Gp130 antigen-binding antibodies

Abstract

Gp130 antigen-binding antibodies are disclosed which inhibit IL-6, IL-11, OSM, LIF, CNTF, CT-1 mediated signal and bind to the cytokine binding region. Also disclosed are nucleic acids and expression vectors encoding, compositions comprising, humanised antibodies and therapeutic methods using, the Gp130 antigen-binding antibodies.

Description

[0001] GP130 ANTIGEN-BINDING ANTIBODIES

[0002] This application claims priority from GB 2311050.5 filed 19 July 2023, 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-1 1 , 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] Monoclonal antibodies that bind to gp130 and antagonise gp130-mediated signalling have been described previously. Monoclonal mouse anti-human gp130 antibody B-R3 is described e.g. in Garbers et al., J Biol Chem. (2013) 288(6): 4346-4354. B-R3 is disclosed in Garbers et al. to bind to the cytokine binding module (CBM) of gp130.

[0008] WO 2019 / 126071 A1 describes gp130-binding antibodies mAb16692, mAb16680, mAb16673, mAb16646, mAb16636 and mAb16618, which are disclosed to inhibit signalling mediated by OSM, LIF and CNTF. WO 2019 / 126071 A1 does not characterise the antibodies for their ability to inhibit signalling mediated by other IL-6 family cytokines. None of the antibodies display binding to mouse gp130 - see Tables 9 and 10 of WO 2019 / 126071 A1 . The antibodies are disclosed to bind to human gp130 with KD values ranging from 1 .66 x 107M to 2.91 x 109M, as determined by surface plasmon resonance analysis by Biacore.

[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 inhibits IL-6-mediated signalling, IL-1 1 -mediated signalling, OSM-mediated signalling, CNTF-mediated signalling, CT-1-mediated signalling, and LIF- mediated signalling.

[0011] In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:89. In some embodiments, the antigen-binding molecule comprises:

[0012] (a)

[0013] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0014] 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

[0015] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0016] 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

[0017] (b)

[0018] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0019] 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:185; and

[0020] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0021] LC-CDR1 having the amino acid sequence of SEQ ID NQ:10 LC-CDR2 having the amino acid sequence of SEQ ID NO:192 LC-CDR3 having the amino acid sequence of SEQ ID NO:12; or

[0022] (c)

[0023] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0024] 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:185; and

[0025] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0026] 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

[0027] (d)

[0028] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0029] 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

[0030] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0031] LC-CDR1 having the amino acid sequence of SEQ ID NQ:10 LC-CDR2 having the amino acid sequence of SEQ ID NO:192 LC-CDR3 having the amino acid sequence of SEQ ID NO:12.

[0032] In some embodiments, the antigen-binding molecule comprises: (i) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to a VH sequence as indicated in Column A of row 68, 71 , 69, 72, 70, 73, 12, 13, 38-67, 3-11 or 1 of Table C, and

[0033] (ii) a VL region having an amino acid sequence having at least 70% amino acid sequence identity to a VL sequence as indicated in Column B of row 68, 71 , 69, 72, 70, 73, 12, 13, 38-67, 3-11 or 1 of Table C, wherein the VH and VL sequences are selected from the same row of Table C.

[0034] In some embodiments, the antigen-binding molecule comprises:

[0035] (a)

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

[0037] HC-CDR1 having the amino acid sequence of SEQ ID NO:18

[0038] HC-CDR2 having the amino acid sequence of SEQ ID NO:19

[0039] HC-CDR3 having the amino acid sequence of SEQ ID NO:218; and

[0040] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0041] LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or

[0042] (b)

[0043] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0044] HC-CDR1 having the amino acid sequence of SEQ ID NO:18

[0045] HC-CDR2 having the amino acid sequence of SEQ ID NO:19

[0046] HC-CDR3 having the amino acid sequence of SEQ ID NQ:204; and

[0047] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0048] LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or

[0049] (c)

[0050] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0051] HC-CDR1 having the amino acid sequence of SEQ ID NO:18

[0052] HC-CDR2 having the amino acid sequence of SEQ ID NO:19

[0053] HC-CDR3 having the amino acid sequence of SEQ ID NQ:20; and

[0054] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0055] LC-CDR1 having the amino acid sequence of SEQ ID NO:26

[0056] LC-CDR2 having the amino acid sequence of SEQ ID NO:27

[0057] LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or

[0058] (d)

[0059] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0060] HC-CDR1 having the amino acid sequence of SEQ ID NO:18

[0061] HC-CDR2 having the amino acid sequence of SEQ ID NO:19

[0062] HC-CDR3 having the amino acid sequence of SEQ ID NO:195; and (ii) a light chain variable (VL) region incorporating the following CDRs:

[0063] LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or

[0064] (e)

[0065] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0066] HC-CDR1 having the amino acid sequence of SEQ ID NO:18 HC-CDR2 having the amino acid sequence of SEQ ID NO:19 HC-CDR3 having the amino acid sequence of SEQ ID NO:214; and

[0067] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0068] LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or

[0069] (f)

[0070] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0071] HC-CDR1 having the amino acid sequence of SEQ ID NO:18 HC-CDR2 having the amino acid sequence of SEQ ID NO:19 HC-CDR3 having the amino acid sequence of SEQ ID NO:215; and

[0072] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0073] LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28.

[0074] In some embodiments, the antigen-binding molecule comprises:

[0075] (i) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to a VH sequence as indicated in Column A of row 89, 90, 80-88, 74-79 or 2 of Table C, and

[0076] (ii) a VL region having an amino acid sequence having at least 70% amino acid sequence identity to a VL sequence as indicated in Column B of row 89, 90, 80-88, 74-79 or 2 of Table C, wherein the VH and VL sequences are selected from the same row of Table C.

[0077] In some embodiments, the antigen-binding molecule is a multispecific antigen-binding molecule, wherein the antigen-binding molecule further comprises an antigen-binding domain which binds to an antigen other than gp130.

[0078] The present disclosure also provides a chimeric antigen receptor (CAR) comprising an antigen-binding molecule according to the present disclosure.

[0079] The present disclosure also provides a nucleic acid, or a plurality of nucleic acids, optionally isolated, encoding an antigen-binding molecule or CAR according to the present disclosure. 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.

[0080] The present disclosure also provides a cell comprising an antigen-binding molecule, CAR, nucleic acid or plurality of nucleic acids or expression vector or plurality of expression vectors according to the present disclosure.

[0081] 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.

[0082] The present disclosure also provides a composition comprising an antigen-binding molecule, CAR, nucleic acid or plurality of nucleic acids, expression vector or plurality of expression vectors or cell according to the present disclosure, and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

[0083] The present disclosure also provides an antigen-binding molecule, CAR, nucleic acid or plurality of nucleic acids, expression vector or plurality of expression vectors, cell or composition according to the present disclosure, for use in a method of medical treatment or prophylaxis.

[0084] The present disclosure also provides an antigen-binding molecule, CAR, nucleic acid or plurality of nucleic acids, expression vector or plurality of expression vectors, cell or 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.

[0085] The present disclosure also provides an in vitro complex, optionally isolated, comprising an antigenbinding molecule according to the present disclosure bound to gp130.

[0086] 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.

[0087] 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.

[0088] The present disclosure also provides the use of an antigen-binding molecule according to the present disclosure as an in vitro or in vivo diagnostic or prognostic agent.

[0089] The present disclosure also provides an antigen-binding molecule which binds to gp130 and inhibits I L-6- mediated signalling, IL-11 -mediated signalling, OSM-mediated signalling, CNTF-mediated signalling, CT- 1 -mediated signalling, and LIF-mediated signalling 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, wherein the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:89.

[0090] The present disclosure also provides the use of an antigen-binding molecule that binds to gp130 and that contacts the region of gp130 shown in SEQ ID NO:89 to inhibit IL-6-mediated signalling, IL-11 -mediated signalling, OSM-mediated signalling, CNTF-mediated signalling, CT-1-mediated signalling, and / or LIF- mediated signalling.

[0091] The present disclosure also provides a method for inhibiting IL-6-mediated signalling, IL-11 -mediated signalling, OSM-mediated signalling, CNTF-mediated signalling, CT-1-mediated signalling, and / or LIF- mediated signalling, comprising contacting cells capable of IL-6-mediated signalling, IL-11 -mediated signalling, OSM-mediated signalling, CNTF-mediated signalling, CT-1-mediated signalling, and / or LIF- mediated signalling with an antigen-binding molecule that binds to gp130 and that contacts the region of gp130 shown in SEQ ID NO:89.

[0092] The present disclosure also provides a method for inhibiting IL-6-mediated signalling, IL-11 -mediated signalling, OSM-mediated signalling, CNTF-mediated signalling, CT-1-mediated signalling, and LIF- mediated signalling in a subject, comprising administering to a subject an antigen-binding molecule that binds to gp130 and that contacts the region of gp130 shown in SEQ ID NO:89.

[0093] In some embodiments, the antigen-binding molecule comprises:

[0094] (a)

[0095] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0096] 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

[0097] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0098] 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

[0099] (b)

[0100] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0101] 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:185; and

[0102] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0103] LC-CDR1 having the amino acid sequence of SEQ ID NQ:10 LC-CDR2 having the amino acid sequence of SEQ ID NO:192 LC-CDR3 having the amino acid sequence of SEQ ID NO:12; or

[0104] (c)

[0105] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0106] 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:185; and

[0107] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0108] 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

[0109] (d)

[0110] (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 NO:10 LC-CDR2 having the amino acid sequence of SEQ ID NO:192 LC-CDR3 having the amino acid sequence of SEQ ID NO:12.

[0111] In some embodiments, the antigen-binding molecule comprises:

[0112] (i) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to a VH sequence as indicated in Column A of row 68, 71 , 69, 72, 70, 73, 12, 13, 38-67, 3-11 or 1 of Table C, and

[0113] (ii) a VL region having an amino acid sequence having at least 70% amino acid sequence identity to a VL sequence as indicated in Column B of row 68, 71 , 69, 72, 70, 73, 12, 13, 38-67, 3-11 or 1 of Table C, wherein the VH and VL sequences are selected from the same row of Table C.

[0114] In some embodiments, the antigen-binding molecule comprises:

[0115] (a)

[0116] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0117] HC-CDR1 having the amino acid sequence of SEQ ID NO:18 HC-CDR2 having the amino acid sequence of SEQ ID NO:19 HC-CDR3 having the amino acid sequence of SEQ ID NO:218; and

[0118] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0119] LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or

[0120] (b)

[0121] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0122] HC-CDR1 having the amino acid sequence of SEQ ID NO:18 HC-CDR2 having the amino acid sequence of SEQ ID NO:19 HC-CDR3 having the amino acid sequence of SEQ ID NQ:204; and

[0123] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0124] LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or

[0125] (c)

[0126] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0127] HC-CDR1 having the amino acid sequence of SEQ ID NO:18 HC-CDR2 having the amino acid sequence of SEQ ID NO:19 HC-CDR3 having the amino acid sequence of SEQ ID NQ:20; and

[0128] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0129] LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or

[0130] (d)

[0131] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0132] HC-CDR1 having the amino acid sequence of SEQ ID NO:18 HC-CDR2 having the amino acid sequence of SEQ ID NO:19 HC-CDR3 having the amino acid sequence of SEQ ID NO:195; and

[0133] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0134] LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or

[0135] (e)

[0136] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0137] HC-CDR1 having the amino acid sequence of SEQ ID NO:18 HC-CDR2 having the amino acid sequence of SEQ ID NO:19 HC-CDR3 having the amino acid sequence of SEQ ID NO:214; and

[0138] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0139] LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or

[0140] (f)

[0141] (i) a heavy chain variable (VH) region incorporating the following CDRs:

[0142] HC-CDR1 having the amino acid sequence of SEQ ID NO:18 HC-CDR2 having the amino acid sequence of SEQ ID NO:19 HC-CDR3 having the amino acid sequence of SEQ ID NO:215; and

[0143] (ii) a light chain variable (VL) region incorporating the following CDRs:

[0144] LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28.

[0145] In some embodiments, the antigen-binding molecule comprises:

[0146] (i) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to a VH sequence as indicated in Column A of row 89, 90, 80-88, 74-79 or 2 of Table C, and

[0147] (ii) a VL region having an amino acid sequence having at least 70% amino acid sequence identity to a VL sequence as indicated in Column B of row 89, 90, 80-88, 74-79 or 2 of Table C, wherein the VH and VL sequences are selected from the same row of Table C.

[0148] 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. Description

[0149] 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.

[0150] The present disclosure is concerned with gp130-binding antigen-binding molecules that inhibit signalling mediated by cytokine receptor complexes comprising gp130. The antigen-binding molecules of the present disclosure are useful to inhibit signalling mediated by the IL-6 family cytokines.

[0151] In particular, the present disclosure provides gp130-binding antigen-binding molecules that bind to a region of gp130 providing for potent inhibition of all of IL-6-, IL-11-, OSM-, CNTF-, CT-1-, and LIF- mediated signalling. Such antigen-binding molecules may be referred to herein as ‘PAN’ inhibitors of gp130.

[0152] While the known anti-gp130 antibody B-R3 has previously been described as being a PAN inhibitor of gp130-mediated signalling, this antibody is demonstrated in the present disclosure not to inhibit LIF- mediated signalling in an assay in which A549 cells were stimulated in vitro for 15 min with 10 ng / ml recombinant human LIF (see Example 7, Figure 8A).

[0153] Gp130-binding antigen-binding molecules according to the present disclosure moreover display cross- reactive binding to both human gp130 and mouse gp130. By contrast, neither BR-3 (see Example 1 , Figure 1 B), nor the known anti-gp130 antibodies mAb16692, mAb16680, mAb16673, mAb16646, mAb16636 and mAb16618 (see Tables 9 and 10 of WO 2019 / 126071 A1) display binding to mouse gp130. qp130

[0154] 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.

[0155] The canonical isoform of human gp130 (isoform 1) has the amino acid sequence shown in SEQ ID NO:70. Alternative splicing of mRNA encoded by the human IL6ST gene yields three main gp130 isoforms: isoform 1 (SEQ ID NO:70), isoform 2 (also known as gp130-RAPS; SEQ ID NO:71) and isoform 3 (SEQ ID NO:72). Isoform 2 differs from isoform 1 in that positions 325 to 329 of SEQ ID NOTO are different, and positions 330-918 are absent. Positions 423 to 483 of SEQ ID NOTO are absent from isoform 3.

[0156] The canonical isoform of human gp130 comprises an N-terminal signal peptide (SEQ ID NO:73), followed by an extracellular domain (SEQ ID NO:75), a single-pass transmembrane domain (SEQ ID NO:76) and a cytoplasmic domain (SEQ ID NO:77) at the C-terminus. The mature form of human gp130 isoform 1 is shown in SEQ ID NO:74. The extracellular domain comprises an N-terminal Ig-like C2-type domain (SEQ ID NO:78), followed by five fibronectin type III (FNIII) domains (shown in SEQ ID NOs:79, 80, 82, 83 and 84, 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:85). FNIII domain 2 comprises the WSXWS motif shown in SEQ ID NO:81. 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 IL-12Rp2 to form the receptor for IL-35.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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).

[0161] 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 ( / .e. after processing to remove signal peptide) form of a specified isoform of the relevant protein from a given species, e.g. human.

