein, isoforms, fragments, variants or homologues of a given reference protein (e.g. gp130) may be characterised as having at least 70% sequence identity, preferably one of >80%, >85%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100% amino acid sequence identity to the amino acid sequence of the reference protein.

[0151] A fragment’ generally refers to a fraction of the reference protein. A ‘variant’ generally refers to a protein having an amino acid sequence comprising one or more amino acid substitutions, insertions, deletions or other modifications relative to the amino acid sequence of the reference protein, but retaining a considerable degree of sequence identity (e.g. at least 60%) to the amino acid sequence of the reference protein. An ‘isoform’ generally refers to a variant of the reference protein expressed by the same species as the species of the reference protein. A ‘homologue’ generally refers to a variant of the reference protein produced by a different species as compared to the species of the reference protein. Homologues include orthologues. Homologues of human gp130 include e.g. mouse gp130 (UniProt Q00560) and rat gp130 (UniProt P40190).

[0152] Isoforms, fragments, variants or homologues of a given reference protein may optionally be characterised as having at least 70%, preferably one of >80%, >85%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100% amino acid sequence identity to the amino acid sequence of an immature or mature (i.e. after processing to remove signal peptide) form of a specified isoform of the relevant protein from a given species, e.g. human.

[0153] Isoforms, fragments, variants or homologues of gp130 according to the present disclosure may optionally be characterised as having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of an immature or mature gp130 isoform from a given species, e.g. human.

[0154] Isoforms, fragments, variants or homologues may optionally be functional isoforms, fragments, variants or homologues, e.g. having a functional property / activity of the reference gp130 (e.g. human gp130 isoform 1), as determined by analysis by a suitable assay for the functional property / activity. For example, an isoform, fragment, variant or homologue of gp130 may association with IL-6Ra, IL-11 Ra, OSMRp, LIFRp and / or CNTFRa.

[0155] In some embodiments, the gp130 comprises, or consists of, an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:129, 130 or 131 .

[0156] In some embodiments, the gp130 comprises, or consists of, an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:129 or 133. A ‘fragment’ of a reference protein may be of any length (by number of amino acids), although may optionally be at least 25% of the length of the reference protein (that is, the protein from which the fragment is derived) and may have a maximum length of one of 50%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the length of the reference protein.

[0157] A fragment of gp130 may have a minimum length of one of 10, 20, 30, 40, 50, 100, 150, 200, 300, 400, 500, 600, 700, 800 or 900 amino acids, and may have a maximum length of one of 20, 30, 40, 50, 100, 150, 200, 300, 400, 500, 600, 700, 800 or 900 amino acids.

[0158] In some embodiments, a fragment of gp130 comprises, or consists of, an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:133.

[0159] In some embodiments, a fragment of gp130 comprises, or consists of, an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:134.

[0160] In some embodiments, a fragment of gp130 comprises, or consists of, an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:144.

[0161] In this specification ‘gp130-mediated signalling’ refers to signalling mediated by gp130 and / or multimeric receptor complexes comprising gp130 (e.g. comprising gp130 and another member of the IL-6 receptor family). ‘Signalling’ refers to signal transduction and other cellular processes governing cellular activity. gp130-mediated signalling may be mediated by a gp130-containing polypeptide complex (i.e. a polypeptide complex comprising one or more gp130 polypeptides). Polypeptide complexes according to the present disclosure may be characterised by non-covalent, protein: protein interaction between constituent polypeptide(s) / peptide(s). In some embodiments, the association comprises electrostatic interaction (e.g. ionic bonding, hydrogen bonding) and / or Van der Waals forces. gp130-mediated signalling may be mediated by heteromultimeric polypeptide complexes comprising one or more gp130 polypeptides, and additionally comprising one or more polypeptides of one or more polypeptides of the IL-6 receptor family (e.g. selected from IL-6Ra, IL-11 Ra, OSMRp, LIFRp, CNTFRa, IL-27Ra and IL-12Rp2).

[0162] In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex forming a receptor for an IL-6 family cytokine. For example, gp130-mediated signalling may be mediated by a polypeptide complex forming a receptor for IL-6, IL-11 , OSM, LIF, CNTF, CT-1 , CLC, IL-27 or IL-35. In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130 and another polypeptide of the IL-6 receptor family (e.g. selected from IL-6Ra, IL-11 Ra, OSMRp, LIFRp, CNTFRa, IL-27Ra and IL-12Rp2). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130 and IL-6Ra ( / .e. a gp130:IL-6Ra complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130 and IL-11 Rci (i.e. a gp130:IL-11 Ra complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130 and OSMRp (i.e. a gp130:OSMRp complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130 and LIFRp (i.e. a gp130:LIFRp complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130, LIFRp and CNTFRa (i.e. a gp130:LIFRp:CNTFRa complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130 and IL-27Ra (i.e. a gp130:IL-27Ra complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130 and I L-12Rp2 (i.e. a gp130:IL-12Rp2 complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising more than one gp130 polypeptide. In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising two gp130 polypeptides. In some embodiments gp130-mediated signalling may be mediated by a polypeptide complex comprising two gp130 polypeptides and IL-6Ra (i.e. a gp130:gp130:IL-6Ra complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising two gp130 polypeptides and IL-11 Ra (i.e. a gp130:gp130:IL-11 Ra complex). gp130-mediated signalling through the polypeptide complexes described in the preceding paragraph may be triggered by binding of their cognate cytokine(s). That is, in some embodiments, gp130-mediated signalling through a polypeptide complex comprising (i) gp130 and (ii) another polypeptide of the IL-6 receptor family may be triggered by binding of a cytokine to the polypeptide complex formed by proteinprotein interaction between (i) and (ii). In some embodiments, gp130-mediated signalling is triggered by binding of IL-6 to a polypeptide complex comprising gp130 and IL-6Ra (i.e. a gp130:IL-6Ra complex). In some embodiments, gp130-mediated signalling is triggered by binding of IL-1 1 to a polypeptide complex comprising gp130 and IL-11 Ra (i.e. a gp130JL-11 Ra complex). In some embodiments, gp130-mediated signalling is triggered by binding of OSM to a polypeptide complex comprising gp130 and OSMRp (i.e. a gp130:OSMRp complex). In some embodiments, gp130-mediated signalling is triggered by binding of OSM, LIF or CT-1 to a polypeptide complex comprising gp130 and LIFRp (i.e. a gp130:LIFRp complex). In some embodiments, gp130-mediated signalling is triggered by binding of CNTF or CLC to a polypeptide complex comprising gp130, LIFRP and CNTFRa (i.e. a gp130:LIFRp:CNTFRa complex). In some embodiments, gp130-mediated signalling is triggered by binding of IL-27 to a polypeptide complex comprising gp130 and IL-27Ra (i.e. a gp130:IL-27Ra complex). In some embodiments, gp130-mediated signalling is triggered by binding of IL-35 to a polypeptide complex comprising gp130 and IL-12Rp2 (i.e. a gp130:IL-12Rp2 complex). Antigen-binding molecules

[0163] The present disclosure provides antigen-binding molecules capable of binding to gp130. An antigenbinding molecule that is capable of binding to gp130 may also be described as an antigen-binding molecule that binds to gp130.

[0164] An ‘antigen-binding molecule’ refers to a molecule that binds to a given target antigen. Antigen-binding molecules include antibodies (i.e. immunoglobulins (Igs)) and antigen-binding fragments thereof. As used herein, antibodies’ include monoclonal antibodies, polyclonal antibodies, monospecific and multispecific (e.g., bispecific, trispecific, etc.) antibodies, and antibody-derived antigen-binding molecules such as scFv, scFab, diabodies, triabodies, scFv-Fc, minibodies, single domain antibodies (e.g. VhH), etc. Antigen-binding fragments of antibodies include e.g. Fv, Fab, F(ab’)2 and F(ab’) fragments. In some embodiments, an antigen-binding molecule may be an antibody or an antigen-binding fragment thereof.

[0165] Antigen-binding molecules according to the present disclosure also include antibody-derived molecules, e.g. molecules comprising an antigen-binding region / domain derived from an antibody. Antibody-derived antigen-binding molecules may comprise an antigen-binding region / domain that comprises, or consists of, the antigen-binding region of an antibody (e.g. an antigen-binding fragment of an antibody). In some embodiments, the antigen-binding region / domain of an antibody-derived antigen-binding molecule may be or comprise the Fv (e.g. provided as an scFv) or the Fab region of an antibody, or the whole antibody. For example, antigen-binding molecules according to the present disclosure include antibody-drug conjugates (ADCs) comprising a (cytotoxic) drug moiety (e.g. as described hereinbelow). Antigen-binding molecules according to the present disclosure also include multispecific antigen-binding molecules such as immune cell engager molecules comprising a domain for recruiting (effector) immune cells (reviewed e.g. in Goebeler and Bargou, Nat. Rev. Clin. Oncol. (2020) 17: 418-434 and Ellerman, Methods (2019) 154:102-117, both of which are hereby incorporated by reference in their entirety), including BiTEs, BiKEs and TriKEs. Antigen-binding molecules according to the present disclosure also include chimeric antigen receptors (CARs), which are recombinant receptors providing both antigen-binding and T cell activating functions (CAR structure, function and engineering is reviewed e.g. in Dotti et al., Immunol Rev (2014) 257(1) and Jayaraman et al., EBioMedicine (2020) 58:102931 , both of which are hereby incorporated by reference in their entirety).

[0166] The antigen-binding molecule of the present disclosure comprises a moiety or moieties capable of binding to a target antigen(s). In some embodiments, the moiety capable of binding to a target antigen comprises an antibody heavy chain variable region (VH) and an antibody light chain variable region (VL) of an antibody capable of specific binding to the target antigen. In some embodiments, the moiety capable of binding to a target antigen comprises or consists of an aptamer capable of binding to the target antigen, e.g. a nucleic acid aptamer (reviewed, for example, in Zhou and Rossi Nat Rev Drug Discov. 2017 16(3) : 181 -202) . In some embodiments, the moiety capable of binding to a target antigen comprises or consists of an antigen-binding peptide / polypeptide, e.g. a peptide aptamer, thioredoxin, monobody, anticalin, Kunitz domain, avimer, knottin, tynomer, atrimer, DARPin, affibody, nanobody (i.e. a singledomain antibody (sdAb)), affilin, armadillo repeat protein (ArmRP), OBody or fibronectin - reviewed e.g. in Reverdatto et al., Curr Top Med Chem. 2015; 15(12): 1082-1101 , which is hereby incorporated by reference in its entirety (see also e.g. Boersma et al., J Biol Chem (201 1) 286:41273-85 and Emanuel et al., Mabs (2011) 3:38-48).

[0167] As used herein, a ‘peptide’ refers to a chain of two or more amino acid monomers linked by peptide bonds. A peptide typically has a length in the region of about 2 to 50 amino acids. A ‘polypeptide’ is a polymer chain of two or more peptides. Polypeptides typically have a length greater than about 50 amino acids.

[0168] The antigen-binding molecules of the present disclosure generally comprise an antigen-binding domain comprising a VH and a VL of an antibody capable of specific binding to the target antigen. The antigenbinding domain formed by a VH and a VL may also be referred to herein as an Fv region.

[0169] An antigen-binding molecule may be, or may comprise, an antigen-binding polypeptide, or an antigenbinding polypeptide complex. An antigen-binding molecule may comprise more than one polypeptide which together form an antigen-binding domain. The polypeptides may associate covalently or non- covalently. In some embodiments, the polypeptides form part of a larger polypeptide comprising the polypeptides (e.g. in the case of scFv comprising VH and VL, or in the case of scFab comprising VH-CH1 and VL-CL).

[0170] An antigen-binding molecule may refer to a non-covalent or covalent complex of more than one polypeptide (e.g. 2, 3, 4, 6, or 8 polypeptides), e.g. an IgG-like antigen-binding molecule comprising two heavy chain polypeptides and two light chain polypeptides.

[0171] The antigen-binding molecules of the present disclosure may be designed and prepared using the sequences of monoclonal antibodies (mAbs) capable of binding to gp130. Antigen-binding regions of antibodies, such as single chain variable fragment (scFv), Fab and F(ab’)2 fragments may also be used / provided. An ‘antigen-binding region’ is any fragment of an antibody that binds to the target for which the given antibody is specific.

[0172] Antibodies generally comprise six complementarity-determining regions CDRs; three in the heavy chain variable (VH) region: HC-CDR1 , HC-CDR2 and HC-CDR3, and three in the light chain variable (VL) region: LC-CDR1 , LC-CDR2, and LC-CDR3. The six CDRs together define the paratope of the antibody, which is the part of the antibody that binds to the target antigen.

[0173] The VH region and VL region comprise framework regions (FRs) either side of each CDR, which provide a scaffold for the CDRs. From N-terminus to C-terminus, VH regions comprise the following structure: N term-[HC-FR1]-[HC-CDR1]-[HC-FR2]-[HC-CDR2]-[HC-FR3]-[HC-CDR3]-[HC-FR4]-C term; and VL regions comprise the following structure: N term-[LC-FR1]-[LC-CDR1]-[LC-FR2]-[LC-CDR2]-[LC-FR3]- [LC-CDR3]-[LC-FR4]-C term.

[0174] There are several different conventions for defining antibody CDRs and FRs, such as those described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991), Chothia et al., J. Mol. Biol. 196:901-917 (1987), and VBASE2, as described in Retter et al., Nucl. Acids Res. (2005) 33 (suppl 1): D671-D674. The CDRs and FRs of the VH regions and VL regions of the antibody clones described herein were defined according to the international IMGT (ImMunoGeneTics) information system (LeFranc et al., Nucleic Acids Res. (2015) 43 (Database issue):D413-22), which uses the IMGT V-DOMAIN numbering rules as described in Lefranc et al., Dev. Comp. Immunol. (2003) 27:55-77. In preferred embodiments, the CDRs and FRs of antigenbinding molecules referred to herein are defined according to the IMGT information system.

[0175] In some embodiments, the antigen-binding molecule comprises the CDRs of an antigen-binding molecule that binds to gp130. In some embodiments, the antigen-binding molecule comprises the FRs of an antigen-binding molecule that binds to gp130. In some embodiments, the antigen-binding molecule comprises the CDRs and the FRs of an antigen-binding molecule that binds to gp130. That is, in some embodiments, the antigen-binding molecule comprises the VH region and the VL region of an antigenbinding molecule that binds to gp130.

[0176] In some embodiments, the antigen-binding molecule comprises the CDRs, FRs and / or the VH and / or VL regions of a gp130-binding antibody described herein, or CDRs, FRs and / or VH and / or VL regions which are derived from those of a gp130-binding antibody described herein. In some embodiments, a gp130- binding antibody is selected from an antibody of Table C herein.

[0177] In some embodiments, a gp130-binding antibody is selected from: 4D4 / 4D4, 4D4_W33var / 4D4, 4D4_M34var / 4D4, 4D4_W33var_M34var / 4D4, 4D4_M34Y / 4D4, 4D4CVH2_D53E / 4D4GVL3_N93G, 4D4CVH2_W33var_D53E / 4D4GVL3_N93G, 4D4CVH2_M34var_D53E / 4D4GVL3_N93G, 4D4CVH2_W33var_M34var_D53E / 4D4GVL3_N93G, 4D4CVH2_M34Y_D53E / 4D4GVL3_N93G, 4D4CVH2.2_D53E / 4D4GVL3_N93G, 4D4CVH2.2_W33var_D53E / 4D4GVL3_N93G, 4D4CVH2.2_M34var_D53E / 4D4GVL3_N93G, 4D4CVH2.2_W33var_M34var_D53E / 4D4GVL3_N93G, 4D4CVH2.2_M34Y_D53E / 4D4GVL3_N93G, CON4D4CVH2 / CVH2.2_D53E / 4D4GVL3_N93G, CON4D4CVH2 / CVH2.2_W33var_D53E / 4D4GVL3_N93G, CON4D4CVH2 / CVH2.2_M34var_D53E / 4D4GVL3_N93G, CON4D4CVH2 / CVH2.2_W33var_M34var_D53E / 4D4GVL3_N93G, CON4D4CVH2 / CVH2.2_M34Y_D53E / 4D4GVL3_N93G, 8C6 / 8C6, 8C6CVH2.1 / 8C6CVL2, 8C6CVH2.1 / 8C6CVL3, 8C6CVH2.1 / 8C6CVL5, 8C6GVH4.1 / 8C6CVL2, 8C6GVH4.1 / 8C6CVL3, 8C6GVH4.1 / 8C6CVL5, 8C6GVH5.1 / 8C6CVL2, 8C6GVH5.1 / 8C6CVL3, 8C6GVH5.1 / 8C6CVL5, 8C6 / 8C6_D94var, 8C6 / 8C6_P95var, 8C6 / 8C6_D94var_P95var, 8C6CVH2.1 / 8C6CVL2_D94var, 8C6CVH2.1 / 8C6CVL2_P95var, 8C6CVH2.1 / 8C6CVL2_D94var_P95var, 8C6CVH2.1 / 8C6CVL3_D94var, 8C6CVH2.1 / 8C6CVL3_P95var, 8C6CVH2.1 / 8C6CVL3_D94var_P95var, 8C6CVH2.1 / 8C6CVL5_D94var, 8C6CVH2.1 / 8C6CVL5_P95var, 8C6CVH2.1 / 8C6CVL5_D94var_P95var, 8C6GVH4.1 / 8C6CVL2_D94var, 8C6GVH4.1 / 8C6CVL2_P95var, 8C6GVH4.1 / 8C6CVL2_D94var_P95var, 8C6GVH4.1 / 8C6CVL3_D94var, 8C6GVH4.1 / 8C6CVL3_P95var, 8C6GVH4.1 / 8C6CVL3_D94var_P95var, 8C6GVH4.1 / 8C6CVL5_D94var, 8C6GVH4.1 / 8C6CVL5_P95var, 8C6GVH4.1 / 8C6CVL5_D94var_P95var, 8C6GVH5.1 / 8C6CVL2_D94var, 8C6GVH5.1 / 8C6CVL2_P95var, 8C6GVH5.1 / 8C6CVL2_D94var_P95var, 8C6GVH5.1 / 8C6CVL3_D94var, 8C6GVH5.1 / 8C6CVL3_P95var, 8C6GVH5.1 / 8C6CVL3_D94var_P95var, 8C6GVH5.1 / 8C6CVL5_D94var, 8C6GVH5.1 / 8C6CVL5_P95var, 8C6GVH5.1 / 8C6CVL5_D94var_P95var, CON8C6H11, CON8C6Hu_D94var, CON8C6Hu_P95var, and CON8C6Hu_D94var_P95var.

[0178] In some embodiments, a gp130-binding antibody is selected from: 4D4_W33var / 4D4, 4D4_M34var / 4D4, 4D4_W33var_M34var / 4D4, 4D4_M34Y / 4D4, 4D4CVH2_W33var_D53E / 4D4GVL3_N93G, 4D4CVH2_M34var_D53E / 4D4GVL3_N93G, 4D4CVH2_W33var_M34var_D53E / 4D4GVL3_N93G, 4D4CVH2_M34Y_D53E / 4D4GVL3_N93G, 4D4CVH2.2_W33var_D53E / 4D4GVL3_N93G, 4D4CVH2.2_M34var_D53E / 4D4GVL3_N93G, 4D4CVH2.2_W33var_M34var_D53E / 4D4GVL3_N93G, 4D4CVH2.2 M34Y D53E / 4D4GVL3 N93G, CON4D4CVH2 / CVH2.2_W33var_D53E / 4D4GVL3_N93G, CON4D4CVH2 / CVH2.2_M34var_D53E / 4D4GVL3_N93G, CON4D4CVH2 / CVH2.2_W33var_M34var_D53E / 4D4GVL3_N93G, CON4D4CVH2 / CVH2.2_M34Y_D53E / 4D4GVL3_N93G, 8C6CVH2.1 / 8C6CVL2, 8C6CVH2.1 / 8C6CVL3, 8C6CVH2.1 / 8C6CVL5, 8C6GVH4.1 / 8C6CVL2, 8C6GVH4.1 / 8C6CVL3, 8C6GVH4.1 / 8C6CVL5, 8C6GVH5.1 / 8C6CVL2, 8C6GVH5.1 / 8C6CVL3, 8C6GVH5.1 / 8C6CVL5, 8C6 / 8C6_D94var, 8C6 / 8C6_P95var, 8C6 / 8C6_D94var_P95var, 8C6CVH2.1 / 8C6CVL2_D94var, 8C6CVH2.1 / 8C6CVL2_P95var, 8C6CVH2.1 / 8C6CVL2_D94var_P95var, 8C6CVH2.1 / 8C6CVL3_D94var, 8C6CVH2.1 / 8C6CVL3_P95var, 8C6CVH2.1 / 8C6CVL3_D94var_P95var, 8C6CVH2.1 / 8C6CVL5_D94var, 8C6CVH2.1 / 8C6CVL5_P95var, 8C6CVH2.1 / 8C6CVL5_D94var_P95var, 8C6GVH4.1 / 8C6CVL2_D94var, 8C6GVH4.1 / 8C6CVL2_P95var, 8C6GVH4.1 / 8C6CVL2_D94var_P95var, 8C6GVH4.1 / 8C6CVL3_D94var, 8C6GVH4.1 / 8C6CVL3_P95var, 8C6GVH4.1 / 8C6OVL3_D94var_P95var, 8C6GVH4.1 / 8C6CVL5_D94var, 8C6GVH4.1 / 8C6CVL5_P95var, 8C6GVH4.1 / 8C6CVL5_D94var_P95var, 8C6GVH5.1 / 8C6CVL2_D94var, 8C6GVH5.1 / 8C6CVL2_P95var, 8C6GVH5.1 / 8C6CVL2_D94var_P95var, 8C6GVH5.1 / 8C6CVL3_D94var, 8C6GVH5.1 / 8C6CVL3_P95var, 8C6GVH5.1 / 8C6CVL3_D94var_P95var, 8C6GVH5.1 / 8C6CVL5_D94var, 8C6GVH5.1 / 8C6CVL5_P95var, 8C6GVH5.1 / 8C6CVL5_D94var_P95var, CON8C6H11, CON8C6Hu_D94var, CON8C6Hu_P95var, and CON8C6Hu_D94var_P95var.

[0179] In some embodiments, a gp130-binding antibody is selected from: 4D4 / 4D4, 4D4CVH2_D53E / 4D4GVL3_N93G, 4D4CVH2.2_D53E / 4D4GVL3_N93G, 4D4CVH2.2_M34Y_D53E / 4D4GVL3_N93G, 8C6 / 8C6, 8C6CVH2.1 / 8C6CVL2, 8C6CVH2.1 / 8C6CVL3, 8C6CVH2.1 / 8C6CVL5, 8C6GVH4.1 / 8C6CVL5, 8C6GVH5.1 / 8C6CVL3, and 8C6GVH5.1 / 8C6CVL5.

[0180] In some embodiments, a gp130-binding antibody is selected from: 4D4CVH2.2_M34Y_D53E / 4D4GVL3_N93G, 8C6CVH2.1 / 8C6CVL2, 8C6CVH2.1 / 8C6CVL3, 8C6CVH2.1 / 8C6CVL5, 8C6GVH4.1 / 8C6CVL5, 8C6GVH5.1 / 8C6CVL3, and 8C6GVH5.1 / 8C6CVL5.