[0162] 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.

[0163] 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 associate with IL-6Ra, IL-11 Ra, OSMRp, LIFRp and / or CNTFRa.

[0164] 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:70, 71 or 72.

[0165] 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:70 or 74.

[0166] 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.

[0167] 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.

[0168] 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:74. 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:75.

[0169] 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:85.

[0170] 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 ( / .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).

[0171] 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.

[0172] 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-11Ra ( / .e. a gp130:IL-11 Ra complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130 and OSMRp ( / .e. a gp130:OSMRp complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130 and LIFRp ( / .e. a gp130:LIFRp complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130, LIFRp and CNTFRa ( / .e. a gp130:LIFRp:CNTFRa complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130 and IL-27Ra ( / .e. a gp130:IL-27Ra complex). In some embodiments, gp130-mediated signalling may be mediated by a polypeptide complex comprising gp130 and IL-12Rp2 ( / .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 ( / .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 ( / .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 ( / .e. a gp130:IL-6Ra complex). In some embodiments, gp130-mediated signalling is triggered by binding of IL-11 to a polypeptide complex comprising gp130 and IL-11Ra ( / .e. a gp130:IL-11 Ra complex). In some embodiments, gp130-mediated signalling is triggered by binding of OSM to a polypeptide complex comprising gp130 and OSMRp ( / .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 ( / .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 ( / .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 ( / .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 ( / .e. a gp130:IL-12Rp2 complex).

[0173] Antigen-binding molecules

[0174] 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.

[0175] An ‘antigen-binding molecule’ refers to a molecule that binds to a given target antigen. Antigen-binding molecules include antibodies ( / .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.

[0176] 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 dsFv) or the Fab region of an antibody, or the whole antibody. For example, antigen-binding molecules according to the present disclosure include antibodydrug conjugates (ADCs) comprising a (cytotoxic) drug moiety (e.g. as described hereinbelow). Antigenbinding 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 antigenbinding 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).

[0177] 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, fynomer, atrimer, DARPin, affibody, nanobody ( / .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 (2011) 286:41273-85 and Emanuel et al., Mabs (2011) 3:38-48).

[0178] 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.

[0179] 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.

[0180] 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).

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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 a!., 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.

[0186] 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.

[0187] In some embodiments, the antigen-binding molecule comprises the CDRs, FRs and / or the VH and / or VL regions of an antibody described herein (e.g. an antibody of Table C herein), or CDRs, FRs and / or VH and / or VL regions which are derived from those of an antibody described herein (e.g. an antibody of Table C herein). 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.

[0188] In some embodiments, a gp130-binding antibody is selected from B035-C03-A3, A3_4.2 VH I A3_3 VL, A3_4.2 VH I A3_4 VL, A3_4.2 VH I A3_5 VL, A3_3.2 VH I A3_3 VL, A3_3.2 VH I A3_4 VL, A3_6.2 VH I A3_3 VL, A3_6.2 VH I A3_4 VL, A3_6.2_l 100T I A3_3_G51 A, A3_3.2_l 100T I A3_4_G51 A, CSP-S-5H8, 5H8CVH4_D98G I 5H8CVL3, 5H8CVH4_D98G I 5H8CVL4, 5H8CVH4_D98G I 5H8GVL3, 5H8GVH4_D98G I 5H8CVL4 and 5H8GVH4_D98G I 5H8GVL3.

[0189] In some embodiments, a gp130-binding antibody is selected from B035-C03-A3, A3_6.2_I1OOT I A3_3_G51A, A3_3.2_I100T / A3_4_G51A, CSP-S-5H8, 5H8CVH4_D98G I 5H8CVL3, 5H8CVH4_D98G I 5H8CVL4, 5H8CVH4_D98G I 5H8GVL3, 5H8GVH4_D98G I 5H8CVL4 and 5H8GVH4_D98G I 5H8GVL3.

[0190] In some embodiments, the antigen-binding molecule comprises: a VH region comprising HC-CDR1 (or a variant thereof in which 1 or 2 or 3 amino acids in HC- CDR1 are substituted with another amino acid), HC-CDR2 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR2 are substituted with another amino acid) and HC-CDR3 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid) as indicated in Column A of row 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table A, wherein the HC-CDR1 , HC-CDR2 and HC-CDR3 sequences of Column A are selected from the same row of Table A.

[0191] By way of illustration, in some embodiments the antigen-binding molecule comprises a VH region comprising HC-CDR1 having the amino acid sequence of SEQ ID NO:2 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:2 are substituted with another amino acid), HC-CDR2 having the amino acid sequence of SEQ ID NO:3 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:3 are substituted with another amino acid) and 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 SEQ ID NO:4 are substituted with another amino acid). It will be appreciated that the HC-CDR1 , HC-CDR2 and HC-CDR3 sequences of the preceding sentence are selected from Column A of the same row (row 1) of Table A. In some embodiments, the antigen-binding molecule comprises: a VH region comprising HC-FR1 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 are substituted with another amino acid), HC-FR2 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR2 are substituted with another amino acid), HC-FR3 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR3 are substituted with another amino acid) and HC-FR4 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid) as indicated in Column A of row 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table B, wherein the HC-FR1 , HC-FR2, HC-FR3 and HC-FR4 sequences of Column A are selected from the same row of Table B.

[0192] By way of illustration, in some embodiments, the antigen-binding molecule comprises a VH region comprising HC-FR1 having the amino acid sequence of SEQ ID NO:5 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:5 are substituted with another amino acid), HC-FR2 having the amino acid sequence of SEQ ID NO:6 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:6 are substituted with another amino acid), HC-FR3 having the amino acid sequence of SEQ ID NOT (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NOT are substituted with another amino acid) and 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 SEQ ID NO:8 are substituted with another amino acid). It will be appreciated that the HC- FR1 , HC-FR2, HC-FR3 and HC-FR4 sequences of the preceding sentence are selected from Column A of the same row (row 1) of Table B.

[0193] In some embodiments, the antigen-binding molecule comprises: a VH region comprising:

[0194] HC-CDR1 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 are substituted with another amino acid), HC-CDR2 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR2 are substituted with another amino acid) and HC-CDR3 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid) as indicated in Column A of row 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49,

[0195] 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75,

[0196] 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table A, wherein the HC-CDR1 ,

[0197] HC-CDR2 and HC-CDR3 sequences of Column A are selected from the same row of Table A; and

[0198] HC-FR1 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 are substituted with another amino acid), HC-FR2 (or a variant thereof in which 1 or 2 or 3 amino acids in HC- FR2 are substituted with another amino acid), HC-FR3 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR3 are substituted with another amino acid) and HC-FR4 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid) as indicated in Column A of row 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47,

[0199] 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73,

[0200] 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table B, wherein the HC-

[0201] FR1 , HC-FR2, HC-FR3 and HC-FR4 sequences of Column A are selected from the same row of

[0202] Table B.

[0203] In some embodiments, the antigen-binding molecule comprises: a VH region comprising:

[0204] HC-CDR1 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR1 are substituted with another amino acid), HC-CDR2 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR2 are substituted with another amino acid) and HC-CDR3 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-CDR3 are substituted with another amino acid) as indicated in Column A of row 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49,

[0205] 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75,

[0206] 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table A; and

[0207] HC-FR1 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR1 are substituted with another amino acid), HC-FR2 (or a variant thereof in which 1 or 2 or 3 amino acids in HC- FR2 are substituted with another amino acid), HC-FR3 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR3 are substituted with another amino acid) and HC-FR4 (or a variant thereof in which 1 or 2 or 3 amino acids in HC-FR4 are substituted with another amino acid) as indicated in Column A of row 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 ,

[0208] 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47,

[0209] 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73,

[0210] 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table B; wherein the HC-CDR1 , HC-CDR2, HC-CDR3 sequences of Column A of Table A and the HC-FR1 , HC-FR2, HC-FR3 and HC-FR4 sequences of Column B of Table B are selected from rows having the same number.

[0211] By way of illustration, in some embodiments, the antigen-binding molecule comprises a VH region comprising: HC-CDR1 having the amino acid sequence of SEQ ID NO:2 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:2 are substituted with another amino acid), HC-CDR2 having the amino acid sequence of SEQ ID NO:3 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:3 are substituted with another amino acid) and 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 SEQ ID NO:4 are substituted with another amino acid), HC-FR1 having the amino acid sequence of SEQ ID NO:5 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:5 are substituted with another amino acid), HC-FR2 having the amino acid sequence of SEQ ID NO:6 (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NO:6 are substituted with another amino acid), HC-FR3 having the amino acid sequence of SEQ ID NOT (or a variant thereof in which 1 or 2 or 3 amino acids in SEQ ID NOT are substituted with another amino acid) and 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 SEQ ID NO:8 are substituted with another amino acid). It will be appreciated that the HC- CDR1 , HC-CDR2 and HC-CDR3 sequences of the preceding sentence are selected from Column A of row 1 of Table A, and that the HC-FR1 , HC-FR2, HC-FR3 and HC-FR4 sequences are selected from Column A of the row of Table B having the same number (row 1).

[0212] In some embodiments, the antigen-binding molecule comprises a VH region comprising 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 a VH region sequence selected from Column A of row 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table C.

[0213] In some embodiments, the antigen-binding molecule comprises: a VL region comprising LC-CDR1 (or a variant thereof in which 1 or 2 or 3 amino acids in LC- CDR1 are substituted with another amino acid), LC-CDR2 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR2 are substituted with another amino acid) and LC-CDR3 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid) as indicated in Column B of row 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table A, wherein the LC-CDR1 , LC-CDR2 and LC-CDR3 sequences of Column B are selected from the same row of Table A.

[0214] In some embodiments, the antigen-binding molecule comprises: a VL region comprising LC-FR1 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 are substituted with another amino acid), LC-FR2 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR2 are substituted with another amino acid), LC-FR3 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR3 are substituted with another amino acid) and LC-FR4 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid) as indicated in Column B of row 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table B, wherein the LC-FR1 , LC-FR2, LC-FR3 and LC-FR4 sequences of Column B are selected from the same row of Table B.

[0215] In some embodiments, the antigen-binding molecule comprises: a VL region comprising:

[0216] LC-CDR1 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 are substituted with another amino acid), LC-CDR2 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR2 are substituted with another amino acid) and LC-CDR3 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid) as indicated in Column B of row 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23,

[0217] 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49,

[0218] 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75,

[0219] 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table A, wherein the LC-CDR1 , LC-

[0220] CDR2 and LC-CDR3 sequences of Column B are selected from the same row of Table A; and

[0221] LC-FR1 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 are substituted with another amino acid), LC-FR2 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR2 are substituted with another amino acid), LC-FR3 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR3 are substituted with another amino acid) and LC-FR4 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid) as indicated in Column B of row 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24,

[0222] 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50,

[0223] 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76,

[0224] 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table B, wherein the LC-FR1 , LC-FR2,

[0225] LC-FR3 and LC-FR4 sequences of Column B are selected from the same row of Table B.

[0226] In some embodiments, the antigen-binding molecule comprises: a VL region comprising:

[0227] LC-CDR1 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR1 are substituted with another amino acid), LC-CDR2 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR2 are substituted with another amino acid) and LC-CDR3 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-CDR3 are substituted with another amino acid) as indicated in Column B of row 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23,

[0228] 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75,

[0229] 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table A; and

[0230] LC-FR1 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR1 are substituted with another amino acid), LC-FR2 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR2 are substituted with another amino acid), LC-FR3 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR3 are substituted with another amino acid) and LC-FR4 (or a variant thereof in which 1 or 2 or 3 amino acids in LC-FR4 are substituted with another amino acid) as indicated in Column B of row 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24,

[0231] 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50,

[0232] 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76,

[0233] 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table B; wherein the LC-CDR1 , LC-CDR2, LC-CDR3 sequences of Column B of Table A and the LC-FR1 , LC-FR2, LC-FR3 and LC-FR4 sequences of Column B of Table B are selected from rows having the same number. In some embodiments, the antigen-binding molecule comprises a VL region comprising 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 a VL region sequence selected from Column B of row 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, or 90 of Table C.

[0234] In some embodiments, the antigen-binding molecule comprises a VH region according to any one embodiment as described herein, and a VL region according to any one embodiment as described herein.

[0235] 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.

[0236] 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:

[0237] 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, lie, Trp, Tyr, Phe and Norleucine. 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:

[0238] 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. 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. In some embodiments, substitution(s) may reduce polyreactivity of the antigen-binding molecule.

[0239] As used herein, ‘polyreactivity’ refers to low-affinity interactions via general nonspecific chemistry to molecules other than the target antigen of the antigen-binding molecule. Polyreactivity of an antigenbinding molecule may also be referred to as ‘stickiness’ of an antigen-binding molecule. High polyreactivity / stickiness of an antigen-binding molecule may result in unacceptably poor PK, potency, bioavailability and / or immunogenicity.

[0240] In some embodiments, one or more amino acids are substituted with another amino acid to reduce / prevent polyreactivity of the antigen-binding molecule.

[0241] Polyreactivity in therapeutic antibodies is reviewed e.g. in Cunningham et al., MAbs, 2021 , 13(1):1999195, which is hereby incorporated by reference in its entirety. The polyreactivity of an antigenbinding molecule may be assessed e.g. by ELISA assays using a range of structurally diverse coating antigens (e.g. E.coli LPS, cardiolipin, insulin, dsDNA, ssDNA, KLH) or by in silica methods (e.g. as reviewed in Harvey et al., Nature Communications, 2022, 13:7554, which is hereby incorporated by reference in its entirety).

[0242] In some embodiments, a VH region according to the present disclosure comprises a HC-CDR3 according to SEQ ID NO:4, comprising substitution of I at position 8 of SEQ ID NO:4 with another amino acid.

[0243] In some embodiments, a VH region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:1 , 94, 98, 174, 112 or 117, wherein the VH region comprises substitution of I at position 100 (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 104 of SEQ ID NO:1) with another amino acid.

[0244] In some embodiments, a VH region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:64, 65, 130, 132, 176, 134, 136, 131 , 133, 177, 135 or 137, wherein the VH region comprises substitution of I at position 100 (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 104 of SEQ ID NO:64) with another amino acid.

[0245] In some embodiments in accordance with the preceding three paragraphs, I is substituted with T, S, E, Q, K, H, G, V, Y, A, C, L, F, P, D, N, M, W or R. In some embodiments, I is substituted with T, S, E, Q, K or H. In some embodiments, I is substituted with T or K. In some embodiments, I is substituted with T.

[0246] In some embodiments, a VH region according to the present disclosure comprises a HC-CDR3 according to SEQ ID NO:4, comprising substitution of V at position 7 of SEQ ID NO:4 with another amino acid. In some embodiments, a VH region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:1 , 94, 98, 174, 112 or 117, wherein the VH region comprises substitution of V at position 99 (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 103 of SEQ ID NO:1) with another amino acid.

[0247] In some embodiments, a VH region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:64, 65, 130, 132, 176, 134, 136, 131 , 133, 177, 135 or 137, wherein the VH region comprises substitution of V at position 99 (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 103 of SEQ ID NO:64) with another amino acid.

[0248] In some embodiments in accordance with the preceding three paragraphs, V is substituted with G, S, T, E, Q, K, H, I, C, Y, A, L, F, P, D, N, M, W or R. In some embodiments, V is substituted with G or S.

[0249] 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 isomerisation, oxidation, fragmentation, deamination, hydrolysis, deglycosylation, racemization, disulphide bond breakage and formation, Maillard reaction, and p-elimination.

[0250] Oxidation is a 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 susceptible 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 susceptible to oxidation).

[0251] Amino acid residues susceptible to oxidation may be identified e.g. by in silico 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). Aspartic acid (Asp) isomerization is a spontaneous non-enzymatic post-translation modification causing a change in the structure of the protein backbone, which is commonly observed in therapeutic antibodies during manufacturing and storage. The Asps in Asp-Gly (DG), Asp-Ser (DS), and Asp-Thr (DT) motifs in the structurally flexible regions, such as complementarity-determining regions (CDRs) in antibodies, are often found to have high rate of isomerization. In some embodiments, one or more amino acids susceptible to isomerisation are substituted with another amino acid (e.g. an amino acid which is not susceptible to isomerisation or is less susceptible to isomerisation). In some embodiments, one or more amino acids present in an amino acid motif susceptible to isomerisation (e.g. Asp-Gly (DG), Asp-Ser (DS), or Asp-Thr (DT)), are substituted with another amino acid (e.g. an amino acid which reduces the susceptibility of an amino acid in the motif to isomerisation).

[0252] The susceptibility of an antigen-binding molecule to isomerisation may be assessed in in vitro assays e.g. as described in Lu et al., MAbs, 2019, 11 (1):45-57, which is hereby incorporated by reference in it’s entirety.

[0253] In some embodiments, a VL region according to the present disclosure comprises a LC-CDR2 according to SEQ ID NO:11 , comprising substitution of D at position 1 of SEQ ID NO:11 with another amino acid. In some embodiments, a VL region according to the present disclosure comprises a LC-CDR2 according to SEQ ID NO:192, comprising substitution of D at position 1 of SEQ ID NO:192 with another amino acid.

[0254] In some embodiments, a VL region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:121 , 126, 9, 102, 106, 109, 186, 187, 188, 189, 190, or 191 wherein the VL region comprises substitution of D at position 50 (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 50 of SEQ ID NO:9) with another amino acid.

[0255] In some embodiments, a polypeptide according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater amino acid sequence identity to SEQ ID NO:141 , 142, 66, 138, 139, 140, 245, 246, 247, 248, 249 or 250, wherein the polypeptide comprises substitution of D at position 50 (numbered according to Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 50 of SEQ ID NO:66) with another amino acid.

[0256] In some embodiments in accordance with the preceding three paragraphs, D is substituted with A, E, N, C, G, I, L, M, F, P, S, T, W, Y, V, R, K, H or Q. In some embodiments, D is substituted with A, E, N, C, G, I, L, M, F, P, S, T, W, Y or V. In some embodiments, D is substituted with A or E. In some embodiments, D is substituted with A.

[0257] In some embodiments, a VL region according to the present disclosure comprises a LC-CDR2 according to SEQ ID NO:11 , comprising substitution of G at position 2 of SEQ ID NO:11 with another amino acid.

[0258] In some embodiments, a VL region according to the present disclosure comprises a LC-CDR2 according to SEQ ID NO:149, comprising substitution of G at position 2 of SEQ ID NO:149 with another amino acid. In some embodiments, a VL region according to the present disclosure comprises a LC-CDR2 according to SEQ ID NO:162, comprising substitution of G at position 2 of SEQ ID NO:162 with another amino acid.

[0259] In some embodiments, a VL region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:121 , 126, 9, 102, 106, 109, 143, 144, 145, 146, 147, 148, 156, 157, 158, 159, 160 or 161 , wherein the VL region comprises substitution of G at position 51 (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 51 of SEQ ID NO:9) with another amino acid.

[0260] In some embodiments, a polypeptide according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater amino acid sequence identity to SEQ ID NO:141 , 142, 66, 138, 139, 140, 150, 151 , 152, 153, 154, 155, 163, 164, 165, 166, 167 or 168, wherein the polypeptide comprises substitution of G at position 51 (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 51 of SEQ ID NO:66) with another amino acid.

[0261] In some embodiments in accordance with the preceding three paragraphs, G is substituted with A, E, N, C, I, D, L, M, F, P, S, T, W, Y, V, R, K, H or Q. In some embodiments, G is substituted with A.

[0262] In some embodiments, a VL region according to the present disclosure comprises a LC-FR3 according to SEQ ID NO:15, comprising substitution of L at position 2 of SEQ ID NO:15 with another amino acid.

[0263] In some embodiments, a VL region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:121 , 126, 9, 102, 106, 109, 143, 144, 145, 146, 147, 148, 156, 157, 158, 159, 160 or 161 , wherein the VL region comprises substitution of L at position 54 (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 54 of SEQ ID NO:9) with another amino acid.

[0264] In some embodiments, a polypeptide according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater amino acid sequence identity to SEQ ID NO:141 , 142, 66, 138, 139, 140, 150, 151 , 152, 153, 154, 155, 163, 164, 165, 166, 167 or 168, wherein the polypeptide comprises substitution of L at position 54 (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 54 of SEQ ID NO:66) with another amino acid. In some embodiments in accordance with the preceding three paragraphs, L is substituted with S, A, E, N, C, I, D, G, M, F, P, T, W, Y, V, R, K, H or Q. In some embodiments, L is substituted with S.

[0265] In some embodiments, a VL region according to the present disclosure comprises a LC-FR3 according to SEQ ID NO:108, comprising substitution of V at position 6 of SEQ ID NO:108 with another amino acid. In some embodiments, a VL region according to the present disclosure comprises a LC-FR3 according to SEQ ID NO:111 , comprising substitution of V at position 6 of SEQ ID NO:111 with another amino acid.

[0266] In some embodiments, a VL region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:121 , 126, 106, 109, 145, 146, 147, 148, 158, 159, 160 or 161 , wherein the VL region comprises substitution of V at position 58 (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 58 of SEQ ID NO:106) with another amino acid.

[0267] In some embodiments, a polypeptide according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater amino acid sequence identity to SEQ ID NO:141 , 142, 139, 140, 152, 153, 154, 155, 165, 166, 167 or 168, wherein the polypeptide comprises substitution of V at position 58 (numbered according to Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 58 of SEQ ID NO:139) with another amino acid.

[0268] In some embodiments in accordance with the preceding three paragraphs, V is substituted with G, A, E, N, C, I, D, L, M, F, P, S, T, W, Y, R, K, H or Q. In some embodiments, V is substituted with G.

[0269] In some embodiments, a VL region according to the present disclosure comprises a LC-FR3 having at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% or greater amino acid sequence identity to SEQ ID NO:124, 129, 15, 104, 108 or 111 , wherein the amino acid at the position corresponding to position 30 of SEQ ID NO:15 is D.

[0270] In some embodiments, a VL region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:121 , 126, 9, 102, 106, 109, 147, 148, 143, 144, 145, 146, 160, 161 , 156, 157, 158 or 159 (e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:121 , 126, 9, 102, 106, or 109; e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:147, 148, 143, 144, 145 or 146; e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NQ:160, 161 , 156, 157, 158 or 159), wherein the amino acid at the position corresponding to position 82a (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 82 of SEQ ID NO:9) is D.

[0271] In some embodiments, a polypeptide according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater amino acid sequence identity to SEQ ID NO:141 , 142, 66, 138, 139, 140, 154, 155, 150, 151 , 152, 153, 167, 168, 163, 164, 165 or 166 (e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:141 , 142, 66, 138, 139 or 140; e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:154, 155, 150, 151 , 152 or 153; e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:167, 168, 163, 164, 165 or 166), wherein the amino acid at the position corresponding to position 82a (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 82 of SEQ ID NO:66) is D.

[0272] In some embodiments, a VL region according to the present disclosure comprises a LC-FR3 having at least 60%, preferably one of 70%, 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97% or greater amino acid sequence identity to SEQ ID NO:124, 129, 15, 104, 108 or 111 , wherein the amino acid at the position corresponding to position 30 of SEQ ID NO:15 is D, and wherein the amino acid sequence comprises one or more (e.g. one of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13 or 14) amino acid substitutions relative to the reference amino acid sequence ( / .e. the amino acid sequence selected from SEQ ID NO:124, 129, 15, 104, 108 and 111), wherein the one or more amino acid substitutions are provided at the position(s) corresponding to the following positions of the reference sequence: 22, 23, 24, 25, 26, 27, 28, 29, 31 , 32, 33, 34, 35, 36 (that is, the one or more amino acid substitutions are provided within the 8 positions immediately N-terminal to (in the context of the amino acid sequence of the LC-FR3) position 30, and / or are provided within the 6 positions immediately C-terminal to position 30).

[0273] In some embodiments, a VL region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:121 , 126, 9, 102, 106, 109, 147, 148, 143, 144, 145, 146, 160, 161 , 156, 157, 158 or 159 (e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:121 , 126, 9, 102, 106, or 109; e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:147, 148, 143, 144, 145 or 146; e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NQ:160, 161 , 156, 157, 158 or 159), wherein the amino acid at the position corresponding to position 82a (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 82 of SEQ ID NO:9) is D, and wherein the amino acid sequence comprises one or more (e.g. one of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or 16) amino acid substitutions relative to the reference amino acid sequence, wherein the one or more amino acid substitutions are provided at the position(s) corresponding to the following positions of the reference sequence: 74, 75, 76, 77, 78, 79, 80, 81 , 83, 84, 85, 86, 87, 88, 89, 90 (that is, the one or more amino acid substitutions are provided within the 8 positions immediately N-terminal to (in the context of the amino acid sequence of the VL region) position 82, and / or are provided within the 8 positions immediately C-terminal to position 82).

[0274] In some embodiments, a polypeptide according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater amino acid sequence identity to SEQ ID NO:141 , 142, 66, 138, 139, 140, 154, 155, 150, 151 , 152, 153, 167, 168, 163, 164, 165 or 166 (e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:141 , 142, 66, 138, 139 or 140; e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:154, 155, 150, 151 , 152 or 153; e.g. comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:167, 168, 163, 164, 165 or 166), wherein the amino acid at the position corresponding to position 82a (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 82 of SEQ ID NO:66) is D, and wherein the amino acid sequence comprises one or more (e.g. one of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or 16) amino acid substitutions relative to the reference amino acid sequence, wherein the one or more amino acid substitutions are provided at the position(s) corresponding to the following positions of the reference sequence: 74, 75, 76, 77, 78, 79, 80, 81 , 83, 84, 85, 86, 87, 88, 89, 90 (that is, the one or more amino acid substitutions are provided within the 8 positions immediately N-terminal to (in the context of the amino acid sequence of the polypeptide) position 82, and / or are provided within the 8 positions immediately C-terminal to position 82).

[0275] In some embodiments, a VH region according to the present disclosure comprises a HC-CDR3 according to SEQ ID NQ:20, comprising substitution of D at position 6 of SEQ ID NQ:20 with another amino acid. In some embodiments, a VH region according to the present disclosure comprises a HC-CDR3 according to SEQ ID NO:195, comprising substitution of D at position 6 of SEQ ID NO:195 with another amino acid. In some embodiments, a VH region according to the present disclosure comprises a HC-CDR3 according to SEQ ID NQ:204, comprising substitution of D at position 6 of SEQ ID NQ:204 with another amino acid.

[0276] In some embodiments, a polypeptide according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater amino acid sequence identity to SEQ ID NO:17, 193, 194, 202 or 203, wherein the polypeptide comprises substitution of D at position 98 (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 101 of SEQ ID NO:17) with another amino acid. In some embodiments, a VH region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:67, 68, 251 , 252, 253, or 254, wherein the VH region comprises substitution of D at position 98 (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 101 of SEQ ID NO:67) with another amino acid.

[0277] In some embodiments in accordance with the preceding three paragraphs, D is substituted with G, S, E, A, N, C, I, L, M, F, P, T, W, Y, V, R, K, H or Q. In some embodiments, D is substituted with G, S, E, or A. In some embodiments, D is substituted with G or S. In some embodiments, D is substituted with G.

[0278] In some embodiments, a VH region according to the present disclosure comprises a HC-CDR3 according to SEQ ID NQ:20, comprising substitution of G at position 7 of SEQ ID NQ:20 with another amino acid. In some embodiments, a VH region according to the present disclosure comprises a HC-CDR3 according to SEQ ID NO:195, comprising substitution of G at position 7 of SEQ ID NO:195 with another amino acid. In some embodiments, a VH region according to the present disclosure comprises a HC-CDR3 according to SEQ ID NQ:204, comprising substitution of G at position 7 of SEQ ID NQ:204 with another amino acid.

[0279] In some embodiments, a polypeptide according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater amino acid sequence identity to SEQ ID NO:17, 193, 194, 202, 203, 211 , 212, 213, 216 or 217 wherein the polypeptide comprises substitution of G at position 99 (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 102 of SEQ ID NO:17) with another amino acid.

[0280] In some embodiments, a VH region according to the present disclosure comprises at least 70%, preferably one of 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or greater amino acid sequence identity to SEQ ID NO:67, 68, 251 , 252, 253, 254, 255, 256, 257, 258 or 259, wherein the VH region comprises substitution of G at position 99 (numbered according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 , which corresponds to position 102 of SEQ ID NO:67) with another amino acid.

[0281] In some embodiments in accordance with the preceding three paragraphs, G is substituted with A, Y, D, S, E, N, C, I, L, M, F, P, T, W, V, R, K, H or Q. In some embodiments, G is substituted with A or Y.

[0282] 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). In some embodiments, the VH and VL regions of the Fv are provided as separate polypeptides stabilised by the introduction of one or more cysteine residues for the formation of an interchain disulfide bond, i.e. a disulfide stabilised Fv (dsFv).

[0283] 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).

[0284] 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.

[0285] 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.

[0286] IgG 1 , lgG2, lgG3, lgG4), IgA (e.g. lgA1 , lgA2), IgD, IgE, or IgM. The light chain may be kappa (K) or lambda (A).

[0287] 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.

[0288] In some embodiments, the antigen-binding molecule described herein comprises, or consists of, an IgG (e.g. IgG 1 , lgG2, lgG3, lgG4), IgA (e.g. lgA1 , lgA2), IgD, IgE, or IgM that binds to gp130. 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. IgG 1 , lgG2, lgG3, lgG4), IgA e.g. Ig A1 , lgA2), IgD, IgE or IgM, e.g. a human IgG (e.g. hlgG 1 , hlgG2, hlgG3, hlgG4), hlgA (e.g. hlgA1 , hlgA2), hlgD, hlg E or hlgM. In some embodiments, the immunoglobulin heavy chain constant sequence is, or is derived from, the heavy chain constant sequence of a human lgG1 allotype (e.g. G1 m1 , G1 m2, G1 m3 or G1 m17).

[0289] 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:33 or 38. 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:48 or 49. 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:41 or 50.

[0290] 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:42, 43, 46 or 47. 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:44 or 57.

[0291] 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:34 or 39. 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:51.

[0292] 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:35. 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:52 or 53.

[0293] 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:36 or 45. 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:54 or 55.

[0294] 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:37 or 40. 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:56.

[0295] 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.

[0296] 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; CA), e.g. IGLC1 , IGLC2, IGLC3, IGLC6 or IGLC7.