[0181] In some embodiments, the antigen-binding molecule comprises a VH region according to one of: (1) a VH region incorporating the following CDRs:

[0182] HC-CDR1 having the amino acid sequence of SEQ ID NO:62 HC-CDR2 having the amino acid sequence of SEQ ID NO:63 HC-CDR3 having the amino acid sequence of SEQ ID NO:64, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0183] (2) a VH region incorporating the following CDRs:

[0184] HC-CDR1 having the amino acid sequence of SEQ ID NO:2

[0185] HC-CDR2 having the amino acid sequence of SEQ ID NO:249

[0186] HC-CDR3 having the amino acid sequence of SEQ ID NO:4, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0187] (3) a VH region incorporating the following CDRs:

[0188] HC-CDR1 having the amino acid sequence of SEQ ID NO:2

[0189] HC-CDR2 having the amino acid sequence of SEQ ID NO:3

[0190] HC-CDR3 having the amino acid sequence of SEQ ID NO:4, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0191] (4) a VH region incorporating the following CDRs:

[0192] HC-CDR1 having the amino acid sequence of SEQ ID NO:2

[0193] HC-CDR2 having the amino acid sequence of SEQ ID NO:244

[0194] HC-CDR3 having the amino acid sequence of SEQ ID NO:4, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0195] (5) a VH region incorporating the following CDRs:

[0196] HC-CDR1 having the amino acid sequence of SEQ ID NO:2

[0197] HC-CDR2 having the amino acid sequence of SEQ ID NO:245

[0198] HC-CDR3 having the amino acid sequence of SEQ ID NO:4, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0199] (6) a VH region incorporating the following CDRs:

[0200] HC-CDR1 having the amino acid sequence of SEQ ID NO:2

[0201] HC-CDR2 having the amino acid sequence of SEQ ID NO:246

[0202] HC-CDR3 having the amino acid sequence of SEQ ID NO:4, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0203] (7) a VH region incorporating the following CDRs:

[0204] HC-CDR1 having the amino acid sequence of SEQ ID NO:2

[0205] HC-CDR2 having the amino acid sequence of SEQ ID NO:247

[0206] HC-CDR3 having the amino acid sequence of SEQ ID NO:4, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0207] (8) a VH region incorporating the following CDRs:

[0208] HC-CDR1 having the amino acid sequence of SEQ ID NO:2

[0209] HC-CDR2 having the amino acid sequence of SEQ ID NO:248

[0210] HC-CDR3 having the amino acid sequence of SEQ ID NO:4, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0211] (9) a VH region incorporating the following CDRs:

[0212] HC-CDR1 having the amino acid sequence of SEQ ID NO:18

[0213] HC-CDR2 having the amino acid sequence of SEQ ID NO:19

[0214] HC-CDR3 having the amino acid sequence of SEQ ID NQ:20, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0215] (10) a VH region incorporating the following CDRs:

[0216] HC-CDR1 having the amino acid sequence of SEQ ID NO:18

[0217] HC-CDR2 having the amino acid sequence of SEQ ID NO:19

[0218] HC-CDR3 having the amino acid sequence of SEQ ID NO:32, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0219] (11) a VH region incorporating the following CDRs:

[0220] HC-CDR1 having the amino acid sequence of SEQ ID NO:37

[0221] HC-CDR2 having the amino acid sequence of SEQ ID NO:38

[0222] HC-CDR3 having the amino acid sequence of SEQ ID NO:39, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0223] (12) a VH region incorporating the following CDRs:

[0224] HC-CDR1 having the amino acid sequence of SEQ ID NO:52

[0225] HC-CDR2 having the amino acid sequence of SEQ ID NO:53

[0226] HC-CDR3 having the amino acid sequence of SEQ ID NO:54, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0227] (13) a VH region incorporating the following CDRs:

[0228] HC-CDR1 having the amino acid sequence of SEQ ID NQ:401

[0229] HC-CDR2 having the amino acid sequence of SEQ ID NO:3

[0230] HC-CDR3 having the amino acid sequence of SEQ ID NO:4, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0231] (14) a VH region incorporating the following CDRs:

[0232] HC-CDR1 having the amino acid sequence of SEQ ID NQ:401

[0233] HC-CDR2 having the amino acid sequence of SEQ ID NO:245

[0234] HC-CDR3 having the amino acid sequence of SEQ ID NO:4, or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 , and / or in which 1 or 2 or 3 amino acids in HC-CDR2, and / or in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid.

[0235] In some embodiments, the antigen-binding molecule comprises a VH region according to one of:

[0236] (15) a VH region incorporating the following FRs:

[0237] HC-FR1 having the amino acid sequence of SEQ ID NO:68

[0238] HC-FR2 having the amino acid sequence of SEQ ID NO:6

[0239] HC-FR3 having the amino acid sequence of SEQ ID NO:69

[0240] HC-FR4 having the amino acid sequence of SEQ ID NO:8, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0241] (16) a VH region incorporating the following FRs:

[0242] HC-FR1 having the amino acid sequence of SEQ ID NO:103

[0243] HC-FR2 having the amino acid sequence of SEQ ID NO:104

[0244] HC-FR3 having the amino acid sequence of SEQ ID NQ:105 HC-FR4 having the amino acid sequence of SEQ ID NO:79, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0245] (17) a VH region incorporating the following FRs:

[0246] HC-FR1 having the amino acid sequence of SEQ ID NO:76

[0247] HC-FR2 having the amino acid sequence of SEQ ID NO:6

[0248] HC-FR3 having the amino acid sequence of SEQ ID NO:77

[0249] HC-FR4 having the amino acid sequence of SEQ ID NO:79, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0250] (18) a VH region incorporating the following FRs:

[0251] HC-FR1 having the amino acid sequence of SEQ ID NO:76

[0252] HC-FR2 having the amino acid sequence of SEQ ID NO:81

[0253] HC-FR3 having the amino acid sequence of SEQ ID NO:82

[0254] HC-FR4 having the amino acid sequence of SEQ ID NO:79, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0255] (19) a VH region incorporating the following FRs:

[0256] HC-FR1 having the amino acid sequence of SEQ ID NO:84

[0257] HC-FR2 having the amino acid sequence of SEQ ID NO:81

[0258] HC-FR3 having the amino acid sequence of SEQ ID NO:85

[0259] HC-FR4 having the amino acid sequence of SEQ ID NO:79, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0260] (20) a VH region incorporating the following FRs:

[0261] HC-FR1 having the amino acid sequence of SEQ ID NO:76

[0262] HC-FR2 having the amino acid sequence of SEQ ID NO:81

[0263] HC-FR3 having the amino acid sequence of SEQ ID NO:77

[0264] HC-FR4 having the amino acid sequence of SEQ ID NO:79, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0265] (21) a VH region incorporating the following FRs: HC-FR1 having the amino acid sequence of SEQ ID NO:76

[0266] HC-FR2 having the amino acid sequence of SEQ ID NO:6

[0267] HC-FR3 having the amino acid sequence of SEQ ID NO:82

[0268] HC-FR4 having the amino acid sequence of SEQ ID NO:79, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0269] (22) a VH region incorporating the following FRs:

[0270] HC-FR1 having the amino acid sequence of SEQ ID NO:5

[0271] HC-FR2 having the amino acid sequence of SEQ ID NO:6

[0272] HC-FR3 having the amino acid sequence of SEQ ID NO:7

[0273] HC-FR4 having the amino acid sequence of SEQ ID NO:8, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0274] (23) a VH region incorporating the following FRs:

[0275] HC-FR1 having the amino acid sequence of SEQ ID NO:21

[0276] HC-FR2 having the amino acid sequence of SEQ ID NO:6

[0277] HC-FR3 having the amino acid sequence of SEQ ID NO:22

[0278] HC-FR4 having the amino acid sequence of SEQ ID NO:8, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0279] (24) a VH region incorporating the following FRs:

[0280] HC-FR1 having the amino acid sequence of SEQ ID NO:21

[0281] HC-FR2 having the amino acid sequence of SEQ ID NO:6

[0282] HC-FR3 having the amino acid sequence of SEQ ID NO:33

[0283] HC-FR4 having the amino acid sequence of SEQ ID NO:8, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0284] (25) a VH region incorporating the following FRs:

[0285] HC-FR1 having the amino acid sequence of SEQ ID NQ:40

[0286] HC-FR2 having the amino acid sequence of SEQ ID NO:41

[0287] HC-FR3 having the amino acid sequence of SEQ ID NO:42

[0288] HC-FR4 having the amino acid sequence of SEQ ID NO:43, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0289] (26) a VH region incorporating the following FRs:

[0290] HC-FR1 having the amino acid sequence of SEQ ID NO:55

[0291] HC-FR2 having the amino acid sequence of SEQ ID NO:41

[0292] HC-FR3 having the amino acid sequence of SEQ ID NO:56

[0293] HC-FR4 having the amino acid sequence of SEQ ID NO:43, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0294] (27) a VH region incorporating the following FRs:

[0295] HC-FR1 having the amino acid sequence of SEQ ID NO:5

[0296] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[0297] HC-FR3 having the amino acid sequence of SEQ ID NO:7

[0298] HC-FR4 having the amino acid sequence of SEQ ID NO:8, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0299] (28) a VH region incorporating the following FRs:

[0300] HC-FR1 having the amino acid sequence of SEQ ID NO:76

[0301] HC-FR2 having the amino acid sequence of SEQ ID NO:402

[0302] HC-FR3 having the amino acid sequence of SEQ ID NO:77

[0303] HC-FR4 having the amino acid sequence of SEQ ID NO:79, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0304] (29) a VH region incorporating the following FRs:

[0305] HC-FR1 having the amino acid sequence of SEQ ID NO:76

[0306] HC-FR2 having the amino acid sequence of SEQ ID NQ:402

[0307] HC-FR3 having the amino acid sequence of SEQ ID NO:82

[0308] HC-FR4 having the amino acid sequence of SEQ ID NO:79, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0309] (30) a VH region incorporating the following FRs:

[0310] HC-FR1 having the amino acid sequence of SEQ ID NO:76 HC-FR2 having the amino acid sequence of SEQ ID NO:6

[0311] HC-FR3 having the amino acid sequence of SEQ ID NO:390

[0312] HC-FR4 having the amino acid sequence of SEQ ID NO:79, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0313] (31) a VH region incorporating the following FRs:

[0314] HC-FR1 having the amino acid sequence of SEQ ID NO:76

[0315] HC-FR2 having the amino acid sequence of SEQ ID NO:402

[0316] HC-FR3 having the amino acid sequence of SEQ ID NQ:390

[0317] HC-FR4 having the amino acid sequence of SEQ ID NO:79, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0318] (32) a VH region incorporating the following FRs:

[0319] HC-FR1 having the amino acid sequence of SEQ ID NO:5

[0320] HC-FR2 having the amino acid sequence of SEQ ID NO:489

[0321] HC-FR3 having the amino acid sequence of SEQ ID NO:7

[0322] HC-FR4 having the amino acid sequence of SEQ ID NO:8, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0323] (33) a VH region incorporating the following FRs:

[0324] HC-FR1 having the amino acid sequence of SEQ ID NO:76

[0325] HC-FR2 having the amino acid sequence of SEQ ID NO:489

[0326] HC-FR3 having the amino acid sequence of SEQ ID NO:77

[0327] HC-FR4 having the amino acid sequence of SEQ ID NO:79, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0328] (34) a VH region incorporating the following FRs:

[0329] HC-FR1 having the amino acid sequence of SEQ ID NO:76

[0330] HC-FR2 having the amino acid sequence of SEQ ID NO:489

[0331] HC-FR3 having the amino acid sequence of SEQ ID NO:82

[0332] HC-FR4 having the amino acid sequence of SEQ ID NO:79, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid. (35) a VH region incorporating the following FRs:

[0333] HC-FR1 having the amino acid sequence of SEQ ID NO:76

[0334] HC-FR2 having the amino acid sequence of SEQ ID NO:489

[0335] HC-FR3 having the amino acid sequence of SEQ ID NO:390

[0336] HC-FR4 having the amino acid sequence of SEQ ID NO:79, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0337] (36) a VH region incorporating the following FRs:

[0338] HC-FR1 having the amino acid sequence of SEQ ID NQ:40

[0339] HC-FR2 having the amino acid sequence of SEQ ID NO:422

[0340] HC-FR3 having the amino acid sequence of SEQ ID NO:424

[0341] HC-FR4 having the amino acid sequence of SEQ ID NO: 43, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0342] (37) a VH region incorporating the following FRs:

[0343] HC-FR1 having the amino acid sequence of SEQ ID NO:421

[0344] HC-FR2 having the amino acid sequence of SEQ ID NO:422

[0345] HC-FR3 having the amino acid sequence of SEQ ID NO:425

[0346] HC-FR4 having the amino acid sequence of SEQ ID NO:79, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0347] (38) a VH region incorporating the following FRs:

[0348] HC-FR1 having the amino acid sequence of SEQ ID NO:421

[0349] HC-FR2 having the amino acid sequence of SEQ ID NO:423

[0350] HC-FR3 having the amino acid sequence of SEQ ID NO:426

[0351] HC-FR4 having the amino acid sequence of SEQ ID NO:79, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0352] (39) a VH region incorporating the following FRs:

[0353] HC-FR1 having the amino acid sequence of SEQ ID NQ:440

[0354] HC-FR2 having the amino acid sequence of SEQ ID NO:441

[0355] HC-FR3 having the amino acid sequence of SEQ ID NO:442

[0356] HC-FR4 having the amino acid sequence of SEQ ID NO:443, or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 , and / or in which 1 or 2 or 3 amino acids in HC-FR2, and / or in which 1 or 2 or 3 amino acids in HC-FR3, and / or in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid.

[0357] In some embodiments, the antigen-binding molecule comprises a VH region comprising the CDRs according to one of (1) to (14) above, and the FRs according to any one of (15) to (39) above.

[0358] In some embodiments, the antigen-binding molecule comprises a VH region according to one of:

[0359] (40) a VH region comprising the CDRs according to (1) and the FRs according to (15).

[0360] (41) a VH region comprising the CDRs according to (2) and the FRs according to (15).

[0361] (42) a VH region comprising the CDRs according to (3) and the FRs according to (16).

[0362] (43) a VH region comprising the CDRs according to (3) and the FRs according to (17).

[0363] (44) a VH region comprising the CDRs according to (3) and the FRs according to (18).

[0364] (45) a VH region comprising the CDRs according to (3) and the FRs according to (19).

[0365] (46) a VH region comprising the CDRs according to (3) and the FRs according to (20).

[0366] (47) a VH region comprising the CDRs according to (3) and the FRs according to (21).

[0367] (48) a VH region comprising the CDRs according to (3) and the FRs according to (22).

[0368] (49) a VH region comprising the CDRs according to (4) and the FRs according to (16).

[0369] (50) a VH region comprising the CDRs according to (4) and the FRs according to (17).

[0370] (51) a VH region comprising the CDRs according to (4) and the FRs according to (18).

[0371] (52) a VH region comprising the CDRs according to (4) and the FRs according to (19).

[0372] (53) a VH region comprising the CDRs according to (4) and the FRs according to (20).

[0373] (54) a VH region comprising the CDRs according to (4) and the FRs according to (21).

[0374] (55) a VH region comprising the CDRs according to (4) and the FRs according to (22).

[0375] (56) a VH region comprising the CDRs according to (5) and the FRs according to (16). (57) a VH region comprising the CDRs according to (5) and the FRs according to (17).

[0376] (58) a VH region comprising the CDRs according to (5) and the FRs according to (18).

[0377] (59) a VH region comprising the CDRs according to (5) and the FRs according to (19).

[0378] (60) a VH region comprising the CDRs according to (5) and the FRs according to (20).

[0379] (61) a VH region comprising the CDRs according to (5) and the FRs according to (21).

[0380] (62) a VH region comprising the CDRs according to (5) and the FRs according to (22).

[0381] (63) a VH region comprising the CDRs according to (6) and the FRs according to (16).

[0382] (64) a VH region comprising the CDRs according to (6) and the FRs according to (17).

[0383] (65) a VH region comprising the CDRs according to (6) and the FRs according to (18).

[0384] (66) a VH region comprising the CDRs according to (6) and the FRs according to (19).

[0385] (67) a VH region comprising the CDRs according to (6) and the FRs according to (20).

[0386] (68) a VH region comprising the CDRs according to (6) and the FRs according to (21).

[0387] (69) a VH region comprising the CDRs according to (6) and the FRs according to (22).

[0388] (70) a VH region comprising the CDRs according to (7) and the FRs according to (16).

[0389] (71) a VH region comprising the CDRs according to (7) and the FRs according to (17).

[0390] (72) a VH region comprising the CDRs according to (7) and the FRs according to (18).

[0391] (73) a VH region comprising the CDRs according to (7) and the FRs according to (19).

[0392] (74) a VH region comprising the CDRs according to (7) and the FRs according to (20).

[0393] (75) a VH region comprising the CDRs according to (7) and the FRs according to (21).

[0394] (76) a VH region comprising the CDRs according to (7) and the FRs according to (22).

[0395] (77) a VH region comprising the CDRs according to (8) and the FRs according to (16). (78) a VH region comprising the CDRs according to (8) and the FRs according to (17).

[0396] (79) a VH region comprising the CDRs according to (8) and the FRs according to (18).

[0397] (80) a VH region comprising the CDRs according to (8) and the FRs according to (19).

[0398] (81) a VH region comprising the CDRs according to (8) and the FRs according to (20).

[0399] (82) a VH region comprising the CDRs according to (8) and the FRs according to (21).

[0400] (83) a VH region comprising the CDRs according to (8) and the FRs according to (22).

[0401] (84) a VH region comprising the CDRs according to (9) and the FRs according to (23).

[0402] (85) a VH region comprising the CDRs according to (10) and the FRs according to (24).

[0403] (86) a VH region comprising the CDRs according to (11) and the FRs according to (25).

[0404] (87) a VH region comprising the CDRs according to (12) and the FRs according to (26).

[0405] (88) a VH region comprising the CDRs according to (13) and the FRs according to (22).

[0406] (89) a VH region comprising the CDRs according to (3) and the FRs according to (27).

[0407] (90) a VH region comprising the CDRs according to (13) and the FRs according to (27).

[0408] (91) a VH region comprising the CDRs according to (3) and the FRs according to (32).

[0409] (92) a VH region comprising the CDRs according to (14) and the FRs according to (17).

[0410] (93) a VH region comprising the CDRs according to (5) and the FRs according to (28).

[0411] (94) a VH region comprising the CDRs according to (14) and the FRs according to (28).

[0412] (95) a VH region comprising the CDRs according to (5) and the FRs according to (33).

[0413] (96) a VH region comprising the CDRs according to (14) and the FRs according to (21).

[0414] (97) a VH region comprising the CDRs according to (5) and the FRs according to (29).

[0415] (98) a VH region comprising the CDRs according to (14) and the FRs according to (29). (99) a VH region comprising the CDRs according to (5) and the FRs according to (34).

[0416] (100) a VH region comprising the CDRs according to (5) and the FRs according to (30).

[0417] (101) a VH region comprising the CDRs according to (14) and the FRs according to (30).

[0418] (102) a VH region comprising the CDRs according to (5) and the FRs according to (31).

[0419] (103) a VH region comprising the CDRs according to (14) and the FRs according to (31).

[0420] (104) a VH region comprising the CDRs according to (5) and the FRs according to (35).

[0421] (105) a VH region comprising the CDRs according to (11) and the FRs according to (36).

[0422] (106) a VH region comprising the CDRs according to (11) and the FRs according to (37).

[0423] (107) a VH region comprising the CDRs according to (11) and the FRs according to (38).

[0424] (108) a VH region comprising the CDRs according to (11) and the FRs according to (39).

[0425] In some embodiments, the antigen-binding molecule comprises a VH region according to one of:

[0426] (109) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:74.

[0427] (110) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:106.

[0428] (111) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:250.

[0429] (112) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:78.

[0430] (113) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NQ:80. (114) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:83.

[0431] (115) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:1 .

[0432] (116) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:214.

[0433] (117) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:215.

[0434] (118) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:216.

[0435] (119) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:217.

[0436] (120) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:218.

[0437] (121) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:219.

[0438] (122) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:220.

[0439] (123) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:221 . (124) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:222.

[0440] (125) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:223.

[0441] (126) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:224.

[0442] (127) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:225.

[0443] (128) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:226.

[0444] (129) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:227.

[0445] (130) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:228.

[0446] (131) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:229.

[0447] (132) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:230.

[0448] (133) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:231 . (134) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:232.

[0449] (135) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:233.

[0450] (136) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:234.

[0451] (137) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:235.

[0452] (138) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:236.

[0453] (139) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:237.

[0454] (140) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:238.

[0455] (141) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:239.

[0456] (142) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:240.

[0457] (143) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:241 . (144) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:242.

[0458] (145) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:243.

[0459] (146) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:17.

[0460] (147) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:31 .

[0461] (148) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:36.

[0462] (149) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:51 .

[0463] (150) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:86.

[0464] (151) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:87.

[0465] (152) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:389.

[0466] (153) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:398. (154) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:399.

[0467] (155) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID N0:400.

[0468] (156) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:485.

[0469] (157) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:406.

[0470] (158) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NQ:407.

[0471] (159) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:408.

[0472] (160) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:486.

[0473] (161) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:412.

[0474] (162) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:413.

[0475] (163) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:414. (164) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:487.

[0476] (165) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:392.

[0477] (166) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:393.

[0478] (167) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:394.

[0479] (168) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:488.

[0480] (169) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:418.

[0481] (170) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:419.

[0482] (171) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:420.

[0483] (172) a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:439.

[0484] In some embodiments, the antigen-binding molecule comprises a VL region according to one of:

[0485] (173) a VL region incorporating the following CDRs:

[0486] LC-CDR1 having the amino acid sequence of SEQ ID NO:65

[0487] LC-CDR2 having the amino acid sequence of SEQ ID NO:66

[0488] LC-CDR3 having the amino acid sequence of SEQ ID NO:67, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0489] (174) a VL region incorporating the following CDRs:

[0490] LC-CDR1 having the amino acid sequence of SEQ ID NO:10

[0491] LC-CDR2 having the amino acid sequence of SEQ ID NO:11

[0492] LC-CDR3 having the amino acid sequence of SEQ ID NO:286, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0493] (175) a VL region incorporating the following CDRs:

[0494] LC-CDR1 having the amino acid sequence of SEQ ID NQ:10

[0495] LC-CDR2 having the amino acid sequence of SEQ ID NO:11

[0496] LC-CDR3 having the amino acid sequence of SEQ ID NO:12, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0497] (176) a VL region incorporating the following CDRs:

[0498] LC-CDR1 having the amino acid sequence of SEQ ID NQ:10

[0499] LC-CDR2 having the amino acid sequence of SEQ ID NO:11

[0500] LC-CDR3 having the amino acid sequence of SEQ ID NO:281 , or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0501] (177) a VL region incorporating the following CDRs:

[0502] LC-CDR1 having the amino acid sequence of SEQ ID NO:10

[0503] LC-CDR2 having the amino acid sequence of SEQ ID NO:11

[0504] LC-CDR3 having the amino acid sequence of SEQ ID NO:282, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0505] (178) a VL region incorporating the following CDRs:

[0506] LC-CDR1 having the amino acid sequence of SEQ ID NO:10

[0507] LC-CDR2 having the amino acid sequence of SEQ ID NO:11

[0508] LC-CDR3 having the amino acid sequence of SEQ ID NO:283, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0509] (179) a VL region incorporating the following CDRs:

[0510] LC-CDR1 having the amino acid sequence of SEQ ID NO:10

[0511] LC-CDR2 having the amino acid sequence of SEQ ID NO:11

[0512] LC-CDR3 having the amino acid sequence of SEQ ID NO:284, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0513] (180) a VL region incorporating the following CDRs:

[0514] LC-CDR1 having the amino acid sequence of SEQ ID NQ:10

[0515] LC-CDR2 having the amino acid sequence of SEQ ID NO:11

[0516] LC-CDR3 having the amino acid sequence of SEQ ID NO:285, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0517] (181) a VL region incorporating the following CDRs:

[0518] LC-CDR1 having the amino acid sequence of SEQ ID NO:24

[0519] LC-CDR2 having the amino acid sequence of SEQ ID NO:25

[0520] LC-CDR3 having the amino acid sequence of SEQ ID NO:26, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0521] (182) a VL region incorporating the following CDRs:

[0522] LC-CDR1 having the amino acid sequence of SEQ ID NO:24

[0523] LC-CDR2 having the amino acid sequence of SEQ ID NO:11

[0524] LC-CDR3 having the amino acid sequence of SEQ ID NO:12, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0525] (183) a VL region incorporating the following CDRs:

[0526] LC-CDR1 having the amino acid sequence of SEQ ID NO:45

[0527] LC-CDR2 having the amino acid sequence of SEQ ID NO:46

[0528] LC-CDR3 having the amino acid sequence of SEQ ID NO:47, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0529] (184) a VL region incorporating the following CDRs:

[0530] LC-CDR1 having the amino acid sequence of SEQ ID NO:24

[0531] LC-CDR2 having the amino acid sequence of SEQ ID NO:11

[0532] LC-CDR3 having the amino acid sequence of SEQ ID NO:58, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0533] (185) a VL region incorporating the following CDRs:

[0534] LC-CDR1 having the amino acid sequence of SEQ ID NO:45

[0535] LC-CDR2 having the amino acid sequence of SEQ ID NO:46

[0536] LC-CDR3 having the amino acid sequence of SEQ ID NO:457, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0537] (186) a VL region incorporating the following CDRs:

[0538] LC-CDR1 having the amino acid sequence of SEQ ID NO:45

[0539] LC-CDR2 having the amino acid sequence of SEQ ID NO:46

[0540] LC-CDR3 having the amino acid sequence of SEQ ID NO:458, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0541] (187) a VL region incorporating the following CDRs:

[0542] LC-CDR1 having the amino acid sequence of SEQ ID NO:45

[0543] LC-CDR2 having the amino acid sequence of SEQ ID NO:46

[0544] LC-CDR3 having the amino acid sequence of SEQ ID NO:459, or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 , and / or in which 1 or 2 or 3 amino acids in LC-CDR2, and / or in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid.