[0297] 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:58, 59, 60, 61 , 62 or 63. 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:58.

[0298] In some embodiments, the antigen-binding molecule is or comprises a monoclonal antibody, or an antigen-binding fragment thereof.

[0299] 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 disulfide-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.

[0300] 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.

[0301] 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 humanized antigenbinding molecule ( / .e. an antigen-binding molecule comprising variable domains derived by humanization 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.

[0302] 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.

[0303] Humanized antigen-binding molecules can be prepared from mouse antibodies by the process of humanization, 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 humanization are also described e.g. in Safdari et al., Biotechnol Genet Eng Rev (2013) 29:175- 86. 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 ( / .e. at least two antigen-binding domains, e.g. comprising non-identical VHs and VLs).

[0304] 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.

[0305] 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.

[0306] 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.

[0307] 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.

[0308] 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.

[0309] 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) 154:102-117, both of which are hereby incorporated by reference in their entirety.

[0310] 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.

[0311] 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.

[0312] 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.

[0313] 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, KA-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.

[0314] 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.

[0315] 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.

[0316] 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.

[0317] 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.

[0318] 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.

[0319] 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-ex pressing 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-ex pressing 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.

[0320] 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:35. 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:52 or 53.

[0321] 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-ex pressing immune cells, e.g. CAR-T or CAR-NK cells. Engineering of CARs into immune cells may be performed during culture, in vitro.

[0322] Fc regions

[0323] In some embodiments, the antigen-binding molecules of the present disclosure comprise an Fc region.

[0324] 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.

[0325] 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. 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. IgG 1 , lgG2, lgG3, lgG4), IgA (e.g. Ig A1 , 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. hlgG1 , 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 lgG1 allotype (e.g. G1 m1 , G1 m2, G1 m3 or G1 m17).

[0326] 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.

[0327] 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.

[0328] 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 lgG1 (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).

[0329] 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.

[0330] 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. 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.

[0331] 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, FcyRI I la 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.

[0332] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions F243L / R292P / Y300LA / 305I / 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 etal., Mol Cancer Ther. (2008) 7:2517-2527.

[0333] 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.

[0334] 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.

[0335] 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).

[0336] 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 hematopoietic cells, which increases efficient recycling of administered mAb and longer half-life in the plasma.

[0337] 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.

[0338] 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 etal. Biol Chem. (2014) 289:15309-15318.

[0339] 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 a reduced level of the relevant effector function as compared to an antigen-binding molecule comprising the corresponding unmodified Fc region.

[0340] 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 FcyRI I lb. 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.

[0341] In some embodiments, the Fc region is not able to induce one or more Fc-mediated functions ( / .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).

[0342] 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.

[0343] 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.

[0344] 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 etal., 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 / P331S 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 V234A / G237A / P238S / H268AA / 309L / A330S / P331S 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.

[0345] 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.

[0346] The combination of substitutions L234A / L235E / G237A / A330S / P331S in lgG1 Fc is disclosed in US 2015 / 0044231 A1 to abolish induction of phagocytosis, ADCC and CDC.

[0347] 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).

[0348] 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.

[0349] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A / P329G.

[0350] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235A / P329G / N297Q.

[0351] In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions L234A / L235E / G237A / A330S / P331 S.

[0352] In some embodiments, the Fc region comprises modification corresponding to the substitution S228P, e.g. in lgG4. It may be desirable for the antigen-binding molecule to have a relatively-short half-life. Because the antigen-binding molecules of the present disclosure influence signalling mediated by multiple cytokines / through multiple cytokine receptors, it might be desirable for their functional effects to be relatively short-lived. Accordingly, in some embodiments the antigen-binding molecule of the present disclosure may comprise an Fc region comprising modification to decrease antigen-binding molecule halflife.

[0353] Fc modifications that reduce half-life include H345A, and the triple substitution I253A / H310A / H345A, which have been reported to reduce binding to FcRn and decrease half-life of antigen-binding molecules bearing Fc regions comprising such modifications relative to their unmodified wildtype counterparts (see e.g. Kruijsen et al., J Virol. (2013) 87(13): 7550-7557, which is hereby incorporated by reference in its entirety.

[0354] In some embodiments, the Fc region comprises modification corresponding to the substitution H345A. In some embodiments, the Fc region comprises modification corresponding to the substitution I253A. In some embodiments, the Fc region comprises modification corresponding to the substitution H310A. In some embodiments, the Fc region comprises modification corresponding to the combination of substitutions I253A / H310A / H345A.

[0355] In some embodiments, the antigen-binding molecule does not comprise an Fc region. In some embodiments, the antigen-binding molecule consists essentially of an Fv moiety (e.g. is a scFv or a dsFv). In some embodiments, the antigen-binding molecule consists essentially of a Fab moiety (e.g. is a Fab, CrossFab, scFab, scCrossFab or F(ab’)2).

[0356] As used herein, an antigen-binding molecule that ‘consists essentially of a reference polypeptide domain(s) / amino acid sequence(s) either (i) consists of the reference domain(s) / amino acid sequence(s), or (ii) comprises the reference domain(s) / amino acid sequence(s), wherein the reference domain(s) / amino acid sequence(s) constitute at least 80% (e.g. one of >85% >86%, >87%, >88%, >89%, >90%, >91 %, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99%) of the molecule. It will be appreciated that an antigen-binding molecule that ‘consists essentially of’ a reference polypeptide domain(s) / amino acid sequence(s) may comprise the reference domain(s) / amino acid sequence(s), and additional amino acid(s) at one or both of the N-terminal and C-terminal ends of the reference domain(s) / amino acid sequence(s), provided that the additional amino acid(s) constitute <20% of the molecule. By way of illustration, antigen-binding molecules that consist essentially of an Fv moiety include scFv molecules, which comprise a VH and VL connected via a linker moiety.

[0357] 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.

[0358] 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.

[0359] Particular exemplary polypeptides and antigen-binding molecules

[0360] The present disclosure also provides polypeptide constituents of antigen-binding molecules. The polypeptides may be provided in isolated or substantially purified form.

[0361] The antigen-binding molecule of the present disclosure may be, or may comprise, a complex of polypeptides.

[0362] 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.

[0363] 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.

[0364] 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).

[0365] 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.

[0366] 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. In some embodiments, the polypeptide according to the present disclosure comprises a structure from N- to C-terminus according to one of the following:

[0367] (i) VH

[0368] (ii) VL

[0369] (iii) VH-CH1

[0370] (iv) VL-CL

[0371] (v) VL-CH1

[0372] (vi) VH-CL

[0373] (vii) VH-CH1-CH2-CH3

[0374] (viii) VL-CL-CH2-CH3

[0375] (ix) VL-CH1-CH2-CH3

[0376] (x) VH-CL-CH2-CH3

[0377] 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:

[0378] (A) VH + VL

[0379] (B) VH-CH1 + VL-CL

[0380] (C) VL-CH1 + VH-CL

[0381] (D) VH-CH1-CH2-CH3 + VL-CL

[0382] (E) VH-CL-CH2-CH3 + VL-CH1

[0383] (F) VL-CH1-CH2-CH3 + VH-CL

[0384] (G) VL-CL-CH2-CH3 + VH-CH1

[0385] (H) VH-CH1-CH2-CH3 + VL-CL-CH2-CH3

[0386] (I) VH-CL-CH2-CH3 + VL-CH1-CH2-CH3

[0387] 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.

[0388] In some embodiments, the antigen-binding molecule of the present disclosure comprises one of the following combinations of polypeptides:

[0389] (J) VH (anti-gp130) + VL (anti-gp130)

[0390] (K) VH (anti-gp130)-CH1 + VL (anti-gp130)-CL

[0391] (L) VL (anti-gp130)-CH1 + VH (anti-gp130)-CL

[0392] (M) VH (anti-gp130)-CH1-CH2-CH3 + VL (anti-gp130)-CL

[0393] (N) VH (anti-gp130)-CL-CH2-CH3 + VL (anti-gp130)-CH1

[0394] (O) VL (anti-gp130)-CH1-CH2-CH3 + VH (anti-gp130)-CL

[0395] (P) VL (anti-gp130)-CL-CH2-CH3 + VH (anti-gp130)-CH1 (Q) VH (anti-gp130)-CH1-CH2-CH3 + VL (anti-gp130)-CL-CH2-CH3

[0396] Wherein: ‘VH(anti-gp130)’ refers to the VH of an antigen-binding molecule capable of binding to gp130 as described herein; and ‘VL(anti-gp130)’ refers to the VL of an antigen-binding molecule capable of binding to gp130 as described herein.

[0397] 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:183, 184, 112, 117, 179, 1 , 180, 94, 181 , 98, 182, or 174.

[0398] 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:216, 217, 202, 203, 211 , 212, 213, 193, 194, or 17.

[0399] 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 NQ:190, 191 , 121 , 126, 186, 9, 187, 188, 189, 102, 106, 109, 147, 148, 143, 144, 145, 146, 160, 161 , 156, 157, 158 or 159. 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 NQ:190, 191 , 121 , 126, 186, 9, 187, 188, 189, 102, 106, or 109. 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:147, 148, 143, 144, 145 or 146. 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 NQ:160, 161 , 156, 157, 158 or 159.

[0400] 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 NQ:230, 231 , 25, 219, 220, or 221.

[0401] 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:243, 244, 135, 137, 134, 136, 239, 65, 240, 131 , 241 , 133, 242, 177, 130, 132, 176 or 64. 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:258, 259, 253, 254, 255, 256, 257, 251 , 252, 67 or 68.

[0402] 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:249, 250, 141 , 142, 245, 66, 246, 247, 248, 138, 139, 140, 154, 155, 150, 151 , 152, 153, 167, 168, 163, 164, 165 or 166. 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:249, 250, 141 , 142, 245, 66, 246, 247, 248, 138, 139 or 140. 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:154, 155, 150, 151 , 152 or 153. 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:167, 168, 163, 164, 165 or 166.

[0403] 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:263, 264, 69, 260, 261 , or 262.

[0404] 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 a clone selected from B035-C03-A3, CSP-S-5H8, A3_3.2 VH / A3_3 VL, A3_3.2 VH I A3_4 VL, A3_3.2 VH I A3_5 VL, A3_4.2 VH I A3_3 VL, A3_4.2 VH I A3_4 VL, A3_4.2 VH I A3_5 VL, A3_6.2 VH I A3_3 VL, A3_6.2 VH I A3_4 VL, A3_6.2 VH I A3_5 VL, A3-derived VH CON I A3-derived VL CON, A3-Hum VH CON I A3-Hum VL CON, B035-C03-A3_D50X, A3_3.2 VH I A3_3_D50X VL, A3_3.2 VH I A3_4_D50X VL, A3_3.2 VH I A3_5_D50X VL, A3_4.2 VH I A3_3_D50X VL, A3_4.2 VH I A3_4_D50X VL, A3_4.2 VH I A3_5_D50X VL, A3_6.2 VH I A3_3_D50X VL, A3_6.2 VH I A3_4_D50X VL, A3_6.2 VH I A3_5_D50X VL, A3-derived VH CON I A3-derived VL_D50X CON, A3-Hum VH CON I A3- Hum A3_3 A3_5 A3-derived VH CON / A3-derived VL_D50A CON and A3-Hum VH CON / A3-Hum VL_D50A CON, B035- C03-A3J100T VH / B035-C03-A3_G51 A VL, B035-C03-A3J 100T VH / B035-C03-A3 VL, B035-C03-A3 derivedJWOT VH CON / A3-derived_G51 A VL CON, A3-derived_l100T VH CON / A3-derived VL CON, A3-derived VH CON / A3-derived_G51A VL CON, A3-Hum_l100T VH CON / A3-Hum_G51A VL CON, A3-Hum_l100T VH CON I A3-Hum VL CON, A3-Hum VH CON I A3-Hum_G51 A VL CON, 5H8CVH4 VH I 5H8CVL3 VL, 5H8CVH4 VH I 5H8CVL4 VL, 5H8CVH4 VH I 5H8GVL3 VL, 5H8GVH4 VH I 5H8CVL3 VL, 5H8GVH4 VH I 5H8CVL4 VL, 5H8GVH4 VH I 5H8GVL3 VL, 5H8-derived VH CON I 5H8-derived VL CON, 5H8-Hum VH CON I 5H8-Hum VL CON, CSP-S-5H8_D98G VH I CSP-S-5H8 VL, 5H8CVH4_D98G VH I 5H8CVL3 VL, 5H8CVH4_D98G VH I 5H8CVL4 VL, 5H8CVH4_D98G VH I 5H8GVL3 VL, 5H8GVH4_D98G VH I 5H8CVL3 VL, 5H8GVH4_D98G VH I 5H8CVL4 VL, 5H8GVH4_D98G VH I 5H8GVL3 VL, 5H8-derived_D98G VH CON 1 5H8-derived VL CON or, 5H8-Hum_D98G VH CON 1 5H8- Hum VL CON 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.

[0405] 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 a clone selected from B035-C03-A3, CSP-S-5H8, A3_3.2 VH I A3_3 VL, A3_3.2 VH I A3_4 VL, A3_3.2 VH I A3_5 VL, A3_4.2 VH I A3_3 VL, A3_4.2 VH I A3_4 VL, A3_4.2 VH I A3_5 VL, A3_6.2 VH I A3_3 VL, A3_6.2 VH I A3_4 VL, A3_6.2 VH I A3_5 VL, A3-derived VH CON I A3-derived VL CON, A3-Hum VH CON I A3-Hum VL CON, B035-C03-A3_D50X, A3_3.2 VH I A3_3_D50X VL, A3_3.2 VH I A3_4_D50X VL, A3_3.2 VH I A3_5_D50X VL, A3_4.2 VH I A3_3_D50X VL, A3_4.2 VH I A3_4_D50X VL, A3_4.2 VH I A3_5_D50X VL, A3_6.2 VH I A3_3_D50X VL, A3_6.2 VH I A3_4_D50X VL, A3_6.2 VH I A3_5_D50X VL, A3-derived VH CON I A3-derived VL_D50X CON, A3-Hum VH CON I A3- derivedJWOT VH CON / A3-derived_G51 A VL CON, A3-derived_l100T VH CON / A3-derived VL CON, A3-derived VH CON / A3-derived_G51A VL CON, A3-Hum_l100T VH CON / A3-Hum_G51A VL CON, A3-Hum_l100T VH CON I A3-Hum VL CON, A3-Hum VH CON I A3-Hum_G51 A VL CON, 5H8CVH4 VH I 5H8CVL3 VL, 5H8CVH4 VH I 5H8CVL4 VL, 5H8CVH4 VH I 5H8GVL3 VL, 5H8GVH4 VH I 5H8CVL3 VL, 5H8GVH4 VH I 5H8CVL4 VL, 5H8GVH4 VH I 5H8GVL3 VL, 5H8-derived VH CON I 5H8-derived VL CON, 5H8-Hum VH CON I 5H8-Hum VL CON, CSP-S-5H8_D98G VH I CSP-S-5H8 VL, 5H8CVH4_D98G VH I 5H8CVL3 VL, 5H8CVH4_D98G VH I 5H8CVL4 VL, 5H8CVH4_D98G VH I 5H8GVL3 VL, 5H8GVH4_D98G VH I 5H8CVL3 VL, 5H8GVH4_D98G VH I 5H8CVL4 VL, 5H8GVH4_D98G VH I 5H8GVL3 VL, 5H8-derived_D98G VH CON 1 5H8-derived VL CON or, 5H8-Hum_D98G VH CON 1 5H8- Hum VL CON 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.