[0545] In some embodiments, the antigen-binding molecule comprises a VL region according to one of:

[0546] (188) a VL region incorporating the following FRs:

[0547] LC-FR1 having the amino acid sequence of SEQ ID NQ:70

[0548] LC-FR2 having the amino acid sequence of SEQ ID NO:71

[0549] LC-FR3 having the amino acid sequence of SEQ ID NO:72

[0550] LC-FR4 having the amino acid sequence of SEQ ID NO:73, or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 , and / or in which 1 or 2 or 3 amino acids in LC-FR2, and / or in which 1 or 2 or 3 amino acids in LC-FR3, and / or in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid.

[0551] (189) a VL region incorporating the following FRs:

[0552] LC-FR1 having the amino acid sequence of SEQ ID NO:107

[0553] LC-FR2 having the amino acid sequence of SEQ ID NO:108

[0554] LC-FR3 having the amino acid sequence of SEQ ID NQ:109

[0555] LC-FR4 having the amino acid sequence of SEQ ID NQ:90, or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 , and / or in which 1 or 2 or 3 amino acids in LC-FR2, and / or in which 1 or 2 or 3 amino acids in LC-FR3, and / or in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid.

[0556] (190) a VL region incorporating the following FRs:

[0557] LC-FR1 having the amino acid sequence of SEQ ID NO:89

[0558] LC-FR2 having the amino acid sequence of SEQ ID NO:14

[0559] LC-FR3 having the amino acid sequence of SEQ ID NO:15

[0560] LC-FR4 having the amino acid sequence of SEQ ID NQ:90, or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 , and / or in which 1 or 2 or 3 amino acids in LC-FR2, and / or in which 1 or 2 or 3 amino acids in LC-FR3, and / or in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid.

[0561] (191) a VL region incorporating the following FRs:

[0562] LC-FR1 having the amino acid sequence of SEQ ID NO:92

[0563] LC-FR2 having the amino acid sequence of SEQ ID NO:93

[0564] LC-FR3 having the amino acid sequence of SEQ ID NO:15

[0565] LC-FR4 having the amino acid sequence of SEQ ID NQ:90, or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 , and / or in which 1 or 2 or 3 amino acids in LC-FR2, and / or in which 1 or 2 or 3 amino acids in LC-FR3, and / or in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid.

[0566] (192) a VL region incorporating the following FRs:

[0567] LC-FR1 having the amino acid sequence of SEQ ID NO:94

[0568] LC-FR2 having the amino acid sequence of SEQ ID NO:93

[0569] LC-FR3 having the amino acid sequence of SEQ ID NO:96

[0570] LC-FR4 having the amino acid sequence of SEQ ID NQ:90, or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 , and / or in which 1 or 2 or 3 amino acids in LC-FR2, and / or in which 1 or 2 or 3 amino acids in LC-FR3, and / or in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid.

[0571] (193) a VL region incorporating the following FRs:

[0572] LC-FR1 having the amino acid sequence of SEQ ID NO:97 LC-FR2 having the amino acid sequence of SEQ ID NO:93

[0573] LC-FR3 having the amino acid sequence of SEQ ID NO:99

[0574] LC-FR4 having the amino acid sequence of SEQ ID NQ:90, or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 , and / or in which 1 or 2 or 3 amino acids in LC-FR2, and / or in which 1 or 2 or 3 amino acids in LC-FR3, and / or in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid.

[0575] (194) a VL region incorporating the following FRs:

[0576] LC-FR1 having the amino acid sequence of SEQ ID NQ:101

[0577] LC-FR2 having the amino acid sequence of SEQ ID NO:93

[0578] LC-FR3 having the amino acid sequence of SEQ ID NQ:102

[0579] LC-FR4 having the amino acid sequence of SEQ ID NQ:90, or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 , and / or in which 1 or 2 or 3 amino acids in LC-FR2, and / or in which 1 or 2 or 3 amino acids in LC-FR3, and / or in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid.

[0580] (195) a VL region incorporating the following FRs:

[0581] LC-FR1 having the amino acid sequence of SEQ ID NO:13

[0582] LC-FR2 having the amino acid sequence of SEQ ID NO:14

[0583] LC-FR3 having the amino acid sequence of SEQ ID NO:15

[0584] LC-FR4 having the amino acid sequence of SEQ ID NO:16, or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 , and / or in which 1 or 2 or 3 amino acids in LC-FR2, and / or in which 1 or 2 or 3 amino acids in LC-FR3, and / or in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid.

[0585] (196) a VL region incorporating the following FRs:

[0586] LC-FR1 having the amino acid sequence of SEQ ID NO:27

[0587] LC-FR2 having the amino acid sequence of SEQ ID NO:28

[0588] LC-FR3 having the amino acid sequence of SEQ ID NO:29

[0589] LC-FR4 having the amino acid sequence of SEQ ID NO:30, or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 , and / or in which 1 or 2 or 3 amino acids in LC-FR2, and / or in which 1 or 2 or 3 amino acids in LC-FR3, and / or in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid.

[0590] (197) a VL region incorporating the following FRs:

[0591] LC-FR1 having the amino acid sequence of SEQ ID NO:27

[0592] LC-FR2 having the amino acid sequence of SEQ ID NO:35

[0593] LC-FR3 having the amino acid sequence of SEQ ID NO:29

[0594] LC-FR4 having the amino acid sequence of SEQ ID NQ:30, or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 , and / or in which 1 or 2 or 3 amino acids in LC-FR2, and / or in which 1 or 2 or 3 amino acids in LC-FR3, and / or in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid. (198) a VL region incorporating the following FRs:

[0595] LC-FR1 having the amino acid sequence of SEQ ID NO:48

[0596] LC-FR2 having the amino acid sequence of SEQ ID NO:49

[0597] LC-FR3 having the amino acid sequence of SEQ ID NQ:50

[0598] LC-FR4 having the amino acid sequence of SEQ ID NQ:30, or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 , and / or in which 1 or 2 or 3 amino acids in LC-FR2, and / or in which 1 or 2 or 3 amino acids in LC-FR3, and / or in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid.

[0599] (199) a VL region incorporating the following FRs:

[0600] LC-FR1 having the amino acid sequence of SEQ ID NO:13

[0601] LC-FR2 having the amino acid sequence of SEQ ID NO:59

[0602] LC-FR3 having the amino acid sequence of SEQ ID NQ:60

[0603] LC-FR4 having the amino acid sequence of SEQ ID NO:61 , or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 , and / or in which 1 or 2 or 3 amino acids in LC-FR2, and / or in which 1 or 2 or 3 amino acids in LC-FR3, and / or in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid.

[0604] (200) a VL region incorporating the following FRs:

[0605] LC-FR1 having the amino acid sequence of SEQ ID NO:476

[0606] LC-FR2 having the amino acid sequence of SEQ ID NO:433

[0607] LC-FR3 having the amino acid sequence of SEQ ID NO:434

[0608] LC-FR4 having the amino acid sequence of SEQ ID NO:436, or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 , and / or in which 1 or 2 or 3 amino acids in LC-FR2, and / or in which 1 or 2 or 3 amino acids in LC-FR3, and / or in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid.

[0609] (201) a VL region incorporating the following FRs:

[0610] LC-FR1 having the amino acid sequence of SEQ ID NO:432

[0611] LC-FR2 having the amino acid sequence of SEQ ID NO:433

[0612] LC-FR3 having the amino acid sequence of SEQ ID NO:434

[0613] LC-FR4 having the amino acid sequence of SEQ ID NO:436, or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 , and / or in which 1 or 2 or 3 amino acids in LC-FR2, and / or in which 1 or 2 or 3 amino acids in LC-FR3, and / or in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid.

[0614] (202) a VL region incorporating the following FRs:

[0615] LC-FR1 having the amino acid sequence of SEQ ID NO:432

[0616] LC-FR2 having the amino acid sequence of SEQ ID NO:433

[0617] LC-FR3 having the amino acid sequence of SEQ ID NO:435

[0618] LC-FR4 having the amino acid sequence of SEQ ID NO:436, or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 , and / or in which 1 or 2 or 3 amino acids in LC-FR2, and / or in which 1 or 2 or 3 amino acids in LC-FR3, and / or in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid.

[0619] (203) a VL region incorporating the following FRs:

[0620] LC-FR1 having the amino acid sequence of SEQ ID NO:484

[0621] LC-FR2 having the amino acid sequence of SEQ ID NO:433

[0622] LC-FR3 having the amino acid sequence of SEQ ID NO:446

[0623] LC-FR4 having the amino acid sequence of SEQ ID NO:436, or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 , and / or in which 1 or 2 or 3 amino acids in LC-FR2, and / or in which 1 or 2 or 3 amino acids in LC-FR3, and / or in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid.

[0624] In some embodiments, the antigen-binding molecule comprises a VL region comprising the CDRs according to any one of (173) to (187) above, and the FRs according to any one of (188) to (203) above.

[0625] In some embodiments, the antigen-binding molecule comprises a VL region according to one of:

[0626] (204) a VL region comprising the CDRs according to (173) and the FRs according to (188).

[0627] (205) a VL region comprising the CDRs according to (174) and the FRs according to (188).

[0628] (206) a VL region comprising the CDRs according to (175) and the FRs according to (189).

[0629] (207) a VL region comprising the CDRs according to (175) and the FRs according to (190).

[0630] (208) a VL region comprising the CDRs according to (175) and the FRs according to (191).

[0631] (209) a VL region comprising the CDRs according to (175) and the FRs according to (192).

[0632] (210) a VL region comprising the CDRs according to (175) and the FRs according to (193).

[0633] (211) a VL region comprising the CDRs according to (175) and the FRs according to (194).

[0634] (212) a VL region comprising the CDRs according to (175) and the FRs according to (195).

[0635] (213) a VL region comprising the CDRs according to (176) and the FRs according to (189).

[0636] (214) a VL region comprising the CDRs according to (176) and the FRs according to (190).

[0637] (215) a VL region comprising the CDRs according to (176) and the FRs according to (191).

[0638] (216) a VL region comprising the CDRs according to (176) and the FRs according to (192). (217) a VL region comprising the CDRs according to (176) and the FRs according to (193).

[0639] (218) a VL region comprising the CDRs according to (176) and the FRs according to (194).

[0640] (219) a VL region comprising the CDRs according to (176) and the FRs according to (195).

[0641] (220) a VL region comprising the CDRs according to (177) and the FRs according to (189).

[0642] (221) a VL region comprising the CDRs according to (177) and the FRs according to (190).

[0643] (222) a VL region comprising the CDRs according to (177) and the FRs according to (191).

[0644] (223) a VL region comprising the CDRs according to (177) and the FRs according to (192).

[0645] (224) a VL region comprising the CDRs according to (177) and the FRs according to (193).

[0646] (225) a VL region comprising the CDRs according to (177) and the FRs according to (194).

[0647] (226) a VL region comprising the CDRs according to (177) and the FRs according to (195).

[0648] (227) a VL region comprising the CDRs according to (178) and the FRs according to (189).

[0649] (228) a VL region comprising the CDRs according to (178) and the FRs according to (190).

[0650] (229) a VL region comprising the CDRs according to (178) and the FRs according to (191).

[0651] (230) a VL region comprising the CDRs according to (178) and the FRs according to (192).

[0652] (231) a VL region comprising the CDRs according to (178) and the FRs according to (193).

[0653] (232) a VL region comprising the CDRs according to (178) and the FRs according to (194).

[0654] (233) a VL region comprising the CDRs according to (178) and the FRs according to (195).

[0655] (234) a VL region comprising the CDRs according to (179) and the FRs according to (189).

[0656] (235) a VL region comprising the CDRs according to (179) and the FRs according to (190).

[0657] (236) a VL region comprising the CDRs according to (179) and the FRs according to (191).

[0658] (237) a VL region comprising the CDRs according to (179) and the FRs according to (192). (238) a VL region comprising the CDRs according to (179) and the FRs according to (193).

[0659] (239) a VL region comprising the CDRs according to (179) and the FRs according to (194).

[0660] (240) a VL region comprising the CDRs according to (179) and the FRs according to (195).

[0661] (241) a VL region comprising the CDRs according to (180) and the FRs according to (189).

[0662] (242) a VL region comprising the CDRs according to (180) and the FRs according to (190).

[0663] (243) a VL region comprising the CDRs according to (180) and the FRs according to (191).

[0664] (244) a VL region comprising the CDRs according to (180) and the FRs according to (192).

[0665] (245) a VL region comprising the CDRs according to (180) and the FRs according to (193).

[0666] (246) a VL region comprising the CDRs according to (180) and the FRs according to (194).

[0667] (247) a VL region comprising the CDRs according to (180) and the FRs according to (195).

[0668] (248) a VL region comprising the CDRs according to (181) and the FRs according to (196).

[0669] (249) a VL region comprising the CDRs according to (182) and the FRs according to (197).

[0670] (250) a VL region comprising the CDRs according to (183) and the FRs according to (198).

[0671] (251) a VL region comprising the CDRs according to (184) and the FRs according to (199).

[0672] (252) a VL region comprising the CDRs according to (183) and the FRs according to (198).

[0673] (253) a VL region comprising the CDRs according to (185) and the FRs according to (198).

[0674] (254) a VL region comprising the CDRs according to (186) and the FRs according to (198).

[0675] (255) a VL region comprising the CDRs according to (187) and the FRs according to (198).

[0676] (256) a VL region comprising the CDRs according to (183) and the FRs according to (200).

[0677] (257) a VL region comprising the CDRs according to (185) and the FRs according to (200).

[0678] (258) a VL region comprising the CDRs according to (186) and the FRs according to (200). (259) a VL region comprising the CDRs according to (187) and the FRs according to (200).

[0679] (260) a VL region comprising the CDRs according to (183) and the FRs according to (201).

[0680] (261) a VL region comprising the CDRs according to (185) and the FRs according to (201).

[0681] (262) a VL region comprising the CDRs according to (186) and the FRs according to (201).

[0682] (263) a VL region comprising the CDRs according to (187) and the FRs according to (201).

[0683] (264) a VL region comprising the CDRs according to (183) and the FRs according to (202).

[0684] (265) a VL region comprising the CDRs according to (185) and the FRs according to (202).

[0685] (266) a VL region comprising the CDRs according to (186) and the FRs according to (202).

[0686] (267) a VL region comprising the CDRs according to (187) and the FRs according to (202).

[0687] (268) a VL region comprising the CDRs according to (183) and the FRs according to (203).

[0688] (269) a VL region comprising the CDRs according to (185) and the FRs according to (203).

[0689] (270) a VL region comprising the CDRs according to (186) and the FRs according to (203).

[0690] (271) a VL region comprising the CDRs according to (187) and the FRs according to (203).

[0691] In some embodiments, the antigen-binding molecule comprises a VL region according to one of:

[0692] (272) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:75.

[0693] (273) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:110.

[0694] (274) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:88. (275) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:91 .

[0695] (276) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:95.

[0696] (277) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:98.

[0697] (278) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID N0:100.

[0698] (279) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:9.

[0699] (280) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:251 .

[0700] (281) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:252.

[0701] (282) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:253.

[0702] (283) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:254.

[0703] (284) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:255. (285) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:256.

[0704] (286) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:257.

[0705] (287) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:258.

[0706] (288) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:259.

[0707] (289) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NQ:260.

[0708] (290) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:261 .

[0709] (291) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:262.

[0710] (292) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:263.

[0711] (293) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:264.

[0712] (294) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:265. (295) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:266.

[0713] (296) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:267.

[0714] (297) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:268.

[0715] (298) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:269.

[0716] (299) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NQ:270.

[0717] (300) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:271 .

[0718] (301) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:272.

[0719] (302) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:273.

[0720] (303) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:274.

[0721] (304) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:275. (305) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:276.

[0722] (306) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:277.

[0723] (307) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:278.

[0724] (308) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:279.

[0725] (309) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NQ:280.

[0726] (310) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:23.

[0727] (311) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:34.

[0728] (312) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:44.

[0729] (313) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:57.

[0730] (314) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:475. (315) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:430.

[0731] (316) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:431 .

[0732] (317) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:448.

[0733] (318) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:449.

[0734] (319) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NQ:450.

[0735] (320) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:478.

[0736] (321) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:479.

[0737] (322) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:480.

[0738] (323) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:451 .

[0739] (324) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:452. (325) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:453.

[0740] (326) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:454.

[0741] (327) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:455.

[0742] (328) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:456.

[0743] (329) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:445.

[0744] (330) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:469.

[0745] (331) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NQ:470.

[0746] (332) a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:471 .

[0747] In some embodiments, the antigen-binding molecule comprises a VH region according to any one of (1) to (172) above, and a VL region according to any one of (173) to (332) above.

[0748] In some embodiments, a VH according according to any one of (109) to (145) or (152) to (168) comprises an amino acid other than ‘D’ at the position corresponding to position 54 of SEQ ID NO:1 . In some embodiments, the amino acid other than amino acid other than ‘D’ is selected from ‘G’, ‘E’, ‘Q’ and ‘L’. In some embodiments, the amino acid other than ‘D’ is ‘G’ or ‘Q’. In some embodiments, the amino acid other than ‘D’ is ‘E’. In some embodiments, a VH according according to any one of (109) to (145) or (152) to (168) comprises an amino acid other than ‘G’ at the position corresponding to position 55 of SEQ ID NO:1 . In some embodiments, the amino acid other than amino acid other than ‘G’ is selected from ‘G’, A’, ‘L’ and T. In some embodiments, the amino acid other than ‘G’ is A’.

[0749] In some embodiments, a VH according ot any one of (109) to (145) or (152) to (168) comprises an ‘E’ at the position corresponding to position 54 of SEQ ID NO:1 and a ‘G’ at the position corresponding to position 55 of SEQ ID NO:1 .

[0750] In some embodiments, a VL according according to any one of (272) to (309) comprises an amino acid other than ‘N’ at the position corresponding to position 93 of SEQ ID NO:9. In some embodiments, the amino acid other than amino acid other than ‘N’ is selected from ‘G’, ‘E’, ‘Q’, ‘L’ and T. In some embodiments, the amino acid other than amino acid other than ‘N’ is selected from ‘G’, ‘E’, ‘Q’ and ‘L’. In some embodiments, the amino acid other than ‘N’ is ‘Q’ or ‘G’. In some embodiments, the amino acid other than ‘N’ is ‘G’.

[0751] In some embodiments, a VL according according to any one of (272) to (309) comprises an amino acid other than G’ at the position corresponding to position 94 of SEQ ID NO:9. In some embodiments, the amino acid other than amino acid other than ‘G’ is ‘A’ or ‘V’. In some embodiments, the amino acid other than ‘G’ is ‘A’.

[0752] In some embodiments, a VL according to any one of (272) to (309) comprises a ‘G’ at the position corresponding to position 93 of SEQ ID NO:9 and a ‘G’ at the position corresponding to position 94 of SEQ ID NO:9.

[0753] In embodiments in accordance with the present disclosure, one or more amino acids are substituted with another amino acid. A substitution comprises substitution of an amino acid residue with a non-identical 'replacement' amino acid residue. A replacement amino acid residue of a substitution according to the present disclosure may be a naturally-occurring amino acid residue ( / .e. encoded by the genetic code) which is non-identical to the amino acid residue at the relevant position of the equivalent, unsubstituted amino acid sequence, selected from: alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gin), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (lie): leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), and valine (Vai). In some embodiments, a replacement amino acid may be a non-naturally occurring amino acid residue - i.e. an amino acid residue other than those recited in the preceding sentence. Examples of non-naturally occurring amino acid residues include norleucine, ornithine, norvaline, homoserine, aib, and other amino acid residue analogues such as those described in Ellman, et al., Meth. Enzym. 202 (1991) 301-336.

[0754] In some embodiments, a substitution may be biochemically conservative. In some embodiments, where an amino acid to be substituted is provided in one of rows 1 to 5 of the table below, the replacement amino acid of the substitution is another, non-identical amino acid provided in the same row:

[0755] By way of illustration, in some embodiments wherein substitution is of a Met residue, the replacement amino acid may be selected from Ala, Vai, Leu, He, Trp, Tyr, Phe and Norleucine.

[0756] In some embodiments, a replacement amino acid in a substitution may have the same side chain polarity as the amino acid residue it replaces. In some embodiments, a replacement amino acid in a substitution may have the same side chain charge (at pH 7.4) as the amino acid residue it replaces: That is, in some embodiments, a nonpolar amino acid is substituted with another, non-identical nonpolar amino acid. In some embodiments, a polar amino acid is substituted with another, non-identical polar amino acid. In some embodiments, an acidic polar amino acid is substituted with another, non-identical acidic polar amino acid. In some embodiments, a basic polar amino acid is substituted with another, non- identical basic polar amino acid. In some embodiments, a neutral amino acid is substituted with another, non-identical neutral amino acid. In some embodiments, a positive amino acid is substituted with another, non-identical positive amino acid. In some embodiments, a negative amino acid is substituted with another, non-identical negative amino acid.

[0757] In some embodiments, substitution(s) may be functionally conservative. That is, in some embodiments, the substitution may not affect (or may not substantially affect) one or more functional properties (e.g. target binding) of the antigen-binding molecule comprising the substitution as compared to the equivalent unsubstituted molecule.

[0758] In some embodiments, substitution(s) may prevent / reduce degradation of the antigen-binding molecule. Degradation of an antigen-binding molecule may occur during manufacturing, processing, storage, handling and / or administration. The degradation may be physical and / or chemical. Degradation processes, e g. chemical degradation processes, include oxidation, fragmentation, deamination, isomerisation, hydrolysis, deglycosylation, racemization, disulphide bond breakage and formation, Maillard reaction, and p-elimination.

[0759] Oxidation is one of the most common chemical modifications in monoclonal antibodies and may be induced by reactive oxygen species. Oxidation may occur at cysteine, methionine, tryptophan, tyrosine, lysine and other amino acid residues. Oxidation of amino acid residues may impact protein structure and / or function. In some embodiments, one or more amino acids are substituted with another amino acid to remove an oxidation site. In some embodiments, one or more amino acids susceptible to oxidation are substituted with another amino acid (e.g. an amino acid which is not susceptible to oxidation or is less susceptioble to oxidation). In some embodiments, one or more amino acids identified as being oxidised, or identified as being susceptible to oxidation, are substituted with another amino acid (e.g. an amino acid which is not susceptible to oxidation or is less susceptioble to oxidation).

[0760] Amino acid residues susceptible to oxidation may be identified e.g. by in silica methods (e.g. as reviewed in Vatsa S, Mabs, 2022, 14(1):2023938, which is hereby incorporated by reference in its entirety) or by forced oxidation assays (e.g. as reviewed in Nowak C et al, Mabs, 2017, 9(8):1217-1230, and Dyck YFK et al, Bioengineering (Basel), 2019, 6(3):62, which are hereby incorporated by reference in their entirety).

[0761] In some embodiments, a VH according according to any one of (109) to (145) or (152) to (168) comprises an amino acid other than W at the position corresponding to position 33 of SEQ ID NO:1 . In some embodiments, the amino acid other than W is selected from ‘A’, ‘R’, ‘N’, ‘D’, ‘E’, ‘Q’, ‘G’, ‘H’, T, ‘L’, ‘K’, ‘M’, ‘F’, ‘P’, ‘S’, T, Y’ and ‘V’. In some embodiments, a VH according according to any one of (109) to (145) or (152) to (168) comprises an amino acid other than ‘M’ at the position corresponding to position 34 of SEQ ID NO:1 . In some embodiments, the amino acid other than ‘M’ is selected from ‘A’, ‘R’, ‘N’, ‘D’, ‘E’, ‘Q’, ‘G’, ‘H’, T, ‘L’, ‘K’, ‘F’, ‘P’, ‘S’, ‘T’, W, ‘Y’ and ‘V’. In some embodiments, the amino acid other than ‘M’ is ‘Y’. For example, in each of SEQ ID NO:74, 106, 250, 78, 80, 83, 1 , 214, 215, 216, 217, 218, 219, 220, 221 , 222, 223, 224, 225, 226, 227, 228, 229, 230, 231 , 232, 233, 234, 235, 236, 237, 238, 239, 240, 241 , 242, 243, 389, 398, 399, 400, 485, 406, 407, 408, 486, 412, 413, 414, 487, 392, 393, 394 and 488 amino acid 34 may be Y.

[0762] In some embodiments, a VH according according to any one of (109) to (145) or (152) to (168) comprises an amino acid other than W at the position corresponding to position 33 of SEQ ID NO:1 and an amino acid other than ‘M’ at the position corresponding to position 34 of SEQ ID NO:1 . In some embodiments, the amino acid other than ‘W’ is selected from ‘A’, ‘R’, ‘N’, ‘D’, ‘E’, ‘Q’, ‘G’, ‘H’, T, ‘L’, ‘K’, ‘M’, ‘F’, ‘P’, ‘S’, ‘T’, ‘Y’ and ‘V’, and the amino acid other than ‘M’ is selected from ‘A’, ‘R’, N’ , ‘D’, ‘E’, ‘Q’, ‘G’, ‘H’, ‘I’, ‘L’, ‘K’, ‘F’, ‘P’, ‘S’, T, ‘W’, ‘Y’ and ‘V’. In some embodiments, the amino acid other than ‘M’ is ‘Y’. For example, in each of SEQ ID NO: 74, 106, 250, 78, 80, 83, 1 , 214, 215, 216, 217, 218, 219, 220, 221 , 222, 223, 224, 225, 226, 227, 228, 229, 230, 231 , 232, 233, 234, 235, 236, 237, 238, 239, 240, 241 , 242, 243, 389, 398, 399, 400, 485, 406, 407, 408, 486, 412, 413, 414, 487, 392, 393, 394 and 488, amino acid 33 may be an amino acid other than W and amino acid 34 may be Y.

[0763] In some embodiments, the antigen-binding molecule comprises a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:398, 406, or 412. In some embodiments, X is A. In some embodiments, X is R. In some embodiments, X is N. In some embodiments, X is D. In some embodiments, X is E. In some embodiments, X is Q. In some embodiments, X is G. In some embodiments, X is H. In some embodiments, X is I. In some embodiments, X is L. In some embodiments, X is K. In some embodiments, X is M. In some embodiments, X is F. In some embodiments, X is P. In some embodiments, X is S. In some embodiments, X is T. In some embodiments, X is Y. In some embodiments, X is V.

[0764] In some embodiments, the antigen-binding molecule comprises a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:399, 407, or 413. In some embodiments, X is A. In some embodiments, X is R. In some embodiments, X is N. In some embodiments, X is D. In some embodiments, X is E. In some embodiments, X is Q. In some embodiments, X is G. In some embodiments, X is H. In some embodiments, X is I. In some embodiments, X is L. In some embodiments, X is K. In some embodiments, X is F. In some embodiments, X is P. In some embodiments, X is S. In some embodiments, X is T. In some embodiments, X is W. In some embodiments, X is Y. In some embodiments, X is V. In some embodiments, the antigen-binding molecule comprises a VH region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID N0:400, 408, or 414. In some embodiments, Xi is A and X2 is A. In some embodiments, Xi is A and X2 is R. In some embodiments, Xi is A and X2 is N. In some embodiments, Xi is A and X2 is D. In some embodiments, Xi is A and X2 is E. In some embodiments, Xi is A and X2 is Q. In some embodiments, Xi is A and X2 is G. In some embodiments, Xi is A and X2 is H. In some embodiments, Xi is A and X2 is I. In some embodiments, Xi is A and X2 is L. In some embodiments, Xi is A and X2 is K. In some embodiments, Xi is A and X2 is F. In some embodiments, Xi is A and X2 is P. In some embodiments, Xi is A and X2 is S. In some embodiments, Xi is A and X2 is T. In some embodiments, Xi is A and X2 is W. In some embodiments, Xi is A and X2 is Y. In some embodiments, Xi is A and X2 is V. In some embodiments, Xi is R and X2 is A. In some embodiments, Xi is R and X2 is R. In some embodiments, Xi is R and X2 is N. In some embodiments, Xi is R and X2 is D. In some embodiments, Xi is R and X2 is E. In some embodiments, Xi is R and X2 is Q. In some embodiments, Xi is R and X2 is G. In some embodiments, Xi is R and X2 is H. In some embodiments, Xi is R and X2 is I. In some embodiments, Xi is R and X2 is L. In some embodiments, Xi is R and X2 is K. In some embodiments, Xi is R and X2 is F. In some embodiments, Xi is R and X2 is P. In some embodiments, Xi is R and X2 is S. In some embodiments, Xi is R and X2 is T. In some embodiments, Xi is R and X2 is W. In some embodiments, Xi is R and X2 is Y. In some embodiments, Xi is R and X2 is V. In some embodiments, Xi is N and X2 is A. In some embodiments, Xi is N and X2 is R. In some embodiments, Xi is N and X2 is N. In some embodiments, Xi is N and X2 is D. In some embodiments, Xi is N and X2 is E. In some embodiments, Xi is N and X2 is Q. In some embodiments, Xi is N and X2 is G. In some embodiments, Xi is N and X2 is H. In some embodiments, Xi is N and X2 is I. In some embodiments, Xi is N and X2 is L. In some embodiments, Xi is N and X2 is K. In some embodiments, Xi is N and X2 is F. In some embodiments, Xi is N and X2 is P. In some embodiments, Xi is N and X2 is S. In some embodiments, Xi is N and X2 is T. In some embodiments, Xi is N and X2 is W. In some embodiments, Xi is N and X2 is Y. In some embodiments, Xi is N and X2 is V. In some embodiments, Xi is D and X2 is A. In some embodiments, Xi is D and X2 is R. In some embodiments, Xi is D and X2 is N. In some embodiments, Xi is D and X2 is D. In some embodiments, Xi is D and X2 is E. In some embodiments, Xi is D and X2 is Q. In some embodiments, Xi is D and X2 is G. In some embodiments, Xi is D and X2 is H. In some embodiments, Xi is D and X2 is I. In some embodiments, Xi is D and X2 is L. In some embodiments, Xi is D and X2 is K. In some embodiments, Xi is D and X2 is F. In some embodiments, Xi is D and X2 is P. In some embodiments, Xi is D and X2 is S. In some embodiments, Xi is D and X2 is T. In some embodiments, Xi is D and X2 is W. In some embodiments, Xi is D and X2 is Y. In some embodiments, Xi is D and X2 is V. In some embodiments, Xi is E and X2 is A. In some embodiments, Xi is E and X2 is R. In some embodiments, Xi is E and X2 is N. In some embodiments, Xi is E and X2 is D. In some embodiments, Xi is E and X2 is E. In some embodiments, Xi is E and X2 is Q. In some embodiments, Xi is E and X2 is G. In some embodiments, Xi is E and X2 is H. In some embodiments, Xi is E and X2 is I. In some embodiments, Xi is E and X2 is L. In some embodiments, Xi is E and X2 is K. In some embodiments, Xi is E and X2 is F. In some embodiments, Xi is E and X2 is P. In some embodiments, Xi is E and X2 is S. In some embodiments, Xi is E and X2 is T. In some embodiments, Xi is E and X2 is W. In some embodiments, Xi is E and X2 is Y. In some embodiments, Xi is E and X2 is V. In some embodiments, Xi is Q and X2 is A. In some embodiments, Xi is Q and X2 is R. In some embodiments, Xi is Q and X2 is N. In some embodiments, Xi is Q and X2 is D. In some embodiments, Xi is Q and X2 is E. In some embodiments, Xi is Q and X2 is Q. In some embodiments, Xi is Q and X2 is G. In some embodiments, Xi is Q and X2 is H. In some embodiments, Xi is Q and X2 is I. In some embodiments, Xi is Q and X2 is L. In some embodiments, Xi is Q and X2 is K. In some embodiments, Xi is Q and X2 is F. In some embodiments, Xi is Q and X2 is P. In some embodiments, Xi is Q and X2 is S. In some embodiments, Xi is Q and X2 is T. In some embodiments, Xi is Q and X2 is W. In some embodiments, Xi is Q and X2 is Y. In some embodiments, Xi is Q and X2 is V. In some embodiments, Xi is G and X2 is A. In some embodiments, Xi is G and X2 is R. In some embodiments, Xi is G and X2 is N. In some embodiments, Xi is G and X2 is D. In some embodiments, Xi is G and X2 is E. In some embodiments, Xi is G and X2 is Q. In some embodiments, Xi is G and X2 is G. In some embodiments, Xi is G and X2 is H. In some embodiments, Xi is G and X2 is I. In some embodiments, Xi is G and X2 is L. In some embodiments, Xi is G and X2 is K. In some embodiments, Xi is G and X2 is F. In some embodiments, Xi is G and X2 is P. In some embodiments, Xi is G and X2 is S. In some embodiments, Xi is G and X2 is T. In some embodiments, Xi is G and X2 is W. In some embodiments, Xi is G and X2 is Y. In some embodiments, Xi is G and X2 is V. In some embodiments, Xi is H and X2 is A. In some embodiments, Xi is H and X2 is R. In some embodiments, Xi is H and X2 is N. In some embodiments, Xi is H and X2 is D. In some embodiments, Xi is H and X2 is E. In some embodiments, Xi is H and X2 is Q. In some embodiments, Xi is H and X2 is G. In some embodiments, Xi is H and X2 is H. In some embodiments, Xi is H and X2 is I. In some embodiments, Xi is H and X2 is L. In some embodiments, Xi is H and X2 is K. In some embodiments, Xi is H and X2 is F. In some embodiments, Xi is H and X2 is P. In some embodiments, Xi is H and X2 is S. In some embodiments, Xi is H and X2 is T. In some embodiments, Xi is H and X2 is W. In some embodiments, Xi is H and X2 is Y. In some embodiments, Xi is H and X2 is V. In some embodiments, Xi is I and X2 is A. In some embodiments, Xi is I and X2 is R. In some embodiments, Xi is I and X2 is N. In some embodiments, Xi is I and X2 is D. In some embodiments, Xi is I and X2 is E. In some embodiments, Xi is I and X2 is Q. In some embodiments, Xi is I and X2 is G. In some embodiments, Xi is I and X2 is H. In some embodiments, Xi is I and X2 is I. In some embodiments, Xi is I and X2 is L. In some embodiments, Xi is I and X2 is K. In some embodiments, Xi is I and X2 is F. In some embodiments, Xi is I and X2 is P. In some embodiments, Xi is I and X2 is S. In some embodiments, Xi is I and X2 is T. In some embodiments, Xi is I and X2 is W. In some embodiments, Xi is I and X2 is Y. In some embodiments, Xi is I and X2 is V. In some embodiments, Xi is L and X2 is A. In some embodiments, Xi is L and X2 is R. In some embodiments, Xi is L and X2 is N. In some embodiments, Xi is L and X2 is D. In some embodiments, Xi is L and X2 is E. In some embodiments, Xi is L and X2 is Q. In some embodiments, Xi is L and X2 is G. In some embodiments, Xi is L and X2 is H. In some embodiments, Xi is L and X2 is I. In some embodiments, Xi is L and X2 is L. In some embodiments, Xi is L and X2 is K. In some embodiments, Xi is L and X2 is F. In some embodiments, Xi is L and X2 is P. In some embodiments, Xi is L and X2 is S. In some embodiments, Xi is L and X2 is T. In some embodiments, Xi is L and X2 is W. In some embodiments, Xi is L and X2 is Y. In some embodiments, Xi is L and X2 is V. In some embodiments, Xi is K and X2 is A. In some embodiments, Xi is K and X2 is R. In some embodiments, Xi is K and X2 is N. In some embodiments, Xi is K and X2 is D. In some embodiments, Xi is K and X2 is E. In some embodiments, Xi is K and X2 is Q. In some embodiments, Xi is K and X2 is G. In some embodiments, Xi is K and X2 is H. In some embodiments, Xi is K and X2 is I. In some embodiments, Xi is K and X2 is L. In some embodiments, Xi is K and X2 is K. In some embodiments, Xi is K and X2 is F. In some embodiments, Xi is K and X2 is P. In some embodiments, Xi is K and X2 is S. In some embodiments, Xi is K and X2 is T. In some embodiments, Xi is K and X2 is W. In some embodiments, Xi is K and X2 is Y. In some embodiments, Xi is K and X2 is V. In some embodiments, Xi is M and X2 is A. In some embodiments, Xi is M and X2 is R. In some embodiments, Xi is M and X2 is N. In some embodiments, Xi is M and X is D. In some embodiments, Xi is M and X2 is E. In some embodiments, Xi is M and X2 is Q. In some embodiments, Xi is M and X2 is G. In some embodiments, Xi is M and X2 is H. In some embodiments, Xi is M and X2 is I. In some embodiments, Xi is M and X2 is L. In some embodiments, Xi is M and X2 is K. In some embodiments, Xi is M and X2 is F. In some embodiments, Xi is M and X2 is P. In some embodiments, Xi is M and X2 is S. In some embodiments, Xi is M and X2 is T. In some embodiments, Xi is M and X2 is W. In some embodiments, Xi is M and X2 is Y. In some embodiments, Xi is M and X2 is V. In some embodiments, Xi is F and X2 is A. In some embodiments, Xi is F and X2 is R. In some embodiments, Xi is F and X2 is N. In some embodiments, Xi is F and X2 is D. In some embodiments, Xi is F and X2 is E. In some embodiments, Xi is F and X2 is Q. In some embodiments, Xi is F and X2 is G. In some embodiments, Xi is F and X2 is H. In some embodiments, Xi is F and X2 is I. In some embodiments, Xi is F and X2 is L. In some embodiments, Xi is F and X2 is K. In some embodiments, Xi is F and X2 is F. In some embodiments, Xi is F and X2 is P. In some embodiments, Xi is F and X2 is S. In some embodiments, Xi is F and X2 is T. In some embodiments, Xi is F and X2 is W. In some embodiments, Xi is F and X2 is Y. In some embodiments, Xi is F and X2 is V. In some embodiments, Xi is P and X2 is A. In some embodiments, Xi is P and X2 is R. In some embodiments, Xi is P and X2 is N. In some embodiments, Xi is P and X2 is D. In some embodiments, Xi is P and X2 is E. In some embodiments, Xi is P and X2 is Q. In some embodiments, Xi is P and X2 is G. In some embodiments, Xi is P and X2 is H. In some embodiments, Xi is P and X2 is I. In some embodiments, Xi is P and X2 is L. In some embodiments, Xi is P and X2 is K. In some embodiments, Xi is P and X2 is F. In some embodiments, Xi is P and X2 is P. In some embodiments, Xi is P and X2 is S. In some embodiments, Xi is P and X2 is T. In some embodiments, Xi is P and X2 is W. In some embodiments, Xi is P and X2 is Y. In some embodiments, Xi is P and X2 is V. In some embodiments, Xi is S and X2 is A. In some embodiments, Xi is S and X2 is R. In some embodiments, Xi is S and X2 is N. In some embodiments, Xi is S and X2 is D. In some embodiments, Xi is S and X2 is E. In some embodiments, Xi is S and X2 is Q. In some embodiments, Xi is S and X2 is G. In some embodiments, Xi is S and X2 is H. In some embodiments, Xi is S and X2 is I. In some embodiments, Xi is S and X2 is L. In some embodiments, Xi is S and X2 is K. In some embodiments, Xi is S and X2 is F. In some embodiments, Xi is S and X2 is P. In some embodiments, Xi is S and X2 is S. In some embodiments, Xi is S and X2 is T. In some embodiments, Xi is S and X2 is W. In some embodiments, Xi is S and X2 is Y. In some embodiments, Xi is S and X2 is V. In some embodiments, Xi is T and X2 is A. In some embodiments, Xi is T and X2 is R. In some embodiments, Xi is T and X2 is N. In some embodiments, Xi is T and X2 is D. In some embodiments, Xi is T and X2 is E. In some embodiments, Xi is T and X2 is Q. In some embodiments, Xi is T and X2 is G. In some embodiments, Xi is T and X2 is H. In some embodiments, Xi is T and X2 is I. In some embodiments, Xi is T and X2 is L. In some embodiments, Xi is T and X2 is K. In some embodiments, Xi is T and X2 is F. In some embodiments, Xi is T and X2 is P. In some embodiments, Xi is T and X2 is S. In some embodiments, Xi is T and X2 is T. In some embodiments, Xi is T and X2 is W. In some embodiments, Xi is T and X2 is Y. In some embodiments, Xi is T and X2 is V. In some embodiments, Xi is Y and X2 is A. In some embodiments, Xi is Y and X2 is R. In some embodiments, Xi is Y and X2 is N. In some embodiments, Xi is Y and X2 is D. In some embodiments, Xi is Y and X2 is E. In some embodiments, Xi is Y and X2 is Q. In some embodiments, Xi is Y and X2 is G. In some embodiments, Xi is Y and X2 is H. In some embodiments, Xi is Y and X2 is I. In some embodiments, Xi is Y and X2 is L. In some embodiments, Xi is Y and X2 is K. In some embodiments, Xi is Y and X2 is F. In some embodiments, Xi is Y and X2 is P. In some embodiments, Xi is

[0765] Y and X2 is S. In some embodiments, Xi is Y and X2 is T. In some embodiments, Xi is Y and X2 is W. In some embodiments, Xi is Y and X2 is Y. In some embodiments, Xi is Y and X2 is V. In some embodiments, Xi is V and X2 is A. In some embodiments, Xi is V and X2 is R. In some embodiments, Xi is V and X2 is N. In some embodiments, Xi is V and X2 is D. In some embodiments, Xi is V and X2 is E. In some embodiments, Xi is V and X2 is Q. In some embodiments, Xi is V and X2 is G. In some embodiments, Xi is V and X2 is H. In some embodiments, Xi is V and X2 is I. In some embodiments, Xi is

[0766] V and X2 is L. In some embodiments, Xi is V and X2 is K. In some embodiments, Xi is V and X2 is F. In some embodiments, Xi is V and X2 is P. In some embodiments, Xi is V and X2 is S. In some embodiments, Xi is V and X2 is T. In some embodiments, Xi is V and X2 is W. In some embodiments, Xi is V and X is Y. In some embodiments, Xi is V and X2 is V.

[0767] In some embodiments, one or more amino acids are substituted with another amino acid to remove an acid-labile site. As used herein, an ‘acid-labile site’ refers to amino acids (e.g. two consecutive amino acids) wherein the bond connecting said amino acids is susceptible to breakage when exposed to acidic conditions (e.g. pH<7.0, pH 6, pH 5, pH4). For example, a consecutive aspartic acid (Asp) residue and proline (Pro) residue in a polypeptide may form an acid-labile site. Asp-Pro bonds in polypeptides are labile under acidic conditions. The amide nitrogen atom from the Pro backbone attacks the carboxyl side chain of the preceding Asp residue, forming an instable cationic imide intermediates readily hydrolysed into peptidyl fragments whose C- and N- terminus are occupied by the subjected Asp and Pro, respectively. Acid labile sites may be identified e.g. by in silico analysis of a given polypeptide sequence.

[0768] In some embodiments, a VL according according to any one of (312) or (314) to (332) comprises an amino acid other than ‘D’ at the position corresponding to position 93 of SEQ ID NO:44. In some embodiments, the amino acid other than ‘D’ is selected from ‘A’, ‘R’, ‘N’, ‘E’, ‘Q’, ‘G’, ‘H’, T, ‘L’, ‘K’, ‘M’, ‘F’, P’, ‘S’, T, W, ‘Y’ and .

[0769] In some embodiments, a VL according according to any one of (312) or (314) to (332) comprises an amino acid other than ‘P’ at the position corresponding to position 94 of SEQ ID NO:44. In some embodiments, the amino acid other than ‘P’ is selected from ‘A’, ‘R’, ‘N’, ‘D’, ‘E’, ‘Q’, ‘G’, ‘H’, T, ‘L’, ‘K’, ‘M’, ‘F’, ‘S’, T, ‘W’, ‘Y’ and ‘V’.

[0770] As explained herein, position(s) of an amino acid sequence which ‘corresponds to’ specified position(s) of a reference amino acid sequence can be identified by sequence alignment of the subject sequence to the reference sequence, e.g. using sequence alignment software such as ClustalOmega (Sdding, J. 2005, Bioinformatics 21 , 951-960). By way of illustration, it will be appreciated that positions 93 and 94 of SEQ ID NO:44 correspond to positions 93 and 94 of SEQ ID NO:475, 448, 449, 450, 478, 479 and 480. Similarly, positions 93 and 94 of SEQ ID NO:44 correspond to positions 94 and 95 of SEQ ID NO:430, 431 , 451 , 452, 453, 454, 455 and 456.

[0771] For example, in each of SEQ ID NO: 44, 475, 448, 449, 450, 478, 479 and 480, the amino acid at position 93 may be an amino acid other than D (e.g. an amino acid selected from A, R, N, E, Q, G, H, I, L, K, M, F, P, S, T, W, Y and V). In a further example, in each of SEQ ID NO: 430, 431 , 451 , 452, 453, 454, 455 and 456, the amino acid at position 94 may be an amino acid other than D (e.g. an amino acid selected from A, R, N, E, Q, G, H, I, L, K, M, F, P, S, T, W, Y and V).

[0772] In a further example, in each of SEQ ID NO: 44, 475, 448, 449, 450, 478, 479 and 480, the amino acid at position 94 may be an amino acid other than P (e.g. an amino acid selected from A, R, N, D, E, Q, G, H, I, L, K, M, F, S, T, W, Y and V). In a further example, in each of SEQ ID NO: 430, 431 , 451 , 452, 453, 454, 455 and 456, the amino acid at position 95 may be an amino acid other than P (e.g. an amino acid selected from A, R, N, D, E, Q, G, H, I, L, K, M, F, S, T, W, Y and V).

[0773] In some embodiments, a VL according according to any one of (312) or (314) to (332) comprises an amino acid other than ‘D’ at the position corresponding to position 93 of SEQ ID NO:44 and an amino acid other than ‘P’ at the position corresponding to position 94 of SEQ ID NO:44. In some embodiments, the amino acid other than ‘D’ is selected from ‘A’, ‘R’, ‘N’, ‘E’, ‘Q’, ‘G’, ‘H’, T, ‘L’, ‘K’, ‘M’, ‘F’, ‘P’, ‘S', T, W, ‘Y’ and ‘V’, and the amino acid other than ‘P’ is selected from ‘A’, ‘R’, ‘N’, ‘D’, ‘E’, ‘Q’, ‘G’, ‘H’, T, ‘L’, K’, ‘M’, ‘F’, ‘S’, T, W, ‘Y’ and .

[0774] In some embodiments, the antigen-binding molecule comprises a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:448, 451 , 454, or 478. In some embodiments, X is A. In some embodiments, X is R. In some embodiments, X is N. In some embodiments, X is E. In some embodiments, X is Q. In some embodiments, X is G. In some embodiments, X is H. In some embodiments, X is I. In some embodiments, X is L. In some embodiments, X is K. In some embodiments, X is M. In some embodiments, X is F. In some embodiments, X is P. In some embodiments, X is S. In some embodiments, X is T. In some embodiments, X is W. In some embodiments, X is Y. In some embodiments, X is V.

[0775] In some embodiments, the antigen-binding molecule comprises a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:449, 452, 455, or 479. In some embodiments, X is A. In some embodiments, X is R. In some embodiments, X is N. In some embodiments, X is D. In some embodiments, X is E. In some embodiments, X is Q. In some embodiments, X is G. In some embodiments, X is H. In some embodiments, X is L In some embodiments, X is L. In some embodiments, X is K. In some embodiments, X is M. In some embodiments, X is F. In some embodiments, X is S. In some embodiments, X is T. In some embodiments, X is W. In some embodiments, X is Y. In some embodiments, X is V.