[0406] 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.

[0407] 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 a clone selected from B035-C03-A3, CSP-S- 5H8, A3_3.2 VH I A3_3 VL, A3_3.2 VH I A3_4 VL, A3_3.2 VH I A3_5 VL, A3_4.2 VH I A3_3 VL, A3_4.2 VH I A3_4 VL, A3_4.2 VH I A3_5 VL, A3_6.2 VH I A3_3 VL, A3_6.2 VH I A3_4 VL, A3_6.2 VH I A3_5 VL, A3-derived VH CON / A3-derived VL CON, A3-Hum VH CON / A3-Hum VL CON, B035-C03-A3_D50X, A3_6.2 VH I A3_4_D50X VL, A3_6.2 VH I A3_5_D50X VL, A3-derived VH CON I A3-derived VL_D50X CON, A3-Hum VH CON I A3-Hum VL_D50X CON, B035-C03-A3_D50A, A3_3.2 VH I A3_3_D50A VL, A3_3.2 VH I A3_4_D50A VL, A3_3.2 VH I A3_5_D50A VL, A3_4.2 VH I A3_3_D50A VL, A3_4.2 VH I A3_4_D50A VL, A3_4.2 VH I A3_5_D50A VL, A3_6.2 VH I A3_3_D50A VL, A3_6.2 VH I A3_4_D50A VL, A3_6.2 VH / A3_5_D50A VL, A3-derived VH CON / A3-derived VL_D50A CON and A3-Hum VH CON / A3-Hum VL_D50A CON, B035-C03-A3J100T VH / B035-C03-A3_G51 A VL, B035-C03-A3J 100T VH / B035-C03-A3 VL, B035-C03-A3 VH I B035-C03-A3_G51 A VL, A3_3.2_I1OOT VH / A3_3_G51A VL, A3_3.2_I1OOT VH / A3_4_G51A VL, A3_3.2_I1OOT VH / A3_5_G51 A VL, A3_3.2_I1OOT VH / A3_3 VL, A3_3.2_I1OOT VH I A3_4 VL, A3_3.2_I1OOT VH / A3_5 VL, A3_3.2 VH I A3_3_G51A VL, A3_3.2 VH I A3_4_G51A VL, A3_3.2 VH / A3_5_G51 A VL, A3_4.2_I1OOT VH / A3_3_G51 A VL, A3_4.2_I1OOT VH I A3_4_G51A VL, A3_4.2_I1OOT VH / A3_5_G51A VL, A3_4.2_I1OOT VH I A3_3 VL, A3_4.2_I1OOT VH I A3_4 VL, A3_4.2_I100T VH I A3_5 VL, A3_4.2 VH I A3_3_G51 A VL, A3_4.2 VH I A3_4_G51 A VL, A3_4.2 VH / A3_5_G51A VL, A3_6.2_I1OOT VH / A3_3_G51A VL, A3_6.2_I1OOT VH / A3_4_G51A VL, A3_6.2_I1OOT VH I A3_5_G51A VL, A3_6.2_I1OOT VH / A3_3 VL, A3_6.2_I1OOT VH / A3_4 VL, A3_6.2_I1OOT VH I A3_5 VL, A3_6.2 VH I A3_3_G51A VL, A3_6.2 VH I A3_4_G51A VL, A3_6.2 VH I A3_5_G51A VL, A3-derived_l100T VH CON I A3-derived_G51A VL CON, A3-derived_l100T VH CON I A3-derived VL CON, A3-derived VH CON I A3-derived_G51A VL CON, A3-Hum_l100T VH CON / A3- Hum_G51 A VL CON, A3-Hum_l100T VH CON I A3-Hum VL CON, A3-Hum VH CON I A3-Hum_G51 A VL CON, 5H8CVH4 VH I 5H8CVL3 VL, 5H8CVH4 VH I 5H8CVL4 VL, 5H8CVH4 VH I 5H8GVL3 VL, 5H8GVH4 VH I 5H8CVL3 VL, 5H8GVH4 VH I 5H8CVL4 VL, 5H8GVH4 VH I 5H8GVL3 VL, 5H8-derived VH CON I 5H8-derived VL CON, 5H8-Hum VH CON I 5H8-Hum VL CON, CSP-S-5H8_D98G VH I CSP- S-5H8 VL, 5H8CVH4_D98G VH I 5H8CVL3 VL, 5H8CVH4_D98G VH I 5H8CVL4 VL, 5H8CVH4_D98G VH I 5H8GVL3 VL, 5H8GVH4_D98G VH I 5H8CVL3 VL, 5H8GVH4_D98G VH I 5H8CVL4 VL, 5H8GVH4_D98G VH I 5H8GVL3 VL, 5H8-derived_D98G VH CON I 5H8-derived VL CON or, 5H8- Hum_D98G VH CON / 5H8-Hum VL CON 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.

[0408] 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.

[0409] 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. Functional properties of the antigen-binding molecules

[0410] 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, rhesus macaque gp130, mouse gp130 and / or rat gp130); binds to gp130-expressing cells; inhibits signalling mediated by a receptor comprising gp130; inhibits signalling mediated by gp130:IL-6Ra, gp130:IL-11 Ra, gp130:OSMRp, gp130:LIFRp, gp130:LIFRp:CNTFRa, gp130:IL-27Ra and / or gp130:IL-12Rp2; inhibits signalling mediated by a cytokine that binds to a receptor comprising gp130; inhibits IL-6-, IL-11-, 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.

[0411] 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.

[0412] 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).

[0413] 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. 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.

[0414] 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 macaque gp130. In some embodiments, the antigen-binding molecule binds to canine gp130.

[0415] In some embodiments, the antigen-binding molecules display cross-reactive binding to human gp130, and to one or more homologues of human gp130 (e.g. selected from rhesus macaque gp130, mouse gp130 and rat gp130). It will be appreciated that cross-reactive binding refers to the ability to bind independently to each antigen, and not simultaneous binding of an antigen-binding domain of the antigenbinding molecule to the two or more antigens.

[0416] In some embodiments, the antigen-binding molecule is cross-reactive for human gp130 and rhesus macaque gp130 ( / .e. is capable of binding to human gp130, and is also capable of binding to rhesus macaque gp130). In some embodiments, the antigen-binding molecule is cross-reactive for human gp130 and mouse gp130. In some embodiments, the antigen-binding molecule is cross-reactive for human gp130 and rat gp130. In some embodiments, the antigen-binding molecule is cross-reactive for human gp130 and rhesus macaque gp130 and mouse gp130 and rat gp130.

[0417] 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.

[0418] 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 radiolabelled 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.

[0419] 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.

[0420] 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.

[0421] 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 10-4to 1 x 10-6M. In some embodiments, the antigen-binding molecule described herein binds to gp130 with sub-micromolar affinity, i.e. KD < 1 x 10-6M. 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 107to 1 x 109M. In some embodiments, the antigen-binding molecule described herein binds to gp130 with sub-nanomolar affinity, i.e. KD < 1 x 109M. 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 1 O-1CIto 1 x 10-12M. In some embodiments, the antigen-binding molecule described herein binds to gp130 with sub-picomolar affinity, i.e. KD < 1 x 10-12M.

[0422] 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 surface plasmon resonance analysis, e.g. performed as described in Example 2 herein). 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 surface plasmon resonance analysis, e.g. performed as described in Example 2 herein). 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.

[0423] In some embodiments, the antigen-binding molecule described herein binds to human gp130 isoform 1 with a KD of <200 nM, preferably one of <190 nM, <180 nM, <170 nM, <160 nM, <150 nM, <140 nM, <130 nM, <120 nM, <110 nM, <100 nM, <95 nM, <90 nM, <85 nM, <80 nM, <75 nM, <60 nM, <55 nM, <50 nM, <45 nM, <40 nM, <35 nM, <30 nM, <25 nM, <20 nM, <15 nM, <10 nM, <9 nM, <8 nM, <7 nM, <6 nM, <5 nM, <4 nM, <3 nM, <2 nM or <1 nM (e.g. as determined by analysis surface plasmon resonance analysis, e.g. performed as described in Example 2 herein). In some embodiments, the antigen-binding molecule described herein binds to human gp130 isoform 1 with a KD of <166 nM. In some embodiments, the antigen-binding molecule described herein binds to human gp130 isoform 1 with a KD of <2.91 nM. In some embodiments, the antigen-binding molecule described herein binds to human gp130 isoform 1 with an EC50 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.

[0424] 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 ( / .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.

[0425] 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.

[0426] 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:75. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:75.

[0427] In some embodiments, the antigen-binding molecule of the present disclosure binds to the cytokine binding module of gp130. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:85. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:85.

[0428] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:89. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:89. 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:89. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:89. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:89.

[0429] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:86. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:86. 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:86. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequence shown in SEQ ID NO:86. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:87. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:87. 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:87. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequence shown in SEQ ID NO:87. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:88. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:88. 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:88. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequence shown in SEQ ID NO:88.

[0430] In some embodiments, the antigen-binding molecule binds to the regions of gp130 shown in SEQ ID NOs:86, 87 and 88. In some embodiments, the antigen-binding molecule contacts the regions of gp130 shown in SEQ ID NOs:86, 87 and 88. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the regions shown in SEQ ID NOs:86, 87 and 88. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequences shown in SEQ ID NOs:86, 87 and 88.

[0431] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:93. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:93. 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:93. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:93. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence shown in SEQ ID NO:93.

[0432] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NQ:90. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NQ:90. 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:90. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequence shown in SEQ ID NQ:90. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:91 . In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:91 . 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:91. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequence shown in SEQ ID NO:91 . In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:92. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:92. 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:92. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequence shown in SEQ ID NO:92.

[0433] In some embodiments, the antigen-binding molecule binds to the regions of gp130 shown in SEQ ID NQs:90, 91 and 92. In some embodiments, the antigen-binding molecule contacts the regions of gp130 shown in SEQ ID NQs:90, 91 and 92. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the regions shown in SEQ ID NQs:90, 91 and 92. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequences shown in SEQ ID NQs:90, 91 and 92.

[0434] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:169. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:169. 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. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequence shown in SEQ ID NO:169. In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NQ:170. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NQ:170. 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:170. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequence shown in SEQ ID NQ:170.

[0435] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:171. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in 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:171. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequence shown in 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 the amino acid sequence shown in SEQ ID NO:172.

[0436] In some embodiments, the antigen-binding molecule binds to the regions of gp130 shown in SEQ ID NOs:169 and 170. In some embodiments, the antigen-binding molecule contacts the regions of gp130 shown in SEQ ID NOs:169 and 170. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the regions shown in SEQ ID NOs:169 and 170. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequences shown in SEQ ID NOs:169 and 170.

[0437] In some embodiments, the antigen-binding molecule binds to the regions of gp130 shown in SEQ ID NOs:171 and 172. In some embodiments, the antigen-binding molecule contacts the regions of gp130 shown in SEQ ID NOs:171 and 172. In some embodiments, the antigen-binding molecule binds to gp130 via contact with one or more amino acids of the regions shown in SEQ ID NOs:171 and 172. In some embodiments, the epitope of the antigen-binding molecule comprises the amino acid sequences shown in SEQ ID NOs:171 and 172.

[0438] In some embodiments, the antigen-binding molecule binds to the region of gp130 shown in SEQ ID NO:173. In some embodiments, the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:173. 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. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence shown in SEQ ID NO:173. 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.

[0439] In some embodiments, the antigen-binding molecule does not bind to the region of gp130 shown in SEQ ID NO:178. In some embodiments, the antigen-binding molecule does not contact the region of gp130 shown in SEQ ID NO:178. 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:178. In some embodiments, the epitope of the antigen-binding molecule does not consist of the amino acid sequence shown in SEQ ID NO:178. In some embodiments, the antigen-binding molecule does not bind to a polypeptide consisting of the amino acid sequence shown in SEQ ID NO:178.

[0440] 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.

[0441] 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 selected from B035-C03-A3, CSP-S-5H8, A3_3.2 VH I A3_3 VL, A3_3.2 VH I A3_4 VL, A3_3.2 VH I A3_5 VL, A3_4.2 VH I A3_3 VL, A3_4.2 VH I A3_4 VL, A3_4.2 VH I A3_5 VL, A3_6.2 VH I A3_3 VL, A3_6.2 VH I A3_4 VL, A3_6.2 VH I A3_5 VL, A3-derived VH CON I A3- derived VL CON, A3-Hum VH CON / A3-Hum VL CON, B035-C03-A3_D50X, A3_3.2 VH / A3_3_D50X VL, A3_3.2 VH I A3_4_D50X VL, A3_3.2 VH I A3_5_D50X VL, A3_4.2 VH I A3_3_D50X VL, A3_4.2 VH I A3_4_D50X VL, A3_4.2 VH I A3_5_D50X VL, A3_6.2 VH I A3_3_D50X VL, A3_6.2 VH I A3_4_D50X VL, A3_6.2 VH I A3_5_D50X VL, A3-derived VH CON I A3-derived VL_D50X CON, A3-Hum VH CON I A3- derivedJWOT VH CON / A3-derived_G51 A VL CON, A3-derived_l100T VH CON / A3-derived VL CON, A3-derived VH CON / A3-derived_G51A VL CON, A3-Hum_l100T VH CON / A3-Hum_G51A VL CON, A3-Hum_l100T VH CON I A3-Hum VL CON, A3-Hum VH CON I A3-Hum_G51 A VL CON, 5H8CVH4 VH I 5H8CVL3 VL, 5H8CVH4 VH I 5H8CVL4 VL, 5H8CVH4 VH I 5H8GVL3 VL, 5H8GVH4 VH I 5H8CVL3 VL, 5H8GVH4 VH I 5H8CVL4 VL, 5H8GVH4 VH I 5H8GVL3 VL, 5H8-derived VH CON I 5H8-derived VL CON, 5H8-Hum VH CON I 5H8-Hum VL CON, CSP-S-5H8_D98G VH I CSP-S-5H8 VL, 5H8CVH4_D98G VH I 5H8CVL3 VL, 5H8CVH4_D98G VH I 5H8CVL4 VL, 5H8CVH4_D98G VH I 5H8GVL3 VL, 5H8GVH4_D98G VH I 5H8CVL3 VL, 5H8GVH4_D98G VH I 5H8CVL4 VL, 5H8GVH4_D98G VH I 5H8GVL3 VL, 5H8-derived_D98G VH CON 1 5H8-derived VL CON, or 5H8-Hum_D98G VH CON 1 5H8- Hum VL CON.

[0442] 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.

[0443] 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 ( / .e. does not substantially bind) to cells lacking surface expression of gp130.

[0444] 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. 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.

[0445] 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:l L-11 Ra may comprise contacting cells expressing gp130:IL-11 Ra complexes with an antigenbinding molecule according to the present disclosure, e.g. in the presence of IL-11 .

[0446] 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 gp130-mediated signalling in response to stimulation with IL-6, IL-11 , OSM, LIF, CT-1 or CNTF) is analysed by evaluating phosphorylation of STAT3 or ERK1 / 2 by western blot.

[0447] 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 is analysed by evaluating the expression of aSMA and MMP2.

[0448] 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).

[0449] In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130 and / or signalling by a receptor comprising gp130 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).

[0450] 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 OSM-mediated signalling. In some embodiments, the antigen-binding molecule inhibits LIF-mediated signalling. In some embodiments, the antigen-binding molecule inhibits CNTF-mediated signalling. In some embodiments, the antigen-binding molecule inhibits CT-1 -mediated signalling. In some embodiments, the antigen-binding molecule inhibits CLC-mediated signalling. In some embodiments, the antigen-binding molecule inhibits IL-27-mediated signalling. In some embodiments, the antigen-binding molecule inhibits IL-35-mediated signalling.

[0451] In some embodiments, the antigen-binding molecule inhibits IL-6-mediated signalling and inhibits IL-11 - mediated signalling and inhibits OSM-mediated signalling and inhibits LIF-mediated signalling and inhibits CNTF-mediated signalling and inhibits CT-1 -mediated signalling.

[0452] In some embodiments, the antigen-binding molecule inhibits IL-6-mediated signalling and inhibits IL-11 - mediated signalling and inhibits OSM-mediated signalling and inhibits LIF-mediated signalling and inhibits CNTF-mediated signalling and inhibits CT-1 -mediated signalling and inhibits CLC-mediated signalling and inhibits IL-27-mediated signalling and inhibits IL-35-mediated signalling.

[0453] 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:OSMRp. In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130:LIFRp. In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130:LIFRp:CNTFRa. In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130:IL-27Ra. In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130:IL-12Rp2. In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130:IL-6Ra and inhibits signalling mediated by gp130:IL-11 Ra and inhibits signalling mediated by gp130:OSMRp and inhibits signalling mediated by gp130:LIFRp and inhibits signalling mediated by gp130:LIFRp:CNTFRa.

[0454] In some embodiments, the antigen-binding molecule inhibits signalling mediated by gp130:IL-6Ra and inhibits signalling mediated by gp130:IL-11 Ra and inhibits signalling mediated by gp130:OSMRp and inhibits signalling mediated by gp130:LIFRp and inhibits signalling mediated by gp130:LIFRp:CNTFRa and inhibits signalling mediated by gp130:IL-27Ra and inhibits signalling mediated by gp130:IL-12Rp2.

[0455] 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 OSM to cells expressing gp130:OSMRp. In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of OSM to cells expressing gp130:LIFRp. In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of LIF to cells expressing gp130:LIFRp. In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp. In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa. In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of CLC to cells expressing gp130:LIFRp:CNTFRa. In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of IL-27 to cells expressing gp130:IL- 27Ra. In some embodiments, the antigen-binding molecule inhibits signalling mediated by binding of IL- 35 to cells expressing gp130:IL-12Rp2.

[0456] In some embodiments, the antigen-binding 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:IL-11 Ra and inhibits signalling mediated by binding of OSM to cells expressing gp130:OSMRp and inhibits signalling mediated by binding of OSM to cells expressing gp130:LIFRp and inhibits signalling mediated by binding of LIF to cells expressing gp130:LIFRp and inhibits signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp and inhibits signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa.

[0457] In some embodiments, the antigen-binding 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:IL-11 Ra and inhibits signalling mediated by binding of OSM to cells expressing gp130:OSMRp and inhibits signalling mediated by binding of OSM to cells expressing gp130:LIFRp and inhibits signalling mediated by binding of LIF to cells expressing gp130:LIFRp and inhibits signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp and inhibits signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa and inhibits signalling mediated by binding of CLC to cells expressing gp130:LIFRp:CNTFRa and inhibits signalling mediated by binding of IL-27 to cells expressing gp130:IL- 27Ra and inhibits signalling mediated by binding of IL-35 to cells expressing gp130:IL-12Rp2. In some embodiments, the antigen-binding molecule inhibits 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). In some embodiments, the antigen-binding molecule inhibits 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). In some embodiments, the antigen-binding molecule inhibits 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 IC50 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 determined in an appropriate in vitro assay of the ability of an antigen-binding molecule to inhibit such signalling.

[0458] In some embodiments, the antigen-binding molecule inhibits IL-11 -mediated signalling / signalling mediated by gp130:IL-11 Ra / signalling mediated by binding of IL-11 to cells expressing gp130:IL-11 Ra 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-11 -mediated signalling / signalling mediated by gp130:IL-11 Ra / signalling mediated by binding of IL-11 to cells expressing gp130:IL-11 Ra). In some embodiments, the antigen-binding molecule inhibits 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-11 -mediated signalling / signalling mediated by gp130:IL- 11 Ra / signalling mediated by binding of IL-11 to cells expressing gp130:IL-1 1 Ra 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-11 -mediated signalling / signalling mediated by gp130:IL-11 Ra / signalling mediated by binding of IL-11 to cells expressing gp130:IL-11 Ra). In some embodiments, the antigen-binding molecule inhibits IL-11 -mediated signalling / signalling mediated by gp130:IL-11 Ra / signalling mediated by binding of IL-11 to cells expressing gp130:IL-11 Ra with an IC50 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 determined in an appropriate in vitro assay of the ability of an antigenbinding molecule to inhibit such signalling.

[0459] In some embodiments, the antigen-binding molecule inhibits OSM-mediated signalling / sig nailing mediated by gp130:OSMRp / signalling mediated by gp130:LIFRp / signalling mediated by binding of OSM to cells expressing gp130:OSMRp / signalling mediated by binding of OSM to cells expressing gp130:LIFRp 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 OSM-mediated signalling / signalling mediated by gp130:OSMRp / signalling mediated by gp130:LI FRp / signalling mediated by binding of OSM to cells expressing gp130:OSMRp / signalling mediated by binding of OSM to cells expressing gp130:LIFRp). In some embodiments, the antigenbinding molecule inhibits 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 OSM-mediated signalling / signalling mediated by gp130:OSMRp / signalling mediated by gp130:LIFRp / signalling mediated by binding of OSM to cells expressing gp130:OSMRp / signalling mediated by binding of OSM to cells expressing gp130:LIFRp 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 OSM-mediated signalling / signalling mediated by gp130:OSMRp / signalling mediated by gp130:LI FRp / signalling mediated by binding of OSM to cells expressing gp130:OSMRp / signalling mediated by binding of OSM to cells expressing gp130:LIFRp). In some embodiments, the antigenbinding molecule inhibits OSM-mediated signalling / signalling mediated by gp130:OSMRp / signalling mediated by gp130:LIFRp / signalling mediated by binding of OSM to cells expressing gp130:OSMRp / signalling mediated by binding of OSM to cells expressing gp130:LIFRp with an IC50 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 determined in an appropriate in vitro assay of the ability of an antigenbinding molecule to inhibit such signalling.

[0460] In some embodiments, the antigen-binding molecule inhibits LIF-mediated signalling / signalling mediated by gp130:LI FR / signalling mediated by binding of LIF to cells expressing gp130:LIFRp 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 LIF-mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of LIF to cells expressing gp130:LIFRp). In some embodiments, the antigen-binding molecule inhibits 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 LIF-mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of LIF to cells expressing gp130:LIFRp 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 LIF-mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of LIF to cells expressing gp130:LIFRp). In some embodiments, the antigen-binding molecule inhibits LIF- mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of LIF to cells expressing gp130:LIFRp with an IC50 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 determined in an appropriate in vitro assay of the ability of an antigen-binding molecule to inhibit such signalling.

[0461] In some embodiments, the antigen-binding molecule inhibits CT-1 -mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp 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 CT-1-mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp). In some embodiments, the antigen-binding molecule inhibits 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 CT-1-mediated signalling / signalling mediated by gp130:LI FRp / signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp 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 CT-1-mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp). In some embodiments, the antigen-binding molecule inhibits CT-1 -mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp with an IC50 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 determined in an appropriate in vitro assay of the ability of an antigen-binding molecule to inhibit such signalling.

[0462] In some embodiments, the antigen-binding molecule inhibits CNTF-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa 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 CNTF-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa). In some embodiments, the antigen-binding molecule inhibits 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 CNTF-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa 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 CNTF-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa). In some embodiments, the antigen-binding molecule inhibits CNTF-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa with an IC50 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 determined in an appropriate in vitro assay of the ability of an antigen-binding molecule to inhibit such signalling.

[0463] In some embodiments, the antigen-binding molecule inhibits CLC-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CLC to cells expressing gp130:LIFRp:CNTFRa 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 CLC-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CLC to cells expressing gp130:LIFRp:CNTFRa). In some embodiments, the antigen-binding molecule inhibits 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 CLC-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CLC to cells expressing gp130:LIFRp:CNTFRa 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 CLC-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CLC to cells expressing gp130:LIFRp:CNTFRa). In some embodiments, the antigen-binding molecule inhibits CLC- mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CLC to cells expressing gp130:LIFRp:CNTFRa with an IC50 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 determined in an appropriate in vitro assay of the ability of an antigen-binding molecule to inhibit such signalling.

[0464] In some embodiments, the antigen-binding molecule inhibits IL-27-mediated signalling / signalling mediated by gp130:IL-27Ra / signalling mediated by binding of IL-27 to cells expressing gp130:IL-27Ra 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-27-mediated signalling / signalling mediated by gp130:IL-27Ra / signalling mediated by binding of IL-27 to cells expressing gp130:IL-27Ra). In some embodiments, the antigen-binding molecule inhibits 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-27-mediated signalling / signalling mediated by gp130:IL- 27Ra / signalling mediated by binding of IL-27 to cells expressing gp130:IL-27Ra 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-27-mediated signalling / signalling mediated by gp130:IL-27Ra / signalling mediated by binding of IL-27 to cells expressing gp130:IL-27Ra). In some embodiments, the antigen-binding molecule inhibits IL-27-mediated signalling / signalling mediated by gp130:IL-27Ra / signalling mediated by binding of IL-27 to cells expressing gp130:IL-27Ra with an IC50 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 determined in an appropriate in vitro assay of the ability of an antigenbinding molecule to inhibit such signalling.

[0465] In some embodiments, the antigen-binding molecule inhibits IL-35-mediated signalling / signalling mediated by gp130:IL-12Rp2 / signalling mediated by binding of IL-35 to cells expressing gp130:IL-12Rp2 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-35-mediated signalling / signalling mediated by gp130:l L-12Rp2 / signalling mediated by binding of IL-35 to cells expressing gp130:IL-12Rp2). In some embodiments, the antigen-binding molecule inhibits 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-35-mediated signalling / signalling mediated by gp130:IL- 12Rp2 / signalling mediated by binding of IL-35 to cells expressing gp130:IL-12Rp2 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-35-mediated signalling / signalling mediated by gp130:IL-12Rp2 / signalling mediated by binding of IL-35 to cells expressing gp130:IL- 12Rp2). In some embodiments, the antigen-binding molecule inhibits IL-35-mediated signalling / signalling mediated by gp130:IL-12Rp2 / signalling mediated by binding of IL-35 to cells expressing gp130:IL-12Rp2 with an IC50 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 determined in an appropriate in vitro assay of the ability of an antigen-binding molecule to inhibit such signalling.

[0466] In some embodiments, the antigen-binding molecule: (i) inhibits 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); (ii) inhibits 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-11 -mediated signalling / signalling mediated by gp130:IL-11 Ra / signalling mediated by binding of IL-11 to cells expressing gp130:IL-11Ra 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-11 -mediated signalling / signalling mediated by gp130:IL-

[0467] 11 Ra / signalling mediated by binding of IL-11 to cells expressing gp130:l L-11 Ra); (iii) inhibits 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 OSM-mediated signalling / signalling mediated by gp130:OSMRp / signalling mediated by gp130:LIFRp / signalling mediated by binding of OSM to cells expressing gp130:OSMRp / signalling mediated by binding of OSM to cells expressing gp130:LIFRp 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 OSM-mediated signalling / signalling mediated by gp130:OSMRp / signalling mediated by gp130:LIFRp / signalling mediated by binding of OSM to cells expressing gp130:OSMRp / signalling mediated by binding of OSM to cells expressing gp130:LIFRp); (iv) inhibits 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 LIF-mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of LIF to cells expressing gp130:LIFRp 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 LIF-mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of LIF to cells expressing gp130:LIFRp); (v) inhibits 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 CT-1- mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp 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 CT-1 -mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp); and (vi) inhibits 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 CNTF- mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa 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 CNTF-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa).

[0468] In some embodiments, the antigen-binding molecule: (i) inhibits 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); (ii) inhibits 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-11 -mediated signalling / signalling mediated by gp130:IL-1 1 Ra / signalling mediated by binding of IL-11 to cells expressing gp130:IL-1 1 Ra 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-1 1 -mediated signalling / signalling mediated by gp130:IL-

[0469] 11 Ra / signalling mediated by binding of IL-11 to cells expressing gp130:l L-1 1 Ra); (iii) inhibits 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 OSM-mediated signalling / signalling mediated by gp130:OSMRp / signalling mediated by gp130:LIFRp / signalling mediated by binding of OSM to cells expressing gp130:OSMRp / signalling mediated by binding of OSM to cells expressing gp130:LIFRp 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 OSM-mediated signalling / signalling mediated by gp130:OSMRp / signalling mediated by gp130:LIFRp / signalling mediated by binding of OSM to cells expressing gp130:OSMRp / signalling mediated by binding of OSM to cells expressing gp130:LIFRp); (iv) inhibits 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 LIF-mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of LIF to cells expressing gp130:LIFRp 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 LIF-mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of LIF to cells expressing gp130:LIFRp); (v) inhibits 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 CT-1- mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp 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 CT-1 -mediated signalling / signalling mediated by gp130:LIFRp / signalling mediated by binding of CT-1 to cells expressing gp130:LIFRp); (vi) inhibits 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 CNTF- mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa 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 CNTF-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CNTF to cells expressing gp130:LIFRp:CNTFRa); (vii) inhibits 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 CLC- mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CLC to cells expressing gp130:LIFRp:CNTFRa 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 CLC-mediated signalling / signalling mediated by gp130:LIFRp:CNTFRa / signalling mediated by binding of CLC to cells expressing gp130:LIFRp:CNTFRa); (viii) inhibits 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-27-mediated signalling / signalling mediated by gp130:IL-27Ra / signalling mediated by binding of IL-27 to cells expressing gp130:IL-27Ra observed in the absence of the antigenbinding molecule (or in the presence of an appropriate control antigen-binding molecule, e.g. an antigenbinding molecule known not to influence IL-27-mediated signalling / signalling mediated by gp130:IL- 27Ra / signalling mediated by binding of IL-27 to cells expressing gp130:IL-27Ra); and (ix) inhibits 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-35-mediated signalling / signalling mediated by gp130:IL-12Rp2 / signalling mediated by binding of IL-35 to cells expressing gp130:IL-12Rp2 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-35-mediated signalling / signalling mediated by gp130:IL-12Rp2 / signalling mediated by binding of IL-35 to cells expressing gp130:IL- 12R 2).

[0470] In some embodiments, an antigen-binding molecule according to the present disclosure reduces inflammation. In some embodiments, an antigen-binding molecule according to the present disclosure reduces fibrosis. In some embodiments, an antigen-binding molecule according to the present disclosure reduces inflammation and fibrosis.