[0776] In some embodiments, the antigen-binding molecule comprises a VL region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:450, 453, 456, or 480. In some embodiments, Xi is A and X2 is A. In some embodiments, Xi is A and X2 is R. In some embodiments, Xi is A and X2 is N. In some embodiments, Xi is A and X2 is D. In some embodiments, Xi is A and X2 is E. In some embodiments, Xi is A and X2 is Q. In some embodiments, Xi is A and X2 is G. In some embodiments, Xi is A and X2 is H. In some embodiments, Xi is A and X2 is I. In some embodiments, Xi is A and X2 is L. In some embodiments, Xi is A and X2 is K. In some embodiments, Xi is A and X2 is M. In some embodiments, Xi is A and X2 is F. In some embodiments, Xi is A and X2 is S. In some embodiments, Xi is A and X2 is T. In some embodiments, Xi is A and X2 is W. In some embodiments, Xi is A and X2 is Y. In some embodiments, Xi is A and X2 is V. In some embodiments, Xi is R and X2 is A. In some embodiments, Xi is R and X2 is R. In some embodiments, Xi is R and X2 is N. In some embodiments, Xi is R and X2 is D. In some embodiments, Xi is R and X2 is E. In some embodiments, Xi is R and X2 is Q. In some embodiments, Xi is R and X2 is G. In some embodiments, Xi is R and X2 is H. In some embodiments, Xi is R and X2 is I. In some embodiments, Xi is R and X2 is L. In some embodiments, Xi is R and X2 is K. In some embodiments, Xi is R and X2 is M. In some embodiments, Xi is R and X2 is F. In some embodiments, Xi is R and X2 is S. In some embodiments, Xi is R and X2 is T. In some embodiments, Xi is R and X2 is W. In some embodiments, Xi is R and X2 is Y. In some embodiments, Xi is R and X2 is V. In some embodiments, Xi is N and X2 is A. In some embodiments, Xi is N and X2 is R. In some embodiments, Xi is N and X2 is N. In some embodiments, Xi is N and X2 is D. In some embodiments, Xi is N and X2 is E. In some embodiments, Xi is N and X2 is Q. In some embodiments, Xi is N and X2 is G. In some embodiments, Xi is N and X2 is H. In some embodiments, Xi is N and X2 is I. In some embodiments, Xi is N and X2 is L. In some embodiments, Xi is N and X2 is K. In some embodiments, Xi is N and X2 is M. In some embodiments, Xi is N and X2 is F. In some embodiments, Xi is N and X2 is S. In some embodiments, Xi is N and X2 is T. In some embodiments, Xi is N and X2 is W. In some embodiments, Xi is N and X2 is Y. In some embodiments, Xi is N and X2 is V. In some embodiments, Xi is E and X2 is A. In some embodiments, Xi is E and X2 is R. In some embodiments, Xi is E and X2 is N. In some embodiments, Xi is E and X2 is D. In some embodiments, Xi is E and X2 is E. In some embodiments, Xi is E and X2 is Q. In some embodiments, Xi is E and X2 is G. In some embodiments, Xi is E and X2 is H. In some embodiments, Xi is E and X2 is I. In some embodiments, Xi is E and X2 is L. In some embodiments, Xi is E and X2 is K. In some embodiments, Xi is E and X2 is M. In some embodiments, Xi is E and X2 is F. In some embodiments, Xi is E and X2 is S. In some embodiments, Xi is E and X2 is T. In some embodiments, Xi is E and X2 is W. In some embodiments, Xi is E and X2 is Y. In some embodiments, Xi is E and X2 is V. In some embodiments, Xi is Q and X2 is A. In some embodiments, Xi is Q and X2 is R. In some embodiments, Xi is Q and X2 is N. In some embodiments, Xi is Q and X2 is D. In some embodiments, Xi is Q and X2 is E. In some embodiments, Xi is Q and X2 is Q. In some embodiments, Xi is Q and X2 is G. In some embodiments, Xi is Q and X2 is H. In some embodiments, Xi is Q and X2 is I. In some embodiments, Xi is Q and X2 is L. In some embodiments, Xi is Q and X2 is K. In some embodiments, Xi is Q and X2 is M. In some embodiments, Xi is Q and X2 is F. In some embodiments, Xi is Q and X2 is S. In some embodiments, Xi is Q and X2 is T. In some embodiments, Xi is Q and X2 is W. In some embodiments, Xi is Q and X2 is Y. In some embodiments, Xi is Q and X2 is V. In some embodiments, Xi is G and X2 is A. In some embodiments, Xi is G and X2 is R. In some embodiments, Xi is G and X2 is N. In some embodiments, Xi is G and X2 is D. In some embodiments, Xi is G and X2 is E. In some embodiments, Xi is G and X2 is Q. In some embodiments, Xi is G and X2 is G. In some embodiments, Xi is G and X2 is H. In some embodiments, Xi is G and X2 is I. In some embodiments, Xi is G and X2 is L. In some embodiments, Xi is G and X2 is K. In some embodiments, Xi is G and X2 is M. In some embodiments, Xi is G and X2 is F. In some embodiments, Xi is G and X2 is S. In some embodiments, Xi is G and X2 is T. In some embodiments, Xi is G and X2 is W. In some embodiments, Xi is G and X2 is Y. In some embodiments, Xi is G and X2 is V. In some embodiments, Xi is H and X2 is A. In some embodiments, Xi is H and X2 is R. In some embodiments, Xi is H and X2 is N. In some embodiments, Xi is H and X2 is D. In some embodiments, Xi is H and X2 is E. In some embodiments, Xi is H and X2 is Q. In some embodiments, Xi is H and X2 is G. In some embodiments, Xi is H and X2 is H. In some embodiments, Xi is H and X2 is I. In some embodiments, Xi is H and X2 is L. In some embodiments, Xi is H and X2 is K. In some embodiments, Xi is H and X2 is M. In some embodiments, Xi is H and X2 is F. In some embodiments, Xi is H and X2 is S. In some embodiments, Xi is H and X2 is T. In some embodiments, Xi is H and X2 is W. In some embodiments, Xi is H and X2 is Y. In some embodiments, Xi is H and X2 is V. In some embodiments, Xi is I and X2 is A. In some embodiments, Xi is I and X2 is R. In some embodiments, Xi is I and X2 is N. In some embodiments, Xi is I and X2 is D. In some embodiments, Xi is I and X2 is E. In some embodiments, Xi is I and X2 is Q. In some embodiments, Xi is I and X2 is G. In some embodiments, Xi is I and X2 is H. In some embodiments, Xi is I and X2 is I. In some embodiments, Xi is I and X2 is L. In some embodiments, Xi is I and X2 is K. In some embodiments, Xi is I and X2 is M. In some embodiments, Xi is I and X2 is F. In some embodiments, Xi is I and X2 is S. In some embodiments, Xi is I and X2 is T. In some embodiments, Xi is I and X2 is W. In some embodiments, Xi is I and X2 is Y. In some embodiments, Xi is I and X2 is V. In some embodiments, Xi is L and X2 is A. In some embodiments, Xi is L and X2 is R. In some embodiments, Xi is L and X2 is N. In some embodiments, Xi is L and X2 is D. In some embodiments, Xi is L and X2 is E. In some embodiments, Xi is L and X2 is Q. In some embodiments, Xi is L and X2 is G. In some embodiments, Xi is L and X2 is H. In some embodiments, Xi is L and X2 is I. In some embodiments, Xi is L and X2 is L. In some embodiments, Xi is L and X2 is K. In some embodiments, Xi is L and X2 is M. In some embodiments, Xi is L and X2 is F. In some embodiments, Xi is L and X2 is S. In some embodiments, Xi is L and X2 is T. In some embodiments, Xi is L and X2 is W. In some embodiments, Xi is L and X2 is Y. In some embodiments, Xi is L and X2 is V. In some embodiments, Xi is K and X2 is A. In some embodiments, Xi is K and X2 is R. In some embodiments, Xi is K and X2 is N. In some embodiments, Xi is K and X2 is D. In some embodiments, Xi is K and X2 is E. In some embodiments, Xi is K and X2 is Q. In some embodiments, Xi is K and X2 is G. In some embodiments, Xi is K and X2 is H. In some embodiments, Xi is K and X2 is I. In some embodiments, Xi is K and X2 is L. In some embodiments, Xi is K and X2 is K. In some embodiments, Xi is K and X2 is M. In some embodiments, Xi is K and X2 is F. In some embodiments, Xi is K and X2 is S. In some embodiments, Xi is K and X2 is T. In some embodiments, Xi is K and X2 is W. In some embodiments, Xi is K and X2 is Y. In some embodiments, Xi is K and X2 is V. In some embodiments, Xi is M and X2 is A. In some embodiments, Xi is M and X2 is R. In some embodiments, Xi is M and X2 is N. In some embodiments, Xi is M and X2 is D. In some embodiments, Xi is M and X2 is E. In some embodiments, Xi is M and X2 is Q. In some embodiments, Xi is M and X2 is G. In some embodiments, Xi is M and X2 is H. In some embodiments, Xi is M and X2 is I. In some embodiments, Xi is M and X2 is L. In some embodiments, Xi is M and X2 is K. In some embodiments, Xi is M and X2 is M. In some embodiments, Xi is M and X2 is F. In some embodiments, Xi is M and X2 is S. In some embodiments, Xi is M and X2 is T. In some embodiments, Xi is M and X2 is W. In some embodiments, Xi is M and X2 is Y. In some embodiments, Xi is M and X2 is V. In some embodiments, Xi is F and X2 is A. In some embodiments, Xi is F and X2 is R. In some embodiments, Xi is F and X2 is N. In some embodiments, Xi is F and X2 is D. In some embodiments, Xi is F and X2 is E. In some embodiments, Xi is F and X2 is Q. In some embodiments, Xi is F and X2 is G. In some embodiments, Xi is F and X2 is H. In some embodiments, Xi is F and X2 is I. In some embodiments, Xi is F and X2 is L. In some embodiments, Xi is F and X2 is K. In some embodiments, Xi is F and X2 is M. In some embodiments, Xi is F and X2 is F. In some embodiments, Xi is F and X2 is S. In some embodiments, Xi is F and X2 is T. In some embodiments, Xi is F and X2 is W. In some embodiments, Xi is F and X2 is Y. In some embodiments, Xi is F and X2 is V. In some embodiments, Xi is P and X2 is A. In some embodiments, Xi is P and X2 is R. In some embodiments, Xi is P and X2 is N. In some embodiments, Xi is P and X2 is D. In some embodiments, Xi is P and X2 is E. In some embodiments, Xi is P and X2 is Q. In some embodiments, Xi is P and X2 is G. In some embodiments, Xi is P and X2 is H. In some embodiments, Xi is P and X2 is I. In some embodiments, Xi is P and X2 is L. In some embodiments, Xi is P and X2 is K. In some embodiments, Xi is P and X2 is M. In some embodiments, Xi is P and X2 is F. In some embodiments, Xi is P and X2 is S. In some embodiments, Xi is P and X2 is T. In some embodiments, Xi is P and X2 is W. In some embodiments, Xi is P and X2 is Y. In some embodiments, Xi is P and X2 is V. In some embodiments, Xi is S and X2 is A. In some embodiments, Xi is S and X2 is R. In some embodiments, Xi is S and X2 is N. In some embodiments, Xi is S and X2 is D. In some embodiments, Xi is S and X2 is E. In some embodiments, Xi is S and X2 is Q. In some embodiments, Xi is S and X2 is G. In some embodiments, Xi is S and X2 is H. In some embodiments, Xi is S and X2 is I. In some embodiments, Xi is S and X2 is L. In some embodiments, Xi is S and X2 is K. In some embodiments, Xi is S and X2 is M. In some embodiments, Xi is S and X2 is F. In some embodiments, Xi is S and X2 is S. In some embodiments, Xi is S and X2 is T. In some embodiments, Xi is S and X2 is W. In some embodiments, Xi is S and X2 is Y. In some embodiments, Xi is S and X2 is V. In some embodiments, Xi is T and X2 is A. In some embodiments, Xi is T and X2 is R. In some embodiments, Xi is T and X2 is N. In some embodiments, Xi is T and X2 is D. In some embodiments, Xi is T and X2 is E. In some embodiments, Xi is T and X2 is Q. In some embodiments, Xi is T and X2 is G. In some embodiments, Xi is T and X2 is H. In some embodiments, Xi is T and X2 is I. In some embodiments, Xi is T and X2 is L. In some embodiments, Xi is T and X2 is K. In some embodiments, Xi is T and X2 is M. In some embodiments, Xi is T and X2 is F. In some embodiments, Xi is T and X2 is S. In some embodiments, Xi is T and X2 is T. In some embodiments, Xi is T and X2 is W. In some embodiments, Xi is T and X2 is Y. In some embodiments, Xi is T and X2 is V. In some embodiments, Xi is W and X2 is A. In some embodiments, Xi is W and X2 is R. In some embodiments, Xi is W and X2 is N. In some embodiments, Xi is W and X2 is D. In some embodiments, Xi is W and X2 is E. In some embodiments, Xi is W and X2 is Q. In some embodiments, Xi is W and X2 is G. In some embodiments, Xi is W and X2 is H. In some embodiments, Xi is W and X2 is I. In some embodiments, Xi is W and X2 is L. In some embodiments, Xi is W and X2 is K. In some embodiments, Xi is W and X2 is M. In some embodiments, Xi is W and X2 is F. In some embodiments, Xi is W and X2 is S. In some embodiments, Xi is W and X2 is T. In some embodiments, Xi is W and X2 is W. In some embodiments, Xi is W and X2 is Y. In some embodiments, Xi is W and X2 is V. In some embodiments, Xi is Y and X2 is A. In some embodiments, Xi is Y and X2 is R. In some embodiments, Xi is Y and X2 is N. In some embodiments, Xi is Y and X2 is D. In some embodiments, Xi is Y and X2 is E. In some embodiments, Xi is Y and X2 is Q. In some embodiments, Xi is Y and X2 is G. In some embodiments, Xi is Y and X2 is H. In some embodiments, Xi is Y and X2 is I. In some embodiments, Xi is Y and X2 is L. In some embodiments, Xi is Y and X2 is K. In some embodiments, Xi is Y and X2 is M. In some embodiments, Xi is Y and X2 is F. In some embodiments, Xi is Y and X2 is S. In some embodiments, Xi is Y and X2 is T. In some embodiments, Xi is Y and X2 is W. In some embodiments, Xi is Y and X2 is Y. In some embodiments, Xi is Y and X2 is V. In some embodiments, Xi is V and X2 is A. In some embodiments, Xi is V and X2 is R. In some embodiments, Xi is V and X2 is N. In some embodiments, Xi is V and X2 is D. In some embodiments, Xi is V and X2 is E. In some embodiments, Xi is V and X2 is Q. In some embodiments, Xi is V and X2 is G. In some embodiments, Xi is V and X2 is H. In some embodiments, Xi is V and X2 is I. In some embodiments, Xi is V and X2 is L. In some embodiments, Xi is V and X2 is K. In some embodiments, Xi is V and X2 is M. In some embodiments, Xi is V and X2 is F. In some embodiments, Xi is V and X2 is S. In some embodiments, Xi is V and X2 is T. In some embodiments, Xi is V and X2 is W. In some embodiments, Xi is V and X2 is Y. In some embodiments, Xi is V and X2 is V.

[0777] The VH and VL region of an antigen-binding region of an antibody together constitute the Fv region. In some embodiments, the antigen-binding molecule according to the present disclosure comprises, or consists of, an Fv region that binds to gp130. In some embodiments, the VH and VL regions of the Fv are provided as single polypeptide joined by a linker sequence, i.e. a single chain Fv (scFv).

[0778] The VL and light chain constant (CL) region, and the VH region and heavy chain constant 1 (CH1) region of an antigen-binding region of an antibody together constitute the Fab region. In some embodiments, the antigen-binding molecule comprises a Fab region comprising a VH, a CH1 , a VL and a CL (e.g. CK or CA). In some embodiments, the Fab region comprises a polypeptide comprising a VH and a CH1 (e.g. a VH-CH1 fusion polypeptide), and a polypeptide comprising a VL and a CL (e.g. a VL-CL fusion polypeptide). In some embodiments, the Fab region comprises a polypeptide comprising a VH and a CL (e.g. a VH-CL fusion polypeptide) and a polypeptide comprising a VL and a CH (e.g. a VL-CH1 fusion polypeptide); that is, in some embodiments, the Fab region is a CrossFab region. In some embodiments, the VH, CH1 , VL and CL regions of the Fab or CrossFab are provided as single polypeptide joined by linker regions, i.e. as a single chain Fab (scFab) or a single chain CrossFab (scCrossFab).

[0779] In some embodiments, the antigen-binding molecule described herein comprises, or consists of, a whole antibody that binds to gp130. As used herein, ‘whole antibody’ refers to an antibody having a structure which is substantially similar to the structure of an immunoglobulin (Ig). Different kinds of immunoglobulins and their structures are described e.g. in Schroeder and Cavacini J Allergy Clin Immunol. (2010) 125(202): S41-S52, which is hereby incorporated by reference in its entirety. Immunoglobulins of type G (i.e. IgG) are -150 kDa glycoproteins comprising two heavy chains and two light chains. From N- to C-terminus, the heavy chains comprise a VH followed by a heavy chain constant region comprising three constant domains (CH1 , CH2, and CH3), and similarly the light chains comprise a VL followed by a CL. Depending on the heavy chain, immunoglobulins may be classed as IgG (e.g.

[0780] IgG 1 , lgG2, lgG3, lgG4), IgA (e.g. lgA1 , lgA2), IgD, IgE, or IgM. The light chain may be kappa (K) or lambda (A).

[0781] Herein, a ‘CH2 domain’ refers to an amino acid sequence corresponding to the CH2 domain of an immunoglobulin (Ig). The CH2 domain is the region of an Ig formed by positions 231 to 340 of the immunoglobulin constant domain, according to the EU numbering system (described in Edelman et al., Proc Natl Acad Sci USA (1969) 63(1): 78-85). A ‘CH3 domain’ refers to an amino acid sequence corresponding to the CH3 domain of an immunoglobulin (Ig). The CH3 domain is the region of an Ig formed by positions 341 to 447 of the immunoglobulin constant domain, according to the EU numbering system. A ‘CH2-CH3 region’ refers to an amino acid sequence corresponding to the CH2 and CH3 domains of an immunoglobulin (Ig). The CH2-CH3 region is the region of an Ig formed by positions 231 to 447 of the immunoglobulin constant domain, according to the EU numbering system.

[0782] In some embodiments, the antigen-binding molecule described herein comprises, or consists of, an IgG (e.g. lgG1 , lgG2, lgG3, lgG4), IgA (e.g. lgA1 , lgA2), IgD, IgE, or IgM that binds to gp130.

[0783] In some embodiments, the antigen-binding molecule of the present disclosure comprises one or more regions (e.g. CH1 , CH2, CH3, etc.) of an immunoglobulin heavy chain constant sequence. In some embodiments, the immunoglobulin heavy chain constant sequence is, or is derived from, the heavy chain constant sequence of an IgG (e.g. lgG1 , lgG2, lgG3, lgG4), IgA (e.g. lgA1 , lgA2), IgD, IgE or IgM, e.g. a human IgG (e.g. hlgG1 , hlgG2, hlgG3, hlgG4), hlgA (e.g. hlgA1 , hlgA2), hlgD, h IgE or hlgM. In some embodiments, the immunoglobulin heavy chain constant sequence is, or is derived from, the heavy chain constant sequence of a human IgG 1 allotype (e.g. G1 ml , G1 m2, G1 m3 or G1 m17).

[0784] In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:111 or 116. In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:192 or 193. In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:119 or 194.

[0785] In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO: 120, 121 , 190 or 191 . In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:122 or 201 .

[0786] In some embodiments, the antigen-binding molecule comprises a CH1 region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:1 12 or 117. In some embodiments, the antigen-binding molecule comprises a CH1 region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:195.

[0787] In some embodiments, the antigen-binding molecule comprises a hinge region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:1 13. In some embodiments, the antigen-binding molecule comprises a hinge region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:196 or 197.

[0788] In some embodiments, the antigen-binding molecule comprises a CH2 region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:1 14 or 189. In some embodiments, the antigen-binding molecule comprises a CH2 region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:198 or 199.

[0789] In some embodiments, the antigen-binding molecule comprises a CH3 region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:1 15 or 118. In some embodiments, the antigen-binding molecule comprises a CH2 region comprising an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NQ:200.

[0790] It will be appreciated that CH2 and / or CH3 regions may be provided with further substitutions in accordance with modification to an Fc region of the antigen-binding molecule as described herein. In some embodiments, the antigen-binding molecule of the present disclosure comprises one or more regions of an immunoglobulin light chain constant sequence. In some embodiments, the immunoglobulin light chain constant sequence is human immunoglobulin kappa constant (IGKC; CK). In some embodiments, the immunoglobulin light chain constant sequence is a human immunoglobulin lambda constant (IGLC; GA), e.g. IGLC1 , IGLC2, IGLC3, IGLC6 or IGLC7.

[0791] In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:123, 124, 125, 126, 127 or 128. In preferred embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:123.

[0792] In some embodiments, the antigen-binding molecule is or comprises a monoclonal antibody, or an antigen-binding fragment thereof.

[0793] In some embodiments, the antigen-binding molecule is or comprises a fully human antibody / antibody fragment. A fully human antibody / antibody fragment may be encoded by human nucleic acid sequence(s). A fully human antibody / antibody fragment may be devoid of non-human amino acid sequences. Commonly employed techniques for the production of fully human antibodies include (i) phage display, in which human antibody genes are expressed in phage display libraries, and (ii) production of antibodies in transgenic mice engineered to have human antibody genes (described in Park and Smolen, Advances in Protein Chemistry (2001) 56: 369-421). Briefly, in the human antibody genephage display technique, genes encoding the VH and VL chains are generated by PCR amplification and cloning from ‘naive’ human lymphocytes, and assembled into a library from which they can be expressed either as disu Ifide-linked Fab fragments or as single-chain Fv (scFv) fragments. The Fab- or scFv- encoding genes are fused to a surface coat protein of filamentous bacteriophage and Fab or scFv capable of binding to the target of interest can then be identified by screening the library with antigen. Molecular evolution or affinity maturation procedures can be employed to enhance the affinity of the Fab / scFv fragment. In the transgenic mouse technique, mice in which the endogenous murine Ig gene loci have been replaced by homologous recombination with their human homologues are immunised with antigen, and monoclonal antibody is prepared by conventional hybridoma technology, to yield a fully human monoclonal antibody.

[0794] In some embodiments, the antigen-binding molecule of the present disclosure is a mouse antibody / antibody fragment. In some embodiments, the antibody / antibody fragment is obtained from phage display using a human naive antibody gene library.

[0795] In some embodiments, the antigen-binding molecule is a mouse / human chimeric antigen-binding molecule ( / .e. an antigen-binding molecule comprising mouse antibody variable domains and human antibody constant regions). In some embodiments, the antigen-binding molecule is a humanised antigen- binding molecule (i.e. an antigen-binding molecule comprising variable domains derived by humanisation of the variable domains of an antibody from a non-human animal, e.g. a mouse) comprising mouse antibody variable domains and human antibody constant regions. In some embodiments, the antigenbinding molecule comprises mouse antibody CDRs and human antibody framework and constant regions.

[0796] Mouse / human chimeric antigen-binding molecules can be prepared from mouse antibodies by the process of chimerisation, e.g. as described in Human Monoclonal Antibodies: Methods and Protocols, Michael Steinitz (Editor), Methods in Molecular Biology 1060, Springer Protocols, Humana Press (2014), in Chapter 8 thereof, in particular section 3 of Chapter 8.

[0797] Humanised antigen-binding molecules can be prepared from mouse antibodies by the process of humanisation, e.g. as described in Human Monoclonal Antibodies: Methods and Protocols, Michael Steinitz (Editor), Methods in Molecular Biology 1060, Springer Protocols, Humana Press (2014), in Chapter 7 thereof, in particular section 3.1 of Chapter 7 entitled ‘Antibody Humanization’. Techniques for antibody humanisation are also described e.g. in Safdari et al., Biotechnol Genet Eng Rev (2013) 29:175- 86.

[0798] Aspects of the present disclosure relate to multispecific antigen-binding molecules. By ‘multispecific’ it is meant that the antigen-binding molecule displays specific binding to more than one target. In some embodiments, the antigen-binding molecule is a bispecific antigen-binding molecule. In some embodiments, the antigen-binding molecule comprises at least two different antigen-binding domains (i.e. at least two antigen-binding domains, e.g. comprising non-identical VHs and VLs).

[0799] In some embodiments, the antigen-binding molecule binds to gp130 and another target (e.g. an antigen other than gp130), and so is at least bispecific. The term ‘bispecific’ means that the antigen-binding molecule is able to bind specifically to at least two distinct antigenic determinants.

[0800] It will be appreciated that an antigen-binding molecule according to the present disclosure (e.g. a multispecific antigen-binding molecule) may comprise antigen-binding molecules capable of binding to the targets for which the antigen-binding molecule is specific. For example, an antigen-binding molecule that binds to gp130 and an antigen other than gp130 may comprise: (i) an antigen-binding molecule that binds to gp130, and (ii) an antigen-binding molecule that binds to an antigen other than gp130.

[0801] It will also be appreciated that an antigen-binding molecule according to the present disclosure (e.g. a multispecific antigen-binding molecule) may comprise antigen-binding polypeptides or antigen-binding polypeptide complexes capable of binding to the targets for which the antigen-binding molecule is specific.

[0802] In some embodiments, a component antigen-binding molecule of a larger antigen-binding molecule (e.g. a multispecific antigen-binding molecule) may be referred to e.g. as an ‘antigen-binding domain’ or antigen-binding region’ of the larger antigen-binding molecule. In some embodiments, the antigen other than gp130 in a multispecific antigen-binding molecule is an immune cell surface molecule. In some embodiments, the antigen is a cancer cell antigen. In some embodiments, the antigen is a receptor molecule, e.g. a cell surface receptor. In some embodiments, the antigen is a cell signalling molecule, e.g. a cytokine, chemokine, interferon, interleukin or lymphokine. In some embodiments, the antigen is a growth factor or a hormone.