[0471] The ability of, and extent to which, a given antigen-binding molecule to reduce inflammation and / or fibrosis can be evaluated in an appropriate in vitro or in vivo model of inflammation / fibrosis. For example, in vitro methods may comprise contacting cells (e.g. gp130-expressing cells) with a proinflammatory, profibrotic or profibroinflammatory stimulus (e.g. IL-6, IL-11 , TGFpl , etc.) in the presence of the antigenbinding molecule, and subsequently evaluating the cells to determine the level of one or more correlates of inflammation / fibrosis. By way of illustration, in the experimental examples of the present disclosure, gp130-specific antigen-binding molecules are evaluated for their ability to reduce fibrosis in in vitro assays in which cells are stimulated with TGFpl or IL-11 , and in which the fibrotic response is subsequently analysed by evaluating the expression of MMP2.

[0472] Analysis in vivo of the ability of, and extent to which, a given antigen-binding molecule reduces inflammation and / or fibrosis may employ a non-human animal model of a disease characterised by inflammation and / or fibrosis. Such models are also useful to evaluate the ability of an antigen-binding molecule to reduce the pathology of a disease / condition characterised by inflammation and / or fibrosis. Such analysis may comprise administering the antigen-binding molecule to a subject having a disease characterised by inflammation and / or fibrosis, and subsequently evaluating one or more correlates of inflammation / fibrosis in the subject. By way of illustration, in the experimental examples of the present disclosure, gp130-specific antigen-binding molecules are evaluated for their ability to reduce inflammation and fibrosis in vivo in a folic acid-induced mouse model of acute kidney injury, by evaluating e.g. serum levels of IL-6, collagen content of the kidney, and renal expression of proinflammatory genes (e.g. Ccl2, Ccl5, 116, Tnfa and 111 / 3), and profibrotic genes (e.g. Col1a1, Col1a2, Col3a1, Fn, Acta2 and 1111).

[0473] In some embodiments, administration of an antigen-binding molecule according to the present disclosure may inhibit the development / progression of a disease / condition characterised by inflammation and / or fibrosis. In some embodiments, administration of the antigen-binding molecule may reduce the severity of the symptoms of a disease / condition characterised by inflammation and / or fibrosis, e.g. as determined in an appropriate model.

[0474] In some embodiments, the antigen-binding molecule of the present disclosure is capable of reducing the level of one of more correlates of inflammation and / or fibrosis (e.g. in an in vitro model of inflammation / fibrosis, or in an in vivo model of a disease / condition characterised by inflammation / fibrosis) 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 observed in the absence of treatment with the antigen-binding molecule (or following treatment with an appropriate control antigen-binding molecule known not to influence the level of the relevant correlate(s)), in a given assay.

[0475] Antigen-binding molecules according to the present disclosure may comprise one or more moieties for potentiating cell killing of, or reducing the number / proportion of, cells expressing gp130. For example, an antigen-binding molecule according to the present disclosure may e.g. comprise an Fc region and / or a drug moiety.

[0476] In some embodiments, an antigen-binding molecule according to the present disclosure may potentiate ( / .e. upregulate, enhance) cell killing of cells comprising / expressing gp130. In some embodiments, the antigen-binding molecule does not potentiate ( / .e. does not substantially potentiate) cell killing of cells lacking surface expression of gp130. Cell killing can be investigated, for example, using any of the methods reviewed in Zaritskaya et al., Expert Rev Vaccines (2011), 9(6):601-616, hereby incorporated by reference in its entirety. Examples of in vitro assays of cytotoxicity / cell killing assays include release assays such as the51Cr release assay, the lactate dehydrogenase (LDH) release assay, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) release assay, and the calcein-acetoxymethyl (calcein-AM) release assay. These assays measure cell killing based on the detection of factors released from lysed cells. Cell killing of a given test cell type by a given effector immune cell type can be analysed e.g. by co-culturing the test cells with the effector immune cells, and measuring the number / proportion of viable / dead (e.g. lysed) test cells after a suitable period of time. Other suitable assays include the xCELLigence real-time cytolytic in vitro potency assay described in Cerignoli et al., PLoS One. (2018) 13(3): e0193498 (hereby incorporated by reference in its entirety).

[0477] In some embodiments an antigen-binding molecule according to the present disclosure is capable of reducing the number / proportion of cells expressing gp130. In some embodiments an antigen-binding molecule according to the present disclosure is capable of reducing the number / proportion of cells expressing gp130. In some embodiments, an antigen-binding molecule according to the present disclosure is capable of depleting / enhancing depletion of such cells.

[0478] Fc regions provide for interaction with Fc receptors and other molecules of the immune system to bring about functional effects. IgG 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.

[0479] In some embodiments, an antigen-binding molecule according to the present disclosure comprises an Fc region capable of potentiating / directing one or more of ADCC, ADCP, CDC against, and / or potentiating formation of a MAC on or cell degranulation of, a cell expressing gp130 (e.g. a cell expressing gp130 at the cell surface).

[0480] In some embodiments, an antigen-binding molecule according to the present disclosure is capable of potentiating / directing ADCC against a cell expressing gp130.

[0481] The ability of, and extent to which, a given antigen-binding molecule is able to induce ADCC of a given target cell type can be analysed e.g. according to the method described in Yamashita et al., Scientific Reports (2016) 6:19772 (hereby incorporated by reference in its entirety), or by51Cr release assay as described e.g. in Jedema et al., Blood (2004) 103: 2677-82 (hereby incorporated by reference in its entirety). The ability of, and extent to which, a given antigen-binding molecule is able to induce ADCP can be analysed e.g. according to the method described in Kamen et al., J Immunol (2017) 198 (1 Supplement) 157.17 (hereby incorporated by reference in its entirety). The ability of, and extent to which, a given antigen-binding molecule is able to induce CDC can be analysed e.g. using a C1q binding assay, e.g. as described in Schlothauer etal., Protein Engineering, Design and Selection (2016), 29(10):457- 466 (hereby incorporated by reference in its entirety).

[0482] In some embodiments, an antigen-binding molecule according to the present disclosure comprises a drug moiety. The antigen-binding molecule may be conjugated to the drug moiety. Antibody-drug conjugates are reviewed e.g. in Parslow et al., Biomedicines. 2016 Sep; 4(3):14 (hereby incorporated by reference in its entirety). In some embodiments, the drug moiety is or comprises a cytotoxic agent, such that the antigen-binding molecule displays cytotoxicity to a cell expressing gp130 (e.g. a cell expressing gp130 at the cell surface).

[0483] Linkers and additional sequences

[0484] The antigen-binding molecules and polypeptides of the present disclosure may additionally comprise further amino acids or sequences of amino acids.

[0485] The antigen-binding molecules and polypeptides of the present disclosure may comprise one or more linker sequences between sequences of amino acids. For example, a linker sequence may be provided between a VH sequence and a VL sequence, providing linkage between the VH and VL (e.g. as in an scFv molecule).

[0486] Linker sequences are known to the skilled person, and are described, for example in Chen et al., Adv Drug Deliv Rev (2013) 65(10): 1357-1369, which is hereby incorporated by reference in its entirety. In some embodiments, a linker sequence may be a flexible linker sequence. Flexible linker sequences allow for relative movement of the amino acid sequences which are linked by the linker sequence. Flexible linkers are known to the skilled person, and several are identified in Chen et al., Adv Drug Deliv Rev (2013) 65(10): 1357-1369. Flexible linker sequences often comprise high proportions of glycine and / or serine residues.

[0487] In some embodiments, the linker sequence comprises at least one glycine residue and / or at least one serine residue. In some embodiments, the linker sequence comprises or consists of glycine and serine residues. In some embodiments, the linker sequence has the structure: (GxS)n or (GxS)nGm; wherein G = glycine, S = serine, x = 3 or 4, n = 2, 3, 4, 5 or 6, and m = 0, 1 , 2 or 3. In some embodiments, the linker sequence comprises one or more (e.g. 1 , 2, 3, 4, 5 or 6) copies (e.g. in tandem) of the sequence motif G4S. In some embodiments, the linker sequence comprises or consists of (G4S)4 or (G4S)e. In some embodiments, the linker sequence has a length of 1-2, 1-3, 1-4, 1-5, 1-10, 1-15, 1-20, 1-25, or 1-30 amino acids. The antigen-binding molecules and polypeptides of the present disclosure may comprise amino acid sequence(s) to facilitate expression, folding, trafficking, processing, purification or detection of the antigen-binding molecule / polypeptide. For example, antigen-binding molecules and polypeptides of the present disclosure may additionally comprise a sequence of amino acids forming a detectable moiety, e.g. as described hereinbelow.

[0488] The antigen-binding molecules and polypeptides of the present disclosure may additionally comprise a signal peptide (also known as a leader sequence or signal sequence). Signal peptides normally consist of a sequence of 5-30 hydrophobic amino acids, which form a single alpha helix. Secreted proteins and proteins expressed at the cell surface often comprise signal peptides. Signal peptides are known for many proteins, and are recorded in databases such as GenBank, UniProt and Ensembl, and / or can be identified / predicted e.g. using amino acid sequence analysis tools such as SignalP (Petersen et al., 201 1 Nature Methods 8: 785-786) or Signal-BLAST (Frank and Sippl, 2008 Bioinformatics 24: 2172-2176).

[0489] The signal peptide may be present at the N-terminus of the antigen-binding molecule / polypeptide, and may be present in the newly synthesised antigen-binding molecule / polypeptide. The signal peptide provides for efficient trafficking of the antigen-binding molecule / polypeptide. Signal peptides are often removed by cleavage, and thus are not comprised in the mature antigen-binding molecule / polypeptide.

[0490] Signal peptides are known for many proteins, and are recorded in databases such as GenBank, UniProt, Swiss-Prot, TrEMBL, Protein Information Resource, Protein Data Bank, Ensembl, and InterPro, and / or can be identified / predicted e.g. using amino acid sequence analysis tools such as SignalP (Petersen et al., 2011 Nature Methods 8: 785-786) or Signal-BLAST (Frank and Sippl, 2008 Bioinformatics 24: 2172- 2176).

[0491] Labels and conjugates

[0492] In some embodiments, the antigen-binding molecule or polypeptide of the present disclosure comprises a detectable moiety.

[0493] In some embodiments, a detectable moiety is a fluorescent label, phosphorescent label, luminescent label, immuno-detectable label (e.g. an epitope tag), radiolabel, chemical, nucleic acid or enzymatic label. The antigen-binding molecule or polypeptide may be covalently or non-covalently labelled with the detectable moiety.

[0494] Fluorescent labels include e.g. fluorescein, rhodamine, allophycocyanin, eosine and NDB, green fluorescent protein (GFP), chelates of rare earths such as europium (Eu), terbium (Tb) and samarium (Sm), tetramethyl rhodamine, Texas Red, 4-methyl umbelliferone, 7-amino-4-methyl coumarin, Cy3, and Cy5. Radiolabels include radioisotopes such as Hydrogen3, Sulfur35, Carbon14, Phosphorus32, Iodine123, Iodine125, Iodine126, Iodine131, Iodine133, Bromine77, Technetium99m, Indium111, lndium113m, Gallium67, Gallium68, Ruthenium95, Ruthenium97, Ruthenium103, Ruthenium105, Mercury207, Mercury203, Rhenium99m, Rhenium101, Rhenium105, Scandium47, Tellurium121m, Tellurium122m, Tellurium125m, Thulium165, Thuliuml167, Thulium168, Copper67, Fluorine18, Yttrium90, Palladium100, Bismuth217and Antimony211. Luminescent labels include as radioluminescent, chemiluminescent (e.g. acridinium ester, luminol, isoluminol) and bioluminescent labels. Immuno-detectable labels include haptens, peptides / polypeptides, antibodies, receptors and ligands such as biotin, avidin, streptavidin or digoxigenin. Nucleic acid labels include aptamers.

[0495] In some embodiments, the antigen-binding molecule / polypeptide comprises an epitope tag, e.g. a His, (e.g. 6XHis), FLAG, c-Myc, StrepTag, haemagglutinin, E, calmodulin-binding protein (CBP), glutathione-s- transferase (GST), maltose-binding protein (MBP), thioredoxin, S-peptide, T7 peptide, SH2 domain, avidin, streptavidin, and haptens (e.g. biotin, digoxigenin, dinitrophenol), optionally at the N- or C- terminus of the antigen-binding molecule / polypeptide.

[0496] In some embodiments, the antigen-binding molecule / polypeptide comprises a moiety having a detectable activity, e.g. an enzymatic moiety. Enzymatic moieties include e.g. luciferases, glucose oxidases, galactosidases (e.g. beta-galactosidase), glucorinidases, phosphatases (e.g. alkaline phosphatase), peroxidases (e.g. horseradish peroxidase) and cholinesterases.

[0497] In some embodiments, the antigen-binding molecule or polypeptide of the present disclosure comprises a chemical moiety. In some embodiments, the antigen-binding molecule / polypeptide of the present disclosure is conjugated to a chemical moiety.

[0498] The chemical moiety may be a moiety for providing a therapeutic effect, i.e. a drug moiety. A drug moiety may be a small molecule (e.g. a low molecular weight (< 1000 daltons, typically between -300-700 daltons) organic compound). Drug moieties are described e.g. in Parslow et al., Biomedicines. 2016 Sep; 4(3):14 (hereby incorporated by reference in its entirety). In some embodiments, a drug moiety may be or comprise a cytotoxic agent. In some embodiments, a drug moiety may be or comprise a chemotherapeutic agent. Drug moieties include e.g. calicheamicin, DM1 , DM4, monomethylauristatin E (MMAE), monomethylauristatin F (MMAF), SN-38, doxorubicin, duocarmycin, D6.5 and PBD.

[0499] Nucleic acids and vectors

[0500] The present disclosure provides a nucleic acid, or a plurality of nucleic acids, encoding an antigen-binding molecule or polypeptide according to the present disclosure. In some embodiments, the nucleic acid(s) comprise or consist of DNA and / or RNA.

[0501] An antigen-binding molecule or polypeptide according to the present disclosure may be produced within a cell by translation of RNA encoding the polypeptide(s). An antigen-binding molecule or polypeptide according to the present disclosure may be produced within a cell by transcription from nucleic acid encoding the polypeptide(s), and subsequent translation of the transcribed RNA. In some embodiments, the nucleic acid(s) may be, or may be comprised / contained in, a vector, or a plurality of vectors. A ‘vector’ as used herein is a nucleic acid molecule used as a vehicle to transfer exogenous nucleic acid into a cell.

[0502] Accordingly, the present disclosure also provides a vector, or plurality of vectors, comprising the nucleic acid or plurality of nucleic acids according to the present disclosure. The vector may facilitate delivery of the nucleic acid(s) encoding a polypeptide according to the present disclosure to a cell. The vector may be an expression vector comprising elements required for expressing a polypeptide according to the present disclosure. The vector may comprise elements facilitating integration of the nucleic acid(s) into the genomic DNA of cell into which the vector is introduced.

[0503] Nucleic acids and vectors according to the present disclosure may be provided in purified or isolated form, i.e. from other nucleic acid, or naturally-occurring biological material.

[0504] A vector may be a vector for expression of the nucleic acid in the cell (i.e. an expression vector). Such vectors may include a promoter sequence operably linked to a nucleotide sequence encoding an antigenbinding molecule or polypeptide according to the present disclosure. A vector may also include a termination codon (i.e. 3’ in the nucleotide sequence of the vector to the nucleotide sequence encoding the polypeptide(s)) and expression enhancers. Any suitable vectors, promoters, enhancers and termination codons known in the art may be used to express a peptide or polypeptide from a vector according to the present disclosure.