[0803] In some embodiments, the antigen-binding molecule is an immune cell engager. Immune cell engagers are reviewed e.g. in Goebeler and Bargou, Nat. Rev. Clin. Oncol. (2020) 17: 418-434 and Ellerman, Methods (2019) 154:102-1 17, both of which are hereby incorporated by reference in their entirety. Immune cell engager molecules comprise an antigen-binding region for a target antigen of interest, and an antigen-binding region for recruiting / engaging an immune cell of interest. Immune cell engagers recruit / engage immune cells through an antigen-binding region specific for an immune cell surface molecule.

[0804] The best studied immune cell engagers are bispecific T cell engagers (BiTEs), which comprise a target antigen binding domain, and a CD3 polypeptide (typically CD3e)-binding domain, through which the BiTE recruits T cells. Binding of the BiTE to its target antigen and to the CD3 polypeptide expressed by the T cell results in activation of the T cell, and ultimately directs T cell effector activity against cells expressing the target antigen. Other kinds of immune cell engagers are well known in the art, and include natural killer cell engagers such as bispecific killer engagers (BiKEs), which recruit and activate NK cells.

[0805] In some embodiments, the immune cell engaged by the immune cell engager is a T cell or an NK cell. In some embodiments, the immune cell engager is a T cell-engager.

[0806] Multispecific antigen-binding molecules according to the present disclosure may be provided in any suitable format, such as those formats described in described in Brinkmann and Kontermann, MAbs (2017) 9(2): 182-212, which is hereby incorporated by reference in its entirety. Suitable formats include those shown in Figure 2 of Brinkmann and Kontermann, MAbs (2017) 9(2): 182-212: antibody conjugates, e.g. lgG2, F(ab’)2 or CovX-Body; IgG or IgG-like molecules, e.g. IgG, chimeric IgG, K -body common HC; CH1 / CL fusion proteins, e.g. scFv2-CH1 / CL, VHH2-CH1 / CL; ‘variable domain only’ bispecific antigenbinding molecules, e.g. tandem scFv (taFV), triplebodies, diabodies (Db), dsDb, Db(kih), DART, scDB, dsFv-dsFv, tandAbs, triple heads, tandem dAbA / HH, tertravalent dAb.VHH; Non-lg fusion proteins, e.g. scFv2-albumin, scDb-albumin, taFv-albumin, taFv-toxin, miniantibody, DNL-Fab2, DNL-Fab2-scFv, DNL- Fab2-lgG-cytokine2, ImmTAC (TCR-scFv); modified Fc and CH3 fusion proteins, e.g. scFv-Fc(kih), scFv- Fc(CH3 charge pairs), scFv-Fc (EW-RVT), scFv-fc (HA-TF), scFv-Fc (SEEDbody), taFv-Fc(kih), scFv- Fc(kih)-Fv, Fab-Fc(kih)-scFv, Fab-scFv-Fc(kih), Fab-scFv-Fc(BEAT), Fab-scFv-Fc (SEEDbody), DART- Fc, scFv-CH3(kih), TriFabs; Fc fusions, e.g. Di-diabody, scDb-Fc, taFv-Fc, scFv-Fc-scFv, HCAb-VHH, Fab-scFv-Fc, scFv4-lg, scFv2-Fcab; CH3 fusions, e.g. Dia-diabody, scDb-CH3; IgE / IgM CH2 fusions, e.g. scFv-EHD2-scFv, scFvMHD2-scFv; Fab fusion proteins, e.g. Fab-scFv (bibody), Fab-scFv2 (tribody), Fab- Fv, Fab-dsFv, Fab-VHH, orthogonal Fab-Fab; non-lg fusion proteins, e.g. DNL-Fabs, DNL-Fab2-scFv, DNL-Fab2-lgG-cytokine2; asymmetric IgG or IgG-like molecules, e g. IgG(kih), IgG(kih) common LC, ZW1 IgG common LC, Biclonics common LC, CrossMab, CrossMab(kih), scFab-lgG(kih), Fab-scFab-lgG(kih), orthogonal Fab IgG(kih), DuetMab, CH3 charge pairs + CH1 / CL charge pairs, hinge / CH3 charge pairs, SEED-body, Duobody, four-in-one-CrossMab(kih), LUZ-Y common LC; LUZ-Y scFab-IgG, FcFc*; appended and Fc-modified IgGs, e.g. lgG(kih)-Fv, IgG HA-TF-Fv, lgG(kih)scFab, scFab-Fc(kih)-scFv2, scFab-Fc(kih)-scFv, half DVD-lg, DVI-lg (four-in-one), CrossMab-Fab; modified Fc and CH3 fusion proteins, e.g. Fab-Fc(kih)-scFv, Fab-scFv-Fc(kih), Fab-scFv-Fc(BEAT), Fab-scFv-Fc-SEEDbody, TriFab; appended IgGs - HC fusions, e.g. IgG-HC, scFv, IgG-dAb, IgG-taFV, IgG-CrossFab, IgG-orthogonal Fab, IgG-(CaCp) Fab, scFv-HC-IgG, tandem Fab-IgG (orthogonal Fab), Fab-lgG(CaCp Fab), Fab-lgG(CR3), Fab-hinge-lgG(CR3); appended IgGs - LC fusions, e.g. IgG-scFv(LC), scFv(LC)-lgG, dAb-IgG; appended IgGs - HC and LC fusions, e.g. DVD-lg, TVD-lg, CODV-lg, scFv4-lgG, Zybody; Fc fusions, e.g. Fab-scFv- Fc, scFv4-lg; F(ab’)2 fusions, e.g. F(ab’)2-scFv2; CH1 / CL fusion proteins e.g. scFv2-CH1-hinge / CL; modified IgGs, e.g. DAF (two-in one-IgG), DutaMab, Mab2; and non-lg fusions, e.g. DNL-Fab4-lgG. The skilled person is readily able to design and produce multispecific antigen-binding molecules.

[0807] The present disclosure also provides Chimeric Antigen Receptors (CARs). CARs are recombinant receptors that provide both antigen-binding and T cell activating functions. CAR structure and engineering is reviewed, for example, in Dotti et al., Immunol Rev (2014) 257(1), hereby incorporated by reference in its entirety. CARs comprise an antigen-binding region linked to a cell membrane anchor region and a signalling region. An optional hinge region may provide separation between the antigen-binding region and cell membrane anchor region, and may act as a flexible linker.

[0808] The antigen-binding domain of a CAR according to the present disclosure comprises or consists of an antigen-binding molecule that binds to gp130 as described herein. Accordingly, a CAR according to the present disclosure comprises an antigen-binding molecule as described herein.

[0809] It will be appreciated that an antigen-binding molecule according to the present disclosure forms, or is comprised in, the antigen-binding domain of the CAR. Accordingly, in some embodiments, the antigenbinding molecule of the present disclosure is comprised in a CAR.

[0810] It will also be appreciated that an antigen-binding molecule according to the present disclosure may be a CAR. A CAR having an antigen-binding domain comprising or consisting of an antigen-binding molecule of the present disclosure (e.g. a gp130-binding Fv) is an antigen-binding molecule. The antigen-binding domain of the CAR of the present disclosure may be provided with any suitable format, e.g. scFv, scFab, etc.

[0811] The cell membrane anchor region is provided between the antigen-binding region and the signalling region of the CAR and provides for anchoring the CAR to the cell membrane of a cell expressing a CAR, with the antigen-binding region in the extracellular space, and signalling region inside the cell. In some embodiments, the CAR comprises a cell membrane anchor region comprising or consisting of an amino acid sequence which comprises, consists of, or is derived from, the transmembrane region amino acid sequence for one of CD3- , CD4, CD8 or CD28. As used herein, a region which is ‘derived from’ a reference amino acid sequence comprises an amino acid sequence having at least 60%, e.g. one of at least 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the reference sequence.

[0812] The signalling region of a CAR allows for activation of the T cell. The CAR signalling regions may comprise the amino acid sequence of the intracellular domain of CD3- , which provides immunoreceptor tyrosine-based activation motifs (ITAMs) for phosphorylation and activation of the CAR-expressing T cell. Signalling regions comprising sequences of other ITAM-containing proteins such as FcyRI have also been employed in CARs (Haynes et al., 2001 J Immunol 166(1):182-187). Signalling regions of CARs may also comprise co-stimulatory sequences derived from the signalling region of co-stimulatory molecules, to facilitate activation of CAR-expressing T cells upon binding to the target protein. Suitable co-stimulatory molecules include CD28, 0X40, 4-1 BB, ICOS and CD27. In some cases CARs are engineered to provide for co-stimulation of different intracellular signalling pathways. For example, signalling associated with CD28 costimulation preferentially activates the phosphatidylinositol 3-kinase (PI3K) pathway, whereas the 4-1 BB-mediated signalling is through TNF receptor associated factor (TRAF) adaptor proteins. Signalling regions of CARs therefore sometimes contain co-stimulatory sequences derived from signalling regions of more than one co-stimulatory molecule. In some embodiments, the CAR of the present disclosure comprises one or more co-stimulatory sequences comprising or consisting of an amino acid sequence which comprises, consists of, or is derived from, the amino acid sequence of the intracellular domain of one or more of CD28, 0X40, 4-1 BB, ICOS and CD27.

[0813] An optional hinge region may provide separation between the antigen-binding domain and the transmembrane domain, and may act as a flexible linker. Hinge regions may be derived from IgG 1 or lgG4. In some embodiments, the CAR of the present disclosure comprises a hinge region comprising or consisting of an amino acid sequence which comprises, consists of, or is derived from, the amino acid sequence of the hinge region of lgG1 or lgG4. In some embodiments, the hinge region of a CAR according to the present disclosure comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:113. In some embodiments, the hinge region of a CAR according to the present disclosure comprises an amino acid sequence having at least 70% sequence identity more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, sequence identity to the amino acid sequence of SEQ ID NO:196 or 197.

[0814] Also provided is a cell comprising a CAR according to the present disclosure. The CAR according to the present disclosure may be used to generate CAR-expressing immune cells, e.g. CAR-T or CAR-NK cells. Engineering of CARs into immune cells may be performed during culture, in vitro.

[0815] Fc regions

[0816] In some embodiments, the antigen-binding molecules of the present disclosure comprise an Fc region. As used herein, an ‘Fc region’ refers to a polypeptide complex formed by interaction between two polypeptides, each polypeptide comprising the CH2-CH3 region of an immunoglobulin (Ig) heavy chain constant sequence.

[0817] Herein, a ‘CH2 region’ refers to an amino acid sequence corresponding to the CH2 region of an immunoglobulin (Ig). The CH2 region is the region of an Ig formed by positions 231 to 340 of the immunoglobulin constant region, according to the EU numbering system described in Edelman et al., Proc Natl Acad Sci USA (1969) 63(1): 78-85. A ‘CH3 region’ refers to an amino acid sequence corresponding to the CH3 region of an immunoglobulin (Ig). The CH3 region is the region of an Ig formed by positions 341 to 447 of the immunoglobulin constant region, according to the EU numbering system described in Edelman et al., Proc Natl Acad Sci USA (1969) 63(1): 78-85. A ‘CH2-CH3 region’ refers to an amino acid sequence corresponding to the CH2 and CH3 regions of an immunoglobulin (Ig). The CH2- CH3 region is the region of an Ig formed by positions 231 to 447 of the immunoglobulin constant region, according to the EU numbering system described in Edelman et al., Proc Natl Acad Sci USA (1969) 63(1): 78-85.

[0818] In some embodiments, a CH2 region, CH3 region and / or a CH2-CH3 region according to the present disclosure corresponds to the CH2 region / CH3 region / CH2-CH3 region of an IgG (e.g. lgG1 , lgG2, lgG3, lgG4), IgA (e.g. lgA1 , lgA2), IgD, IgE or IgM. In some embodiments, the CH2 region, CH3 region and / or a CH2-CH3 region corresponds to the CH2 region / CH3 region / CH2-CH3 region of a human IgG (e.g. hlgG 1 , hlgG2, hlgG3, hlgG4), hlgA (e.g. hlgA1 , hlgA2), hlgD, hlgE or hlgM. In some embodiments, the CH2 region, CH3 region and / or a CH2-CH3 region corresponds to the CH2 region / CH3 region / CH2-CH3 region of a human IgG 1 allotype (e.g. G1 ml , G1 m2, G1 m3 or G1 m17).

[0819] Fc regions provide for interaction with Fc receptors and other molecules of the immune system to bring about functional effects. Fc-mediated effector functions are reviewed e.g. in Jefferis et al., Immunol Rev 1998 163:59-76 (hereby incorporated by reference in its entirety), and are brought about through Fc- mediated recruitment and activation of immune cells (e.g. macrophages, dendritic cells, neutrophils, basophils, eosinophils, platelets, mast cells, NK cells and T cells) through interaction between the Fc region and Fc receptors expressed by the immune cells, recruitment of complement pathway components through binding of the Fc region to complement protein C1q, and consequent activation of the complement cascade. Fc-mediated functions include Fc receptor binding, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), formation of the membrane attack complex (MAC), cell degranulation, cytokine and / or chemokine production, and antigen processing and presentation.

[0820] Modifications to antibody Fc regions that influence Fc-mediated functions are known in the art, such as those described e.g. in Wang et al., Protein Cell (2018) 9(1):63-73, which is hereby incorporated by reference in its entirety. Exemplary Fc region modifications known to influence antibody effector function are summarised in Table 1 of Wang et al., Protein Cell (2018) 9(1):63-73. In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising modification to increase or reduce an Fc-mediated function as compared to an antigen-binding molecule comprising the corresponding unmodified Fc region.

[0821] Where an Fc region / CH2 / CH3 is described as comprising modification(s) ‘corresponding to’ reference substitution(s), equivalent substitution(s) in the homologous Fc / CH2 / CH3 are contemplated. By way of illustration, L234A / L235A substitutions in human IgG 1 (numbered according to the EU numbering system as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991) correspond to L to A substitutions at positions 117 and 118 of the mouse Ig gamma-2A chain C region (UniProtKB: P01863-1 , v1).

[0822] Where an Fc region is described as comprising a modification, the modification may be present in one or both of the polypeptide chains which together form the Fc region.

[0823] In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising modification. In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising modification in one or more of the CH2 and / or CH3 regions.

[0824] In some embodiments, the Fc region comprises modification to increase an Fc-mediated function. In some embodiments, the Fc region comprises modification to increase ADCC. In some embodiments, the Fc region comprises modification to increase ADCP. In some embodiments, the Fc region comprises modification to increase CDC. An antigen-binding molecule comprising an Fc region comprising modification to increase an Fc-mediated function (e.g. ADCC, ADCP, CDC) induces an increased level of the relevant effector function as compared to an antigen-binding molecule comprising the corresponding unmodified Fc region.

[0825] In some embodiments, the Fc region comprises modification to increase binding to an Fc receptor. In some embodiments, the Fc region comprises modification to increase binding to an Fey receptor. In some embodiments, the Fc region comprises modification to increase binding to one or more of FcyRI, FcyRlla, FcyRllb, FcyRllc, FcyRllla and FcyRlllb. In some embodiments, the Fc region comprises modification to increase binding to FcyRllla. In some embodiments, the Fc region comprises modification to increase binding to FcyRlla. In some embodiments, the Fc region comprises modification to increase binding to FcyRllb. In some embodiments, the Fc region comprises modification to increase binding to FcRn. In some embodiments, the Fc region comprises modification to increase binding to a complement protein. In some embodiments, the Fc region comprises modification to increase binding to C1q. In some embodiments, the Fc region comprises modification to promote hexamerisation of the antigen-binding molecule. In some embodiments, the Fc region comprises modification to increase antigen-binding molecule half-life. In some embodiments, the Fc region comprises modification to increase coengagement.

[0826] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions F243L / R292P / Y300L / V305I / P396L as described in Stavenhagen et al. Cancer Res. (2007) 67:8882-8890. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions S239D / I332E or S239D / I332E / A330L as described in Lazar et al., Proc Natl Acad Sci USA. (2006)103:4005-4010. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions S298A / E333A / K334A as described in Shields et al., J Biol Chem. (2001) 276:6591-6604. In some embodiments, the Fc region comprises modification to one of heavy chain polypeptides corresponding to the combination of substitutions L234Y / L235Q / G236W / S239M / H268D / D270E / S298A, and modification to the other heavy chain polypeptide corresponding to the combination of substitutions D270E / K326D / A330M / K334E, as described in Mimoto et al., MAbs. (2013): 5:229-236. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions G236A / S239D / I332E as described in Richards et al., Mol Cancer Ther. (2008) 7:2517-2527.

[0827] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions K326W / E333S as described in Idusogie et al. J Immunol. (2001) 166(4):2571-5. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions S267E / H268F / S324T as described in Moore et al. MAbs. (2010) 2(2):181-9. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions described in Natsume et al., Cancer Res. (2008) 68(10):3863-72. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions E345R / E430G / S440Y as described in Diebolder et al. Science (2014) 343(6176): 1260-3.

[0828] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions M252Y / S254T / T256E as described in Dall’Acqua et al. J Immunol. (2002) 169:5171-5180.

[0829] In some embodiments, the Fc region comprises a CH2-CH3 region comprising an amino acid difference at one or more of the following positions, relative to the amino acid sequence of a CH2-CH3 region of a reference Fc region: 252, 254 or 256 (according to the EU numbering system). In some embodiments, the Fc region comprises a CH2-CH3 region comprising one or more of the following specified amino acid residues: Y252, T254 or E256 (according to the EU numbering system). In some embodiments, the Fc region comprises a CH2-CH3 region comprising Y252, T254 and E256. In some embodiments, the Fc region comprises a CH2-CH3 region comprising one or more of the following amino acid substitutions, relative to the amino acid sequence of a CH2-CH3 region of the reference Fc region: M252Y, S254T or T256E (according to the EU numbering system).

[0830] These so called ‘YTE’ modifications located at the CH2-CH3 interface of the Fc region have been shown to increase the binding affinity at pH 6.0 to the MHC Class I neonatal Fc receptor (FcRn), localised within the acidic endosomes of endothelial and haematopoietic cells, which increases efficient recycling of administered mAb and longer half-life in the plasma.

[0831] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions M428L / N434S as described in Zalevsky et al. Nat BiotechnoL (2010) 28:157-159. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions S267E / L328F as described in Chu et al., Mol Immunol. (2008) 45:3926-3933. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions N325S / L328F as described in Shang et al. Biol Chem. (2014) 289:15309-15318.

[0832] In some embodiments, the Fc region comprises modification to reduce / prevent an Fc-mediated function. In some embodiments, the Fc region comprises modification to reduce / prevent ADCC. In some embodiments, the Fc region comprises modification to reduce / prevent ADCP. In some embodiments, the Fc region comprises modification to reduce / prevent CDC. An antigen-binding molecule comprising an Fc region comprising modification to reduce / prevent an Fc-mediated function (e.g. ADCC, ADCP, CDC) induces an reduced level of the relevant effector function as compared to an antigen-binding molecule comprising the corresponding unmodified Fc region.

[0833] In some embodiments, the Fc region comprises modification to reduce / prevent binding to an Fc receptor. In some embodiments, the Fc region comprises modification to reduce / prevent binding to an Fey receptor. In some embodiments, the Fc region comprises modification to reduce / prevent binding to one or more of FcyRI, FcyRlla, FcyRllb, FcyRllc, FcyRllla and FcyRlllb. In some embodiments, the Fc region comprises modification to reduce / prevent binding to FcyRllla. In some embodiments, the Fc region comprises modification to reduce / prevent binding to FcyRlla. In some embodiments, the Fc region comprises modification to reduce / prevent binding to FcyRllb. In some embodiments, the Fc region comprises modification to reduce / prevent binding to a complement protein. In some embodiments, the Fc region comprises modification to reduce / prevent binding to C1q. In some embodiments, the Fc region comprises modification to reduce / prevent glycosylation of the amino acid residue corresponding to N297.

[0834] In some embodiments, the Fc region is not able to induce one or more Fc-mediated functions (i.e. lacks the ability to elicit the relevant Fc-mediated function(s)). Accordingly, antigen-binding molecules comprising such Fc regions also lack the ability to induce the relevant function(s). Such antigen-binding molecules may be described as being devoid of the relevant function(s).

[0835] In some embodiments, the Fc region is not able to induce ADCC. In some embodiments, the Fc region is not able to induce ADCP. In some embodiments, the Fc region is not able to induce CDC. In some embodiments, the Fc region is not able to induce ADCC and / or is not able to induce ADCP and / or is not able to induce CDC.

[0836] In some embodiments, the Fc region is not able to bind to an Fc receptor. In some embodiments, the Fc region is not able to bind to an Fey receptor. In some embodiments, the Fc region is not able to bind to one or more of FcyRI, FcyRlla, FcyRllb, FcyRllc, FcyRllla and FcyRlllb. In some embodiments, the Fc region is not able to bind to FcyRllla. In some embodiments, the Fc region is not able to bind to FcyRlla. In some embodiments, the Fc region is not able to bind to FcyRllb. In some embodiments, the Fc region is not able to bind to FcRn. In some embodiments, the Fc region is not able to bind to a complement protein. In some embodiments, the Fc region is not able to bind to C1q. In some embodiments, the Fc region is not glycosylated at the amino acid residue corresponding to N297. In some embodiments, the Fc region comprises modification corresponding to N297A or N297Q or N297G as described in Leabman et al., MAbs. (2013) 5:896-903. In some embodiments, the Fc region comprises modification corresponding to L235E as described in Alegre et al., J Immunol. (1992) 148:3461-3468. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A or F234A / L235A as described in Xu et al., Cell Immunol. (2000) 200:16-26. In some embodiments, the Fc region comprises modification corresponding to P329A or P329G as described in Schlothauer et al., Protein Engineering, Design and Selection (2016), 29(10):457-466. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A / P329G as described in Lo et al. J. Biol. Chem (2017) 292(9):3900-3908. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions described in Rother et al., Nat Biotechnol. (2007) 25:1256-1264. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions S228P / L235E as described in Newman et al., Clin. Immunol. (2001) 98:164-174. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions H268Q / V309L / A330S / P331 S as described in An et al., MAbs. (2009) 1 :572-579. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions

[0837] V234A / G237A / P238S / H268A / V309L / A330S / P331 S as described in Vafa et al., Methods. (2014) 65:114- 126. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235E / G237A / A330S / P331S as described in US 2015 / 0044231 A1.

[0838] The combination of substitutions ‘L234A / L235A’ and corresponding substitutions (such as e.g. F234A / L235A in human lgG4) are known to disrupt binding of Fc to Fey receptors and inhibit ADCC, ADCP, and also to reduce C1q binding and thus CDC (Schlothauer et al., Protein Engineering, Design and Selection (2016), 29(10):457-466, hereby incorporated by reference in entirety). The substitutions ‘P329G’ and ‘P329A’ reduce C1q binding (and thereby CDC). Substitution of ‘N297’ with ‘A’, ‘G’ or ‘Q’ is known to eliminate glycosylation, and thereby reduce Fc binding to C1q and Fey receptors, and thus CDC and ADCC. Lo et al. J. Biol. Chem (2017) 292(9) :3900-3908 (hereby incorporated by reference in its entirety) reports that the combination of substitutions L234A / L235A / P329G eliminated complement binding and fixation as well as Fc y receptor dependent, antibody-dependent, cell-mediated cytotoxicity in both murine lgG2a and human lgG1.

[0839] The combination of substitutions L234A / L235E / G237A / A330S / P331 S in lgG1 Fc is disclosed in US 2015 / 0044231 A1 to abolish induction of phagocytosis, ADCC and CDC.

[0840] In some embodiments, the Fc region comprises modification corresponding to the substitution S228P as described in Silva et al., J Biol Chem. (2015) 290(9): 5462-5469. The substitution S228P in lgG4 Fc reduces Fab-arm exchange (Fab-arm exchange can be undesirable).

[0841] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A. In some embodiments, the Fc region comprises modification corresponding to the substitution P329G. In some embodiments, the Fc region comprises modification corresponding to the substitution N297Q.

[0842] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A / P329G.

[0843] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A / P329G / N297Q.

[0844] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235E / G237A / A330S / P331S.

[0845] In some embodiments, the Fc region comprises modification corresponding to the substitution S228P, e.g. in lgG4.