[0505] The term ‘operably linked’ may include the situation where nucleic acid encoding a polypeptide according to the present disclosure and regulatory nucleic acid sequence(s) (e.g. a promoter and / or enhancers) are covalently linked in such a way as to place the expression of the nucleic acid encoding a polypeptide under the influence or control of the regulatory nucleic acid sequence(s) (thereby forming an expression cassette). Thus, a regulatory sequence is operably linked to the selected nucleic acid sequence if the regulatory sequence is capable of effecting transcription of the nucleic acid sequence. The resulting transcript(s) may then be translated into the desired polypeptide(s).

[0506] Vectors contemplated in connection with the present disclosure include DNA vectors, RNA vectors, plasmids (e.g. conjugative plasmids (e.g. F plasmids), non-conjugative plasmids, R plasmids, col plasmids, episomes), viral vectors (e.g. retroviral vectors, e.g. gammaretroviral vectors (e.g. murine Leukemia virus (MLV)-derived vectors, e.g. SFG vector), lentiviral vectors, adenovirus vectors, adeno- associated virus vectors, vaccinia virus vectors and herpesvirus vectors), transposon-based vectors, and artificial chromosomes (e.g. yeast artificial chromosomes), e.g. as described in Maus et al., Annu Rev Immunol (2014) 32:189-225 and Morgan and Boyerinas, Biomedicines (2016) 4:9, which are both hereby incorporated by reference in their entirety. In some embodiments, a vector according to the present disclosure is a lentiviral vector. In some embodiments, the vector may be a eukaryotic vector, i.e. a vector comprising the elements necessary for expression of protein from the vector in a eukaryotic cell. In some embodiments, the vector may be a mammalian vector, e.g. comprising a cytomegalovirus (CMV) or SV40 promoter to drive protein expression.

[0507] Constituent polypeptides of an antigen-binding molecule according to the present disclosure may be encoded by different nucleic acids of the plurality of nucleic acids, or by different vectors of the plurality of vectors.

[0508] Producing the antigen-binding molecules and polypeptides

[0509] Antigen-binding molecules and polypeptides according to the present disclosure may be prepared according to methods for the production of polypeptides known to the skilled person.

[0510] Antigen-binding molecules and polypeptides may be prepared by chemical synthesis, e.g. liquid or solid phase synthesis. For example, peptides / polypeptides can be synthesised using the methods described in, for example, Chandrudu et al., Molecules (2013), 18: 4373-4388, which is hereby incorporated by reference in its entirety.

[0511] Alternatively, antigen-binding molecules and polypeptides may be produced by recombinant expression. Molecular biology techniques suitable for recombinant production of polypeptides are well known in the art, such as those set out in Green and Sambrook, Molecular Cloning: A Laboratory Manual (4th Edition), Cold Spring Harbor Press, 2012, and in Nat Methods. (2008); 5(2): 135-146 both of which are hereby incorporated by reference in their entirety. Methods for the recombinant production of antigen-binding molecules are also described in Frenzel et al., Front Immunol. (2013); 4: 217 and Kunert and Reinhart, Appl Microbiol Biotechnol. (2016) 100: 3451-3461 , both of which are hereby incorporated by reference in their entirety.

[0512] In some cases, the antigen-binding molecules of the present disclosure are comprised of more than one polypeptide chain. In such cases, production of the antigen-binding molecule may comprise transcription and translation of more than one polypeptide, and subsequent association of the polypeptide chains to form the antigen-binding molecule.

[0513] For recombinant production according to the present disclosure, any cell suitable for the expression of polypeptides may be used. The cell may be a prokaryote or eukaryote. In some embodiments, the cell is a prokaryotic cell, such as a cell of archaea or bacteria. In some embodiments, the bacteria may be Gram-negative bacteria such as bacteria of the family Enterobacteriaceae, for example Escherichia coli. In some embodiments, the cell is a eukaryotic cell such as a yeast cell, a plant cell, insect cell or a mammalian cell, e.g. a cell described hereinabove.

[0514] In some cases, the cell is not a prokaryotic cell because some prokaryotic cells do not allow for the same folding or post-translational modifications as eukaryotic cells. In addition, very high expression levels are possible in eukaryotes and proteins can be easier to purify from eukaryotes using appropriate tags. Specific plasmids may also be utilised which enhance secretion of the protein into the media.

[0515] In some embodiments polypeptides may be prepared by cell-free-protein synthesis (CFPS), e.g. according to a system described in Zemella et al. Chembiochem (2015) 16(17): 2420-2431 , which is hereby incorporated by reference in its entirety.

[0516] Production may involve culture or fermentation of a eukaryotic cell modified to express the polypeptide(s) of interest. The culture or fermentation may be performed in a bioreactor provided with an appropriate supply of nutrients, air / oxygen and / or growth factors. Secreted proteins can be collected by partitioning culture media / fermentation broth from the cells, extracting the protein content, and separating individual proteins to isolate secreted polypeptide(s). Culture, fermentation and separation techniques are well known to those of skill in the art, and are described, for example, in Green and Sambrook, Molecular Cloning: A Laboratory Manual (4th Edition; incorporated by reference herein above).

[0517] Bioreactors include one or more vessels in which cells may be cultured. Culture in the bioreactor may occur continuously, with a continuous flow of reactants into, and a continuous flow of cultured cells from, the reactor. Alternatively, the culture may occur in batches. The bioreactor monitors and controls environmental conditions such as pH, oxygen, flow rates into and out of, and agitation within the vessel such that optimum conditions are provided for the cells being cultured.

[0518] Following culturing the cells that express the polypeptide(s), the polypeptide(s) of interest may be isolated. Any suitable method for separating proteins from cells known in the art may be used. In order to isolate the polypeptide, it may be necessary to separate the cells from nutrient medium. If the polypeptide(s) are secreted from the cells, the cells may be separated by centrifugation from the culture media that contains the secreted polypeptide(s) of interest. If the polypeptide(s) of interest collect within the cell, protein isolation may comprise centrifugation to separate cells from cell culture medium, treatment of the cell pellet with a lysis buffer, and cell disruption e.g. by Bonification, rapid freeze-thaw or osmotic lysis.

[0519] It may then be desirable to isolate the polypeptide(s) of interest from the supernatant or culture medium, which may contain other protein and non-protein components. A common approach to separating protein components from a supernatant or culture medium is by precipitation. Proteins of different solubilities are precipitated at different concentrations of precipitating agent such as ammonium sulfate. For example, at low concentrations of precipitating agent, water soluble proteins are extracted. Thus, by adding different increasing concentrations of precipitating agent, proteins of different solubilities may be distinguished. Dialysis may be subsequently used to remove ammonium sulfate from the separated proteins.

[0520] Other methods for distinguishing different proteins are known in the art, for example ion exchange chromatography and size chromatography. These may be used as an alternative to precipitation or may be performed subsequently to precipitation. Once the polypeptide(s) of interest have been isolated from culture it may be desired or necessary to concentrate the polypeptide(s). A number of methods for concentrating proteins are known in the art, such as ultrafiltration or lyophilisation.

[0521] Cells comprisinq / expressinq the antigen-binding molecules and polypeptides

[0522] The present disclosure also provides a cell comprising or expressing an antigen-binding molecule or polypeptide according to the present disclosure. Also provided is a cell comprising or expressing a nucleic acid, a plurality of nucleic acids, a vector or a plurality of vectors according to the present disclosure.

[0523] It will be appreciated that where cells are referred to herein in the singular ( / .e. ‘a / the cell’), pluralities / populations of such cells are also contemplated.

[0524] The cell may be a eukaryotic cell, e.g. a mammalian cell. The mammal may be a primate (rhesus, cynomolgous, non-human primate or human) or a non-human mammal (e.g. rabbit, guinea pig, rat, mouse or other rodent (including any animal in the order Rodentia), cat, dog, pig, sheep, goat, cattle (including cows, e.g. dairy cows, or any animal in the order Bos), horse (including any animal in the order Equidae), donkey, and non-human primate).

[0525] In some embodiments, the cell is, or is derived from, a cell type commonly used for the expression of polypeptides for use in therapy in humans. Exemplary cells are described e.g. in Kunert and Reinhart, Appl Microbiol Biotechnol. (2016) 100:3451-3461 (hereby incorporated by reference in its entirety), and include e.g. CHO, HEK 293, PER.C6, NSO and BHK cells. In preferred embodiments, the cell is, or is derived from, a CHO cell.

[0526] The present disclosure also provides a method for producing a cell comprising a nucleic acid(s) or vector(s) according to the present disclosure, comprising introducing a nucleic acid, a plurality of nucleic acids, a vector or a plurality of vectors according to the present disclosure into a cell. In some embodiments, introducing an isolated nucleic acid(s) or vector(s) according to the present disclosure into a cell comprises transformation, transfection, electroporation or transduction (e.g. retroviral transduction).

[0527] The present disclosure also provides a method for producing a cell expressing / comprising an antigenbinding molecule or polypeptide according to the present disclosure, comprising introducing a nucleic acid, a plurality of nucleic acids, a vector or a plurality of vectors according to the present disclosure in a cell. In some embodiments, the methods additionally comprise culturing the cell under conditions suitable for expression of the nucleic acid(s) or vector(s) by the cell. In some embodiments, the methods are performed in vitro.

[0528] The present disclosure also provides cells obtained or obtainable by the methods according to the present disclosure. Compositions

[0529] The present disclosure also provides compositions comprising the antigen-binding molecules, polypeptides, nucleic acids, expression vectors and cells described herein.

[0530] The antigen-binding molecules, polypeptides, nucleic acids, expression vectors and cells described herein may be formulated as pharmaceutical compositions or medicaments for clinical use and may comprise a pharmaceutically acceptable carrier, diluent, excipient or adjuvant. Thus, the present disclosure also provides a pharmaceutical composition / medicament comprising an antigen-binding molecule, polypeptide, nucleic acid / plurality, expression vector / plurality or cell described herein.

[0531] The compositions of the present disclosure may comprise one or more pharmaceutically-acceptable carriers (e.g. liposomes, micelles, microspheres, nanoparticles), diluents / excipients (e.g. starch, cellulose, a cellulose derivative, a polyol, dextrose, maltodextrin, magnesium stearate), adjuvants, fillers, buffers, preservatives (e.g. vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methyl paraben, propyl paraben), anti-oxidants (e.g. vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium), lubricants (e.g. magnesium stearate, talc, silica, stearic acid, vegetable stearin), binders (e.g. sucrose, lactose, starch, cellulose, gelatin, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), xylitol, sorbitol, mannitol), stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents or colouring agents (e.g. titanium oxide).

[0532] The term ‘pharmaceutically-acceptable’ as used herein pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g. a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, diluent, excipient, adjuvant, filler, buffer, preservative, anti-oxidant, lubricant, binder, stabiliser, solubiliser, surfactant, masking agent, colouring agent, flavouring agent or sweetening agent of a composition according to the present disclosure must also be ‘acceptable’ in the sense of being compatible with the other ingredients of the formulation. Suitable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, binders, stabilisers, solubilisers, surfactants, masking agents, colouring agents, flavouring agents or sweetening agents can be found in standard pharmaceutical texts, for example, Remington’s ‘The Science and Practice of Pharmacy’ (Ed. A. Adejare), 23rd Edition (2020), Academic Press.

[0533] Compositions may be formulated for topical, parenteral, systemic, intracavitary, intravenous, intra-arterial, intramuscular, intrathecal, intraocular, intraconjunctival, intratumoral, subcutaneous, intradermal, intrathecal, oral or transdermal routes of administration. In some embodiments, a pharmaceutical composition / medicament may be formulated for administration by injection or infusion, or administration by ingestion.

[0534] Suitable formulations may comprise the relevant article in a sterile or isotonic medium. Medicaments and pharmaceutical compositions may be formulated in fluid, including gel, form. Fluid formulations may be formulated for administration by injection or infusion (e.g. via catheter) to a selected region of the human or animal body.

[0535] In some embodiments, the composition is formulated for injection or infusion, e.g. into a blood vessel, tissue / organ of interest, or a tumor.

[0536] The present disclosure also provides methods for the production of pharmaceutically-useful compositions and medicaments. Such methods may comprise one or more steps selected from: producing an antigenbinding molecule, polypeptide, nucleic acid (or plurality thereof), expression vector (or plurality thereof) or cell described herein; isolating an antigen-binding molecule, polypeptide, nucleic acid (or plurality thereof), expression vector (or plurality thereof) or cell described herein; and / or mixing an antigen-binding molecule, polypeptide, nucleic acid (or plurality thereof), expression vector (or plurality thereof) or cell described herein with a pharmaceutically-acceptable carrier, adjuvant, excipient or diluent.

[0537] For example, a further aspect of the present disclosure relates to a method of formulating or producing a medicament or pharmaceutical composition for use in the treatment of a disease / condition (e.g. a disease / condition described herein), the method comprising formulating a pharmaceutical composition or medicament by mixing an antigen-binding molecule, polypeptide, nucleic acid (or plurality thereof), expression vector (or plurality thereof) or cell described herein with a pharmaceutically acceptable carrier, adjuvant, excipient or diluent.

[0538] Therapeutic and prophylactic applications

[0539] The antigen-binding molecules, polypeptides, nucleic acids, expression vectors, cells and compositions described herein find use in therapeutic and prophylactic methods.

[0540] The present disclosure provides an antigen-binding molecule, polypeptide, nucleic acid (or plurality thereof), expression vector (or plurality thereof), cell or composition described herein for use in a method of medical treatment or prophylaxis. Also provided is an antigen-binding molecule, polypeptide, nucleic acid (or plurality thereof), expression vector (or plurality thereof), cell or composition described herein for use in a method of treating or preventing a disease or condition described herein. Also provided is the use of an antigen-binding molecule, polypeptide, nucleic acid (or plurality thereof), expression vector (or plurality thereof), cell or composition described herein in the manufacture of a medicament for treating or preventing a disease or condition described herein. Also provided is a method of treating or preventing a disease or condition described herein, comprising administering to a subject a therapeutically or prophylactically effective amount of an antigen-binding molecule, polypeptide, nucleic acid (or plurality thereof), expression vector (or plurality thereof), cell or composition described herein.

[0541] The methods may be effective to reduce the development or progression of a disease / condition, alleviation of the symptoms of a disease / condition or reduction in the pathology of a disease / condition. The methods may be effective to prevent progression of the disease / condition, e.g. to prevent worsening of, or to slow the rate of development of, the disease / condition. In some embodiments, the methods may lead to an improvement in the disease / condition, e.g. a reduction in the symptoms of the disease / condition or reduction in some other correlate of the severity / activity of the disease / condition. In some embodiments, the methods may prevent development of the disease / condition a later stage (e.g. a chronic stage or metastasis).

[0542] It will be appreciated that the articles of the present disclosure may be used for the treatment / prevention of any disease / condition that would derive therapeutic or prophylactic benefit from a reduction in the level / activity of signalling mediated by gp130, a gp130-containing complex (e.g. selected from a gp130:IL- 6Ra complex, a gp130:IL-11 Ra