[0846] In some embodiments - particularly embodiments in which the antigen-binding molecule is a multispecific (e.g. bispecific) antigen-binding molecule - the antigen-binding molecule comprises an Fc region comprising modification in one or more of the CH2 and CH3 regions promoting association of the Fc region. Recombinant co-expression of constituent polypeptides of an antigen-binding molecule and subsequent association leads to several possible combinations. To improve the yield of the desired combinations of polypeptides in antigen-binding molecules in recombinant production, it is advantageous to introduce in the Fc regions modification(s) promoting association of the desired combination of heavy chain polypeptides. Modifications may promote e.g. hydrophobic and / or electrostatic interaction between CH2 and / or CH3 regions of different polypeptide chains. Suitable modifications are described e.g. in Ha et al., Front. Immnol (2016) 7:394, which is hereby incorporated by reference in its entirety.

[0847] In some embodiments, the antigen-binding molecule of the present disclosure comprises an Fc region comprising paired substitutions in the CH3 regions of the Fc region according to one of the following formats, as shown in Table 1 of Ha et al., Front. Immnol (2016) 7:394: KiH, KiHs-s, HA-TF, ZW1 , 7.8.60, DD-KK, EW-RVT, EW-RVTs-s, SEED or A107.

[0848] Particular exemplary polypeptides and antigen-binding molecules

[0849] The present disclosure also provides polypeptide constituents of antigen-binding molecules. The polypeptides may be provided in isolated or substantially purified form.

[0850] The antigen-binding molecule of the present disclosure may be, or may comprise, a complex of polypeptides.

[0851] In the present specification where a polypeptide comprises more than one domain or region, it will be appreciated that the plural domains / regions are preferably present in the same polypeptide chain. That is, the polypeptide comprising more than one domain or region is a fusion polypeptide comprising the domains / regions. In some embodiments a polypeptide according to the present disclosure comprises, or consists of, a VH as described herein. In some embodiments a polypeptide according to the present disclosure comprises, or consists of, a VL as described herein.

[0852] In some embodiments, the polypeptide additionally comprises one or more antibody heavy chain constant regions (CH). In some embodiments, the polypeptide additionally comprises one or more antibody light chain constant regions (CL). In some embodiments, the polypeptide comprises a CH1 , CH2 region and / or a CH3 region of an immunoglobulin (Ig).

[0853] In some embodiments, the polypeptide comprises one or more regions of an immunoglobulin heavy chain constant sequence. In some embodiments, the polypeptide comprises a CH1 region as described herein. In some embodiments, the polypeptide comprises a CH1-CH2 hinge region as described herein. In some embodiments, the polypeptide comprises a CH2 region as described herein. In some embodiments, the polypeptide comprises a CH3 region as described herein.

[0854] In some embodiments, the polypeptide comprises one or more regions of an immunoglobulin light chain constant sequence. In some embodiments, the polypeptide comprises a CL region as described herein.

[0855] In some embodiments, the polypeptide according to the present disclosure comprises a structure from N- to C-terminus according to one of the following:

[0856] (i) VH

[0857] (ii) VL

[0858] (iii) VH-CH1

[0859] (iv) VL-CL

[0860] (v) VL-CH1

[0861] (vi) VH-CL

[0862] (vii) VH-CH1-CH2-CH3

[0863] (viii) VL-CL-CH2-CH3

[0864] (ix) VL-CH1-CH2-CH3

[0865] (x) VH-CL-CH2-CH3

[0866] Also provided by the present disclosure are antigen-binding molecules composed of the polypeptides of the present disclosure. In some embodiments, the antigen-binding molecule of the present disclosure comprises one of the following combinations of polypeptides:

[0867] (A) VH + VL

[0868] (B) VH-CH1 + VL-CL

[0869] (C) VL-CH1 + VH-CL

[0870] (D) VH-CH1-CH2-CH3 + VL-CL

[0871] (E) VH-CL-CH2-CH3 + VL-CH1

[0872] (F) VL-CH1-CH2-CH3 + VH-CL

[0873] (G) VL-CL-CH2-CH3 + VH-CH1 (H) VH-CH1-CH2-CH3 + VL-CL-CH2-CH3

[0874] (I) VH-CL-CH2-CH3 + VL-CH1-CH2-CH3

[0875] In some embodiments, the antigen-binding molecule comprises more than one of a polypeptide of the combinations shown in (A) to (I) above. By way of example, with reference to (D) above, In some embodiments, the antigen-binding molecule comprises two polypeptides comprising the structure VH- CH1-CH2-CH3, and two polypeptides comprising the structure VL-CL.

[0876] In some embodiments, the antigen-binding molecule of the present disclosure comprises one of the following combinations of polypeptides:

[0877] (J) VH (anti-gp130) + VL (anti-gp130)

[0878] (K) VH (anti-gp130)-CH1 + VL (anti-gp130)-CL

[0879] (L) VL (anti-gp130)-CH1 + VH (anti-gp130)-CL

[0880] (M) VH (anti-gp130)-CH1-CH2-CH3 + VL (anti-gp130)-CL

[0881] (N) VH (anti-gp130)-CL-CH2-CH3 + VL (anti-gp130)-CH1

[0882] (O) VL (anti-gp130)-CH1-CH2-CH3 + VH (anti-gp130)-CL

[0883] (P) VL (anti-gp130)-CL-CH2-CH3 + VH (anti-gp130)-CH1

[0884] (Q) VH (anti-gp130)-CH1-CH2-CH3 + VL (anti-gp130)-CL-CH2-CH3

[0885] Wherein: VH(anti-gp130)’ refers to the VH of an antigen-binding molecule capable of binding to gp130 as described herein, e.g. as defined in one of (1) to (172); and ‘VL(anti-gp130)’ refers to the VL of an antigen-binding molecule capable of binding to gp130 as described herein, e.g. as defined in one of (173) to (332).

[0886] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:1 , 17, 31 , 36, 51 , 74, 78, 80, 83, 106, 86, 87, 214, 215, 216, 217, 218, 219, 220, 221 , 222, 223, 224, 225, 226, 227, 228, 229, 230, 231 , 232, 233, 234, 235, 236, 237, 238, 239, 240, 241 , 242, 243, 389, 392, 393, 394, 398, 399, 400, 406, 407, 408, 412, 413, 414, 418, 419, 420, 439, 485, 486, 487, or 488.

[0887] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:221 . In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:219. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:241 . In some embodiments, the antigen- binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:239. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:220. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:240. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:487. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:418. In some embodiments, the antigenbinding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:419. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:420.

[0888] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:9, 23, 34, 44, 57, 75, 88, 91 , 95, 98, 100, 110, 251 , 252, 253, 254, 255, 256, 257, 258, 259, 260, 261 , 262, 263, 264, 265, 266, 267, 268, 269, 270, 271 , 272, 273, 274, 275, 276, 277, 278, 279, 280, 287, 430, 431 , 445, 448, 449, 450, 451 , 452, 453, 454, 455, 456, 469, 470, 471 , 475, 478, 479, or 480.

[0889] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:271 . In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:269. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:430. In some embodiments, the antigenbinding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:431. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:475.

[0890] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:145, 146, 147, 148, 149, 150, 151 , 152, 153, 154, 155, 156, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211 , 212, 213, 288, 289, 290, 291 , 292, 293, 294, 295, 296, 297, 298, 299, 300, 301 , 302,

[0891] 303, 304, 305, 306, 307, 308, 309, 310, 311 , 312, 313, 314, 315, 316, 317, 318, 319, 320, 321 , 322, 323,

[0892] 324, 325, 326, 327, 328, 329, 330, 331 , 332, 333, 334, 335, 336, 337, 338, 339, 340, 341 , 342, 343, 344,

[0893] 345, 346, 347, 348, 349, 403, 404, 405, 490, 409, 410, 411 , 491 , 415, 416, 417, 492, 391 , 395, 396, 397,

[0894] 493, 427, 428, 429, or 444.

[0895] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:295. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:326. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:315. In some embodiments, the antigenbinding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:346. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:293. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:324. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:313. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:344. In some embodiments, the antigenbinding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:294. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:325. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:314. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:345. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:485. In some embodiments, the antigenbinding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:486. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:487. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:418. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:419. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:420.

[0896] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:157, 158, 159, 160, 161 , 162, 163, 164, 165, 166, 167, 168, 350, 351 , 352, 353, 354, 355, 356, 357, 358, 359, 360, 361 , 362, 363, 364, 365, 366, 367, 368, 369, 370, 371 , 372, 373, 374, 375, 376, 377, 378, 379, 380, 477, 437, 438, 460, 461 , 462, 481 , 482, 483, 463, 464, 465, 466, 467, 468, 447, 472, 473 or 474. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:370. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:373. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:477. In some embodiments, the antigenbinding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:437. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide which comprises or consists of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:438.

[0897] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide or polypeptides comprising a VH region comprising the heavy chain CDRs, and a VL region comprising the light chain CDRs, of an antibody selected from an antibody as shown in Table A herein. That is, in some embodiments, the antigen-binding molecule comprises a polypeptide or polypeptides comprising: (i) a VH region comprising HC-CDR1 , HC-CDR2 and HC-CDR3 as indicated in column A of Table A, and (ii) a VL region comprising LC-CDR1 , LC-CDR2 and LC-CDR3 as indicated in column B of Table A, wherein the sequences of columns A and B are selected from the same row of Table A. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide or polypeptides comprising a VH region comprising the heavy chain CDRs, and a VL region comprising the light chain CDRs, of an antibody selected from 4D4 / 4D4, 4D4CVH2_D53E / 4D4GVL3_N93G, 4D4CVH2.2_D53E / 4D4GVL3_N93G, 4D4CVH2.2_M34Y_D53E / 4D4GVL3_N93G, 8C6 / 8C6, 8C6CVH2.1 / 8C6CVL2, 8C6CVH2.1 / 8C6CVL3, 8C6CVH2.1 / 8C6CVL5, 8C6GVH4.1 / 8C6CVL5, 8C6GVH5.1 / 8C6CVL3, and 8C6GVH5.1 / 8C6CVL5 (as shown in Table A). In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide or polypeptides comprising a VH region comprising the heavy chain CDRs, and a VL region comprising the light chain CDRs, of an antibody selected from 4D4 / 4D4, 4D4CVH2_D53E / 4D4GVL3_N93G, 4D4CVH2.2_D53E / 4D4GVL3_N93G, 4D4CVH2.2_M34Y_D53E / 4D4GVL3_N93G, 8C6 / 8C6, 8C6CVH2.1 / 8C6CVL2, 8C6CVH2.1 / 8C6CVL3, 8C6CVH2.1 / 8C6CVL5, 8C6GVH4.1 / 8C6CVL5, 8C6GVH5.1 / 8C6CVL3, and 8C6GVH5.1 / 8C6CVL5 (as shown in Table A).

[0898] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide or polypeptides comprising a VH region comprising the heavy chain FRs, and a VL region comprising the light chain FRs, of an antibody selected from an antibody as shown in Table B herein. That is, in some embodiments, the antigen-binding molecule comprises a polypeptide or polypeptides comprising: (i) a VH region comprising HC-FR1 , HC-FR2, HC-FR3 and HC-FR4 as indicated in column A of Table B, and (ii) a VL region comprising LC-FR1 , LC-FR2, LC-FR3, and LC-FR4 as indicated in column B of Table B, wherein the sequences of columns A and B are selected from the same row of Table B. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide or polypeptides comprising a VH region comprising the heavy chain FRs, and a VL region comprising the light chain FRs, of an antibody selected from 4D4 / 4D4, 4D4CVH2_D53E / 4D4GVL3_N93G, 4D4CVH2.2_D53E / 4D4GVL3_N93G, 4D4CVH2.2_M34Y_D53E / 4D4GVL3_N93G, 8C6 / 8C6, 8C6CVH2.1 / 8C6CVL2, 8C6CVH2.1 / 8C6CVL3, 8C6CVH2.1 / 8C6CVL5, 8C6GVH4.1 / 8C6CVL5, 8C6GVH5.1 / 8C6CVL3, and 8C6GVH5.1 / 8C6CVL5 (as shown in Table B). In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide or polypeptides comprising a VH region comprising the heavy chain FRs, and a VL region comprising the light chain FRs, of an antibody selected from 4D4 / 4D4, 4D4CVH2_D53E / 4D4GVL3_N93G, 4D4CVH2.2_D53E / 4D4GVL3_N93G, 4D4CVH2.2_M34Y_D53E / 4D4GVL3_N93G, 8C6 / 8C6, 8C6CVH2.1 / 8C6CVL2, 8C6CVH2.1 / 8C6CVL3, 8C6CVH2.1 / 8C6CVL5, 8C6GVH4.1 / 8C6CVL5, 8C6GVH5.1 / 8C6CVL3, and 8C6GVH5.1 / 8C6CVL5 (as shown in Table B).

[0899] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide or polypeptides comprising: (I) an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to an amino acid sequence indicated in column A of Table C, and (ii) an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to an amino acid sequence indicated in column B of Table C, wherein the sequences of columns A and B are selected from the same row of Table C.

[0900] In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide or polypeptides comprising a VH region and a VL region of an antibody clone selected from an antibody as shown in Table C herein. That is, in some embodiments, the antigen-binding molecule comprises a polypeptide or polypeptides comprising: (I) an amino acid sequence indicated in column A of Table C, and (ii) an amino acid sequence indicated in column B of Table C, wherein the sequences of columns A and B are selected from the same row of Table C. In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide or polypeptides comprising a VH region and a VL region of an antibody clone selected from 4D4 / 4D4, 4D4CVH2_D53E / 4D4GVL3_N93G, 4D4CVH2.2_D53E / 4D4GVL3_N93G, 4D4CVH2.2_M34Y_D53E / 4D4GVL3_N93G, 8C6 / 8C6, 8C6CVH2.1 / 8C6CVL2, 8C6CVH2.1 / 8C6CVL3, 8C6CVH2.1 / 8C6CVL5, 8C6GVH4.1 / 8C6CVL5, 8C6GVH5.1 / 8C6CVL3, and 8C6GVH5.1 / 8C6CVL5 (as shown in Table C). In some embodiments, the antigen-binding molecule of the present disclosure comprises a polypeptide or polypeptides comprising a VH region and a VL region of an antibody clone selected from 4D4 / 4D4, 4D4CVH2_D53E / 4D4GVL3_N93G, 4D4CVH2.2_D53E / 4D4GVL3_N93G, 4D4CVH2.2_M34Y_D53E / 4D4GVL3_N93G, 8C6 / 8C6, 8C6CVH2.1 / 8C6CVL2, 8C6CVH2.1 / 8C6CVL3, 8C6CVH2.1 / 8C6CVL5, 8C6GVH4.1 / 8C6CVL5, 8C6GVH5.1 / 8C6CVL3, and 8C6GVH5.1 / 8C6CVL5 (as shown in Table C). In some embodiments, the antigen-binding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to an amino acid sequence indicated in column A of Table D, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to an amino acid sequence indicated in column B of Table D, wherein the sequences of columns A and B are selected from the same row of Table D.

[0901] In some embodiments, the antigen-binding molecule of the present disclosure comprises the polypeptides of an antigen-binding molecule according to Table D herein. That is, in some embodiments, the antigenbinding molecule comprises: (i) a polypeptide comprising or consisting of an amino acid sequence indicated in column A of Table D, and (ii) a polypeptide comprising or consisting of an amino acid sequence indicated in column B of Table D, wherein the sequences of columns A and B are selected from the same row of Table D.

[0902] In some embodiments, the antigen-binding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:295, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:370. In some embodiments, the antigenbinding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:326, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:370.

[0903] In some embodiments, the antigen-binding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:315, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:370. In some embodiments, the antigenbinding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:346, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:370. In some embodiments, the antigen-binding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:293, and (II) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:373. In some embodiments, the antigenbinding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:324, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:373.

[0904] In some embodiments, the antigen-binding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:313, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:373. In some embodiments, the antigenbinding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:344, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:373.

[0905] In some embodiments, the antigen-binding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:294, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:370. In some embodiments, the antigenbinding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:325, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:370.

[0906] In some embodiments, the antigen-binding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:314, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:370. In some embodiments, the antigenbinding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:345, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:370.

[0907] In some embodiments, the antigen-binding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:492, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NQ:370.

[0908] In some embodiments, the antigen-binding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:427, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:477. In some embodiments, the antigenbinding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:427, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:437. In some embodiments, the antigen-binding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:427, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:438.

[0909] In some embodiments, the antigen-binding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:428, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:438. In some embodiments, the antigen-binding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:429, and (II) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:437. In some embodiments, the antigenbinding molecule of the present disclosure comprises: (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:429, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:438.

[0910] Functional properties of the antigen-binding molecules

[0911] The antigen-binding molecules described herein may be characterised by reference to certain functional properties. In some embodiments, the antigen-binding molecule described herein may possess one or more of the following properties: binds to gp130 (e.g. human gp130, mouse gp130, rat gp130 and / or non-human primate gp130); binds to gp130-expressing cells; inhibits signalling mediated by a receptor comprising gp130; inhibits signalling mediated by gp130:IL-6Ra and / or gp130:IL-11 Ra; inhibits signalling mediated by a cytokine that binds to a receptor comprising gp130; inhibits IL-6- and / or IL-1 1 -mediated signalling; does not inhibit signalling mediated by gp130:OSMRp, gp130:LIFRp, gp130:LIFRp:CNTFRa, gp130:IL-27Ra and / or gp130:IL-12Rp2; does not inhibit OSM-, LIF-, CNTF-, CT-1-, CLC-, IL-27- and / or IL-35-mediated signalling; reduces inflammation and / or fibrosis; reduces the pathology of a disease / condition characterised by inflammation and / or fibrosis;and / or increases killing of cells expressing gp130.

[0912] It will be appreciated that a given antigen-binding molecule may display more than one of the properties recited in the preceding paragraph. A given antigen-binding molecule may be evaluated for the properties recited in the preceding paragraph using suitable assays. For example, the assays may be e.g. in vitro assays, optionally cell-based assays or cell-free assays. In some embodiments, the assays may be e.g. in vivo assays, i.e. performed in non-human animals. In some embodiments, the assays may be e.g. ex vivo assays, i.e. performed using cells / tissue / an organ obtained from a subject.

[0913] Where assays are cell-based assays, they may comprise treating cells with a given antigen-binding molecule in order to determine whether the antigen-binding molecule displays one or more of the recited properties. Assays may employ species labelled with detectable entities in order to facilitate their detection. Assays may comprise evaluating the recited properties following treatment of cells separately with a range of quantities / concentrations of a given antigen-binding molecule (e.g. a dilution series). It will be appreciated that the cells preferably express the target antigen for the antigen-binding molecule (i.e. gpi30).

[0914] Analysis of the results of such assays may comprise determining the concentration at which 50% of the maximal level of the relevant activity is attained. The concentration of a given agent at which 50% of the maximal level of the relevant activity is attained may be referred to as the ‘half-maximal effective concentration’ of the agent in relation to the relevant activity, which may also be referred to as the EC50’. By way of illustration, the EC50 of a given antigen-binding molecule for binding to human gp130 may be the concentration of the antigen-binding molecule at which 50% of the maximal level of binding to human gp130 is achieved.

[0915] Depending on the property, the EC50 may also be referred to as the half-maximal inhibitory concentration’ or ‘IC50’, this being the concentration of the agent at which 50% of the maximal level of inhibition of a given property is observed.

[0916] The antigen-binding molecules described herein bind to gp130. In some embodiments, the antigenbinding molecule binds to human gp130. In some embodiments, the antigen-binding molecule binds to mouse gp130. In some embodiments, the antigen-binding molecule binds to rat gp130. In some embodiments, the antigen-binding molecule binds to Rhesus gp130. In some embodiments, the antigenbinding molecule binds to canine gp130. In some embodiments, the antigen-binding molecule binds to human gp130 and mouse gp130. In some embodiments, the antigen-binding molecule binds to human gp130 and rat gp130. In some embodiments, the antigen-binding molecule binds to human gp130, mouse gp130 and rat gp130.

[0917] The antigen-binding molecules and antigen-binding domains described herein preferably display specific binding to gp130. As used herein, ‘specific binding’ refers to binding which is selective for the antigen, and which can be discriminated from non-specific binding to non-target antigen. An antigen-binding molecule / domain that specifically binds to a target molecule preferably binds the target with greater affinity, and / or with greater duration than it binds to other, non-target molecules.

[0918] The ability of a given polypeptide to bind specifically to a given molecule can be determined by analysis according to methods known in the art, such as by ELISA, Surface Plasmon Resonance (SPR; see e.g. Hearty et al., Methods Mol Biol (2012) 907:411-442), Bio-Layer Interferometry (BLI; see e.g. Lad et al., (2015) J Biomol Screen 20(4): 498-507), flow cytometry, or by a radiolabeled antigen-binding assay (RIA) enzyme-linked immunosorbent assay. Through such analysis binding to a given molecule can be measured and quantified. In some embodiments, the binding may be the response detected in a given assay.

[0919] In some embodiments, the extent of binding of the antigen-binding molecule to a non-target molecule is less than about 10% of the binding of the antibody to the target molecule as measured, e.g. by ELISA, SPR, BLI or by RIA. Alternatively, binding specificity may be reflected in terms of binding affinity where the antigen-binding molecule binds with a dissociation constant (KD) that is at least 0.1 order of magnitude (i.e. 0.1 x 10n, where n is an integer representing the order of magnitude) greater than the KD of the antigen-binding molecule towards a non-target molecule. This may optionally be one of at least 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 1 .5, or 2.0.

[0920] The affinity of binding to a given target antigen for an antigen-binding molecule described herein may be determined by SPR, e.g. as described in the Examples of the present disclosure.

[0921] In some embodiments, the antigen-binding molecule described herein binds to gp130 with an affinity in the micromolar range, i.e. KD = 9.9 x 104to 1 x 106M. In some embodiments, the antigen-binding molecule described herein binds to gp130 with sub-micromolar affinity, i.e. KD < 1 x 106M. In some embodiments, the antigen-binding molecule described herein binds to gp130 with an affinity in the nanomolar range, i.e. KD = 9.9 x 10-7to 1 x 10-9M. In some embodiments, the antigen-binding molecule described herein binds to gp130 with sub-nanomolar affinity, i.e. KD < 1 x 10-9M. In some embodiments, the antigen-binding molecule described herein binds to gp130 with an affinity in the picomolar range, i.e. KD = 9.9 x 1010to 1 x 1012M. In some embodiments, the antigen-binding molecule described herein binds to gp130 with sub-picomolar affinity, i.e. KD < 1 x 1012M.

[0922] In some embodiments, the antigen-binding molecule described herein binds to human gp130 isoform 1 with a KD of 10 pM or less, preferably one of <5 pM, <2 pM, <1 pM, <500 nM, <100 nM, <75 nM, <50 nM, <40 nM, <30 nM, <20 nM, <15 nM, <12.5 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM <3 nM, <2 nM, <1 nM, <500 pM, <400 pM, <300 pM, <200 pM, <100 pM, <50 pM, <40 pM, <30 pM, <20 pM, <10 pM or <1 pM (e.g. as determined by analysis as described in Example 4 of WO 2024 / 121233 A1 (hereby incorporated by reference in its entirety). In some embodiments, the antigen-binding molecule described herein binds to human gp130 isoform 1 with a KD of 100 nM or less, preferably one of <50 nM, <40 nM, <30 nM, <20 nM, <15 nM, <12.5 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM <3 nM, <2 nM, <1 nM, <500 pM, <400 pM, <300 pM, <200 pM, <100 pM, <50 pM, <40 pM, <30 pM, <20 pM, <10 pM or <1 pM (e.g. as determined by analysis as described in Example 4 of WO 2024 / 121233 A1). In some embodiments, the antigen-binding molecule described herein binds to human gp130 isoform 1 with a KD of 3 nM or less, preferably one of <2.5 nM, <2 nM, <1 .5 nM, <1 nM, <750 pM, <500 pM, or <400 pM. In some embodiments, the antigen-binding molecule described herein binds to human gp130 isoform 1 with a KD of 1 nM or less, preferably one of <900 pM, <800 pM, <700 pM, <600 pM, <500 pM, <400 pM, <300 pM, <200 pM or <100 pM (e.g. as determined by analysis as described in Example 4 or 25 of WO 2024 / 121233 A1).

[0923] In some embodiments, the antigen-binding molecule described herein binds to human gp130 isoform 1 with an ECso of 10 pM or less, preferably one of <5 pM, <2 pM, <1 pM, <500 nM, <100 nM, <75 nM, <50 nM, <40 nM, <30 nM, <20 nM, <15 nM, <12.5 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM <3 nM, <2 nM, <1 nM, <500 pM, <400 pM, <300 pM, <200 pM, <100 pM, <50 pM, <40 pM, <30 pM, <20 pM, <10 pM or <1 pM. The antigen-binding molecules of the present disclosure may bind to a particular region of interest of gp130. Antigen-binding molecules according to the present disclosure may bind to linear epitope of gp130, consisting of a contiguous sequence of amino acids (j.e. an amino acid primary sequence). In some embodiments, an antigen-binding molecules may bind to a conformational epitope of gp130, consisting of a discontinuous sequence of amino acids of the amino acid sequence.

[0924] The region of a given target molecule to which an antigen-binding molecule binds can be determined by the skilled person using various methods well known in the art, including X-ray co-crystallography analysis of antibody-antigen complexes, peptide scanning, mutagenesis mapping, hydrogen-deuterium exchange analysis by mass spectrometry, phage display, competition ELISA and proteolysis-based ‘protection’ methods. Such methods are described, for example, in Gershoni et al., BioDrugs, 2007, 21 (3) : 145-156, which is hereby incorporated by reference in its entirety.

[0925] In some embodiments, the antigen-binding molecule of the present disclosure binds to the extracellular domain of gp130. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:134. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:134.

[0926] In some embodiments, the antigen-binding molecule of the present disclosure does not bind to the cytokine-binding module of gp130. In some embodiments, the antigen-binding molecule does not bind to the region of gp130 shown in SEQ ID NO:144. In some embodiments, the antigen-binding molecule does not contact the region of gp 130 shown in SEQ ID NO:144. In some embodiments, the antigen-binding molecule does not bind to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:144. In some embodiments, the antigen-binding molecule does not bind to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:144.

[0927] In some embodiments, the antigen-binding molecule of the present disclosure binds to membrane- proximal region of gp130. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:388. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:388. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:388. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:388.

[0928] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:169, SEQ ID NO:170 and / or SEQ ID NO:171. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:169, SEQ ID NQ:170 and / or SEQ ID NO:171 . In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:169, SEQ ID NQ:170 and / or SEQ ID NO:171 . In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:169, SEQ ID NO:170 and / or SEQ ID NO:171. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:169, SEQ ID NO:170 and / or SEQ ID NO:171 . In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:172. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:172. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:172. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:172. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:172.

[0929] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:173 and / or SEQ ID NO:174. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:173 and / or SEQ ID NO:174. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:173 and / or SEQ ID NO:174. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:173 and / or SEQ ID NO:174. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:173 and / or SEQ ID NO:174. In some embodiments, the antigenbinding molecule binds to the region of gp130 shown in SEQ ID NO:175. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:175. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:175. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:175. In some embodiments, the antigenbinding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:175.

[0930] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:176, SEQ ID NO:177 and / or SEQ ID NO:178. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:176, SEQ ID NO:177 and / or SEQ ID NO:178. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:176, SEQ ID NO:177 and / or SEQ ID NO:178. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:176, SEQ ID NO:177 and / or SEQ ID NO:178. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:176, SEQ ID NO:177 and / or SEQ ID NO:178. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:179. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:179. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:179. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:179. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:179.

[0931] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NQ:180, SEQ ID NO:181 , SEQ ID NO:382 and / or SEQ ID NO:385. In some embodiments, the antigen- binding molecule contacts the region of gp130 shown in SEQ ID NO:180, SEQ ID NO:181 , SEQ ID NO:382 and / or SEQ ID NO:385. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NQ:180, SEQ ID NO:181 , SEQ ID NO:382 and / or SEQ ID NO:385. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:180, SEQ ID NO:181 , SEQ ID NO:382 and / or SEQ ID NO:385. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NQ:180, SEQ ID NO:181 , SEQ ID NO:382 and / or SEQ ID NO:385. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:182. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:182. In some embodiments, the antigenbinding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:182. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:182. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:182. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:386. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:386. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:386. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:386. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:386.

[0932] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:381 and / or SEQ ID NO:382. In some embodiments, the antigenbinding molecule contacts the region of gp130 shown in SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:381 and / or SEQ ID NO:382. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:381 and / or SEQ ID NO:382. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:381 and / or SEQ ID NO:382. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:381 and / or SEQ ID NO:382. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:185. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:185. In some embodiments, the antigenbinding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:185. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:185. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:185. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:383. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:383. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:383. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:383. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:383. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:384. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:384. In some embodiments, the antigenbinding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:384. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:384. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:384.

[0933] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:186 and / or SEQ ID NO:187. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:186 and / or SEQ ID NO:187. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:186 and / or SEQ ID NO:187. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:186 and / or SEQ ID NO:187. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:186 and / or SEQ ID NO:187. In some embodiments, the antigenbinding molecule binds to the region of gp130 shown in SEQ ID NO:188. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:188. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the region shown in SEQ ID NO:188. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:188. In some embodiments, the antigenbinding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:188.

[0934] The ability of an antigen-binding molecule to bind to a given peptide / polypeptide can be analysed by methods well known to the skilled person, including analysis by ELISA, immunoblot (e.g. western blot), immunoprecipitation, SPR and BLI.

[0935] In some embodiments, the antigen-binding molecule is capable of binding the same region of gp130, or an overlapping region of gp130, to the region of gp130 which is bound by an antibody comprising the VH and VL regions (see e.g. Table C) of an antibody as indicated in Table C.

[0936] Whether a test antigen-binding molecule binds to the same or an overlapping region of a given target as a reference antigen-binding molecule can be evaluated, for example, by analysis of (i) interaction between the test antigen-binding molecule and the target in the absence of the reference binding molecule, and (ii) interaction between the test antigen-binding molecule in the presence of the reference antigen-binding molecule, or following incubation of the target with the reference antigen-binding molecule. Determination of a reduced level of interaction between the test antigen-binding molecule and the target following analysis according to (ii) as compared to (i) might support an inference that the test and reference antigen-binding molecule bind to the same or an overlapping region of the target. Suitable assays for such analysis include e.g. competition ELISA assays and epitope binning assays.

[0937] In some embodiments, the antigen-binding molecule of the present disclosure binds to gp130 in a region which is accessible to an antigen-binding molecule ( / .e., an extracellular antigen-binding molecule) when gp130 is expressed at the cell surface ( / .e. in or at the cell membrane). In some embodiments, the antigen-binding molecule binds to gp130 expressed at the cell surface of a cell expressing gp130. In some embodiments, the antigen-binding molecule binds to gp130-expressing cells (e.g. fibroblasts). In some embodiments, the antigen-binding molecule does not bind (i.e. does not substantially bind) to cells lacking surface expression of gp130.

[0938] The ability of an antigen-binding molecule to bind to a given cell type (e.g. cells expressing gp130, or cells not expressing gp130) can be analysed by contacting cells with the antigen-binding molecule, and detecting antigen-binding molecule bound to the cells, e.g. after a washing step to remove unbound antigen-binding molecule. The ability of an antigen-binding molecule to bind to a given cell type can be analysed by methods such as flow cytometry and immunofluorescence microscopy.

[0939] In some embodiments, the antigen-binding molecule of the present disclosure inhibits signalling mediated by a receptor comprising gp130. In some embodiments, the antigen-binding molecule inhibits gp130- mediated signalling (e.g. gp130-mediated signalling as described hereinabove). Signalling mediated by gp130 and / or by receptors comprising gp130 can be analysed using cells expressing gp130 / the relevant receptor, e.g. using an assay for detecting and / or quantifying gp130-mediated signalling. Suitable assays include e.g. assays for detecting the phosphorylation / activity / expression of factors which are phosphorylated / activated / expressed as a consequence of signalling though gp130 / receptors comprising gp130.

[0940] Such assays may comprise contacting cells expressing a given cytokine receptor comprising gp130 with an antigen-binding molecule according to the present disclosure, e.g. in the presence of a ligand for the cytokine receptor. By way of illustration, an assay for investigating the ability of an antigen-binding molecule to inhibit IL-6-mediated signalling and / or the ability of an antigen-binding molecule to inhibit signalling mediated by gp130:IL-6Ra may comprise contacting cells expressing gp130:IL-6Ra complexes with an antigen-binding molecule according to the present disclosure, e.g. in the presence of IL-6. By way of further illustration, an assay for investigating the ability of an antigen-binding molecule to inhibit IL-11 - mediated signalling and / or the ability of an antigen-binding molecule to inhibit signalling mediated by gp130:IL-11 Ra may comprise contacting cells expressing gp130JL-1 1 Ra complexes with an antigenbinding molecule according to the present disclosure, e.g. in the presence of IL-11 .

[0941] For example, gp130-mediated signalling can be investigated by evaluating phosphorylation of one or more signal transduction molecules of a signal transduction pathway triggered by signalling through gp130 / cytokine receptors comprising gp130 (e.g. the JAK / STAT, MAPK / ERK or PI3K / AKT pathways). For example, the level of gp130-mediated signalling can be analysed by detection and / or quantification of the level of phosphorylation of JAK1 , JAK2, STAT1 , STAT3, STAT5 and / or ERK (e.g. STAT3 and / or ERK). By way of illustration, in the experimental examples of the present disclosure, gp130-mediated signalling (particularly signalling mediated by gp130:IL-6Ra in response to stimulation with IL-6, and signalling mediated by gp130:IL-11 Ra in response to stimulation with IL-11) is analysed by evaluating phosphorylation of STAT3 or ERK1 / 2 by western blot (see in particular Example 1 1 of WO 2024 / 121233 A1).

[0942] The level of gp130-mediated signalling can also be evaluated by analysing one or more correlates of gp130-mediated signalling. For example, gp130-mediated signalling may be investigated by detecting and / or quantifying the expression or activity of a factor whose expression / activity is upregulated or downregulated as a consequence of gp130-mediated signalling. In some embodiments, gp130-mediated signalling may be investigated by detecting and / or quantifying the expression of a factor whose expression is upregulated as a consequence of gp130-mediated signalling, e.g. a proinflammatory / profibrotic / profibroinflammatory factor. By way of illustration, in the experimental examples of the present disclosure, gp130-mediated signalling (particularly signalling mediated by gp130:l L-11 Ra in response to stimulation with IL-11) is analysed by evaluating the expression of aSMA and MMP2.

[0943] The level of gp130-mediated signalling can also be analysed using reporter-based methods. For example, gp130-mediated signalling can be investigated using a reporter cell line stably expressing a luciferase reporter driven by gp130-mediated signalling, By way of illustration, in the experimental examples of the present disclosure, gp130-mediated signalling is investigated using a HEK293 reporter cell line comprising a luciferase gene under the control of STAT3 response elements (STAT3 Reporter (Luc)-HEK293 cell line (puromycin), BPS Bioscience).

[0944] In some embodiments, the antigen-binding molecule is capable of inhibiting signalling mediated by gp130 and / or signalling by a receptor comprising g p 130 to less than 1 times, e.g. <0.99 times, <0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, <0.5 times, <0.45 times, <0.4 times, <0.35 times, <0.3 times, <0.25 times, <0.2 times, <0.15 times, <0.1 times, <0.05 times, or <0.01 times the level of signalling observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence signalling mediated by gp130 and / or signalling by a receptor comprising gp130).

[0945] In some embodiments, the antigen-binding molecule inhibits IL-6-mediated signalling. In some embodiments, the antigen-binding molecule inhibits IL-11 -mediated signalling. In some embodiments, the antigen-binding molecule inhibits IL-6-mediated signalling and inhibits IL-11 -mediated signalling.

[0946] In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130:IL-6Ra. In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130:IL-11 Ra. In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130:IL-6Ra, and inhibits signalling mediated by gp130:IL-11 Ra.

[0947] In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of IL-6 to cells expressing gp130:IL-6Ra. In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of IL-11 to cells expressing gp130:IL-11 Ra. In some embodiments, the antigenbinding molecule inhibits signalling mediated by binding of IL-6 to cells expressing gp130:IL-6Ra, and inhibits signalling mediated by binding of IL-11 to cells expressing gp130: 1 L-11 Ra.

[0948] In some embodiments, the antigen-binding molecule is capable of inhibiting IL-6-mediated signalling / signalling mediated by gp130:IL-6Ra / signalling mediated by binding of IL-6 to cells expressing gp130:IL-6Ra to less than 1 times, e.g. <0.99 times, <0.95 times, <0.9 times, <0.85 times, <0.8 times, <0.75 times, <0.7 times, <0.65 times, <0.6 times, <0.55 times, <0.5 times, <0.45 times, <0.4 times, <0.35 times, <0.3 times, <0.25 times, <0.2 times, <0.15 times, <0.1 times, <0.05 times, or <0.01 times the level of signalling observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence IL- 6-mediated signalling / signalling mediated by gp130:IL-6Ra / signalling mediated by binding of IL-6 to cells expressing gp130:IL-6Ra).

[0949] In some embodiments, the antigen-binding molecule is capable of inhibiting more than 25%, e.g. >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, >96%, >97%, >98% or >99% of the IL-6-mediated signalling / signalling mediated by gp130:IL-6Ra / signalling mediated by binding of IL-6 to cells expressing gp130:IL-6Ra observed in the absence of the antigen-binding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigen-binding molecule known not to influence IL-6-mediated signalling / signalling mediated by gp130:IL-6Ra / signalling mediated by binding of IL-6 to cells expressing gp130:IL-6Ra), e.g. as determined in an assay performed as described in Examples 1 and 11 of WO 2024 / 121233 A1 .

[0950] In some embodiments, the antigen-binding molecule is capable of inhibiting IL-6-mediated signalling / signalling mediated by gp130:IL-6Ra / signalling mediated by binding of IL-6 to cells expressing gp130:IL-6Ra with an ICso of less than 1 pM, preferably one of <500 nM, <100 nM, <75 nM, <50 nM, <40 nM, <30 nM, <20 nM, <15 nM, <12.5 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM <3 nM, <2 nM, <1 nM, <900 pM, <800 pM, <700 pM, <600 pM, <500 pM, <400 pM, <300 pM, <200 pM, <100 pM, <50 pM, <40 pM, <30 pM, <20 pM, <10 pM or <1 pM, e.g. as ...

Claims

Claims:1 . An antigen-binding molecule, optionally isolated, which binds to gp130, wherein the antigen-binding molecule comprises:(a)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:2 HC-CDR2 having the amino acid sequence of SEQ ID NO:245 HC-CDR3 having the amino acid sequence of SEQ ID NO:4; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NQ:10 LC-CDR2 having the amino acid sequence of SEQ ID NO:11 LC-CDR3 having the amino acid sequence of SEQ ID NO:281 ; or(b)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:2 HC-CDR2 having the amino acid sequence of SEQ ID NO:3 HC-CDR3 having the amino acid sequence of SEQ ID NO:4; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NQ:10 LC-CDR2 having the amino acid sequence of SEQ ID NO:11 LC-CDR3 having the amino acid sequence of SEQ ID NO:12; or(c)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NQ:401 HC-CDR2 having the amino acid sequence of SEQ ID NO:3 HC-CDR3 having the amino acid sequence of SEQ ID NO:4; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NQ:10 LC-CDR2 having the amino acid sequence of SEQ ID NO:11 LC-CDR3 having the amino acid sequence of SEQ ID NO:12; or(d)(i) a heavy chain variable (VH) region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NQ:401 HC-CDR2 having the amino acid sequence of SEQ ID NO:245 HC-CDR3 having the amino acid sequence of SEQ ID NO:4; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:10 LC-CDR2 having the amino acid sequence of SEQ ID NO:11LC-CDR3 having the amino acid sequence of SEQ ID NO:281 ; or(e)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:37 HC-CDR2 having the amino acid sequence of SEQ ID NO:38 HC-CDR3 having the amino acid sequence of SEQ ID NO:39; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:45 LC-CDR2 having the amino acid sequence of SEQ ID NO:46 LC-CDR3 having the amino acid sequence of SEQ ID NO:47; or(f)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:37 HC-CDR2 having the amino acid sequence of SEQ ID NO:38 HC-CDR3 having the amino acid sequence of SEQ ID NO:39; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:45 LC-CDR2 having the amino acid sequence of SEQ ID NO:46 LC-CDR3 having the amino acid sequence of SEQ ID NO:457; or(g)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:37 HC-CDR2 having the amino acid sequence of SEQ ID NO:38 HC-CDR3 having the amino acid sequence of SEQ ID NO:39; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:45 LC-CDR2 having the amino acid sequence of SEQ ID NO:46 LC-CDR3 having the amino acid sequence of SEQ ID NO:458; or(h)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:37 HC-CDR2 having the amino acid sequence of SEQ ID NO:38 HC-CDR3 having the amino acid sequence of SEQ ID NO:39; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:45 LC-CDR2 having the amino acid sequence of SEQ ID NO:46 LC-CDR3 having the amino acid sequence of SEQ ID NO:459.

2. The antigen-binding molecule according to claims 1 , wherein the antigen-binding molecule comprises: a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:1 , 36, 106, 220, 240, 398, 399, 400, 485, 406, 407, 408, 486, 412, 413, 414, 487, 389, 392, 393, 394, 488, 418, 419, 420, or 439; and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:9, 44, 110, 271 , 475, 430, 431 , 445, 448, 449, 450, 478, 479, 480, 451 , 452, 453, 454, 455, 456, 469, 470, or 471 .

3. The antigen-binding molecule according to claim 1 or claim 2, wherein the antigen-binding molecule comprises:(a) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:1 , and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:9; or(b) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:106, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:110; or(c) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:220, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or(d) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:240, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or(e) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:398, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:9; or(f) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:399, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:9; or(g) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:400, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:9; or(h) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:485, anda VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:9; or(I) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:406, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or(j) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:407, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or(k) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:408, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or(l) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:486, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or(m) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:412, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or(n) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:413, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNO:271 ; or(o) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:414, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or(p) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:487, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or(q) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:389, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or(r) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:392, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or(s) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:393, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or(t) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:394, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNO:271 ; or(u) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:488, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:271 ; or(v) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:36, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:44; or(w) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:475; or(x) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:430; or(y) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:431 ; or(z) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:475; or(aa) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:430; or(ab) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:431 ; or(ac) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:420, anda VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:475; or(ad) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNQ:430; or(ae) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNO:431 ; or(at) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:36, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNO:475; or(ag) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:36, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNO:430; or(ah) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:36, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNO:431 ; or(al) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNO:478; or(aj) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNO:479; or(ak) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNQ:480; or(al) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNO:451 ; or(am) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:452; or(an) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:453; or(ao) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:454; or(ap) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:455; or(aq) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:418, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:456; or(ar) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:478; or(as) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:479; or(at) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:480; or(au) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:451 ; or(av) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:452; or(aw) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:453; or(ax) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, anda VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:454; or(ay) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNO:455; or(az) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:419, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNO:456; or(ba) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNO:478; or(bb) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNO:479; or(be) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNQ:480; or(bd) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNO:451 ; or(be) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNO:452; or(bf) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNO:453; or(bg) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ IDNO:454; or(bh) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:455; or(bi) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:420, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:456; or(bj) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:439, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:445; or(bk) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:439, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:469; or(bl) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:439, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NQ:470; or(bm) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:439, and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO:471.

4. The antigen-binding molecule according to any one of claims 1 to 3, wherein the antigen-binding molecule is a multispecific antigen-binding molecule, and wherein the antigen-binding molecule further comprises an antigen-binding domain which binds to an antigen other than gp130.

5. A chimeric antigen receptor (CAR) comprising an antigen-binding molecule according to any one of claims 1 to 4.

6. A nucleic acid, or a plurality of nucleic acids, optionally isolated, encoding an antigen-binding molecule according to any one of claims 1 to 4, or a CAR according to claim 5.

7. An expression vector, or a plurality of expression vectors, comprising a nucleic acid or a plurality of nucleic acids according to claim 6.

8. A cell comprising an antigen-binding molecule according to any one of claims 1 to 4, a CAR according to claim 5, a nucleic acid or a plurality of nucleic acids according to claim 6, or an expression vector or a plurality of expression vectors according to claim 7.

9. A method comprising culturing a cell according to claim 8 under conditions suitable for expression of an antigen-binding molecule or CAR by the cell.

10. A composition comprising an antigen-binding molecule according to any one of claims 1 to 4, a CAR according to claim 5, a nucleic acid or a plurality of nucleic acids according to claim 6, an expression vector or a plurality of expression vectors according to claim 7, or a cell according to claim 8, and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.11 . An antigen-binding molecule according to any one of claims 1 to 4, a CAR according to claim 5, a nucleic acid or a plurality of nucleic acids according to claim 6, an expression vector or a plurality of expression vectors according to claim 7, a cell according to claim 8, or a composition according to claim 10, for use in a method of medical treatment or prophylaxis.

12. An antigen-binding molecule according to any one of claims 1 to 4, a CAR according to claim 5, a nucleic acid or a plurality of nucleic acids according to claim 6, an expression vector or a plurality of expression vectors according to claim 7, a cell according to claim 8, or a composition according to claim 10, for use in a method of treatment or prevention of: pathological inflammation, fibrosis, a disease / condition characterised by inflammation, a disease / condition characterised by fibrosis, a disease / condition characterised by inflammation and fibrosis, a disease / condition in which signalling through a gp130-containing complex is pathologically-implicated, a disease / condition in which a cytokine that signals through a gp130-containing complex is pathologically-implicated, an autoimmune disease, metabolic syndrome, a neurodegenerative disease, a chronic inflammatory disease, arthritis, rheumatoid arthritis, juvenile arthritis, systemic juvenile idiopathic arthritis, lupus, systemic lupus erythematosus, pancreatitis, thyroiditis, periodontitis, rhinitis, allergic rhinitis, dermatitis, dermatitis, atopic dermatitis, psoriasis, Hermansky-Pudlak syndrome, Graves' disease, obesity, insulin resistance, diabetes, type 1 diabetes, type 2 diabetes, pregnancy-associated hyperglycemia, multiple sclerosis, giant cell arteritis, Takayasu arteritis, cardiovascular disease, atherosclerosis, atrial fibrillation, ventricular fibrillation, cardiac hypertrophy, hypertrophic cardiomyopathy, dilated cardiomyopathy, myocarditis, cardiogenic shock, heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, ischemic heart disease, myocardial infarction, Marfan syndrome, systemic sclerosis, keloid, scleroderma, Alzheimer’s disease, Parkinson's disease, Huntington’s disease, amyotrophic lateral sclerosis, hippocampal atrophy, pulmonary disease, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, hepatitis, liver fibrosis, cirrhosis, hepatotoxicity, acetaminophen-induced hepatotoxicity, alcoholic liver disease, pancreatitis, steatosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, cholestasis, primary biliary cholangitis, primary sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, colitis, ulcerative colitis, endometriosis, stroke, ischemic stroke, nephropathy, kidney injury, acute kidney injury, nephrotoxicity, glomerulonephritis, chronic kidney disease, kidney fibrosis, Alport syndrome, adult-onset Still’s disease, Castleman’s disease, cytokine release syndrome, sepsis, septic shock, a retinal disorder, retinal fibrosis, age-related macular degeneration, wet age-related macular degeneration, retinitis pigmentosa, dry eye syndrome, COVID-19, Peutz-Jeghers syndrome, a skeletal muscle disorder, muscular dystrophy, amyotrophy, cachexia, an endocrine disorder, polycystic ovary syndrome, a cancer, a hematologic malignancy, leukemia, plasmacytoma, Hodgkin’s lymphoma, lung cancer, colorectal cancer, intestinal cancer, urinary cancer, bladder cancer, vulvar cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, bone cancer, glioblastoma, breast cancer, stomach cancer, renal cancer, metastatic renal cell cancer,prostate cancer, skin cancer, melanoma, liver cancer, hepatocellular carcinoma, frailty, age-related increase in fat mass, sarcopenia, age-related hyperlipidaemia, age-related hypertriglyceridemia, age- related hypercholesterolemia, age-related liver steatosis, age-related non-alcoholic fatty liver disease, age-related non-alcoholic fatty liver, age-related non-alcoholic steatohepatitis, age-related cardiovascular disease, age-related hypertension, age-related renal disease, age-related skin disease, an infectious disease, a viral disease, viral hepatitis, hepatitis B, HIV infection, influenza infection, malaria, tuberculosis, an allergic disease, transplant rejection and graft-versus-host disease.

13. An in vitro complex, optionally isolated, comprising an antigen-binding molecule according to any one of claims 1 to 4 bound to gp130.

14. A method for detecting gp130 in a sample, comprising contacting a sample containing, or suspected to contain, gp130 with an antigen-binding molecule according to any one of claims 1 to 4, and detecting the formation of a complex of the antigen-binding molecule with gp130.

15. A method of selecting or stratifying a subject for treatment with a gp130-targeted agent, the method comprising contacting, in vitro, a sample from the subject with an antigen-binding molecule according to any one of claims 1 to 4, and detecting the formation of a complex of the antigen-binding molecule with gp130.

16. Use of an antigen-binding molecule according to any one of claims 1 to 4 as an in vitro or in vivo diagnostic or prognostic agent.

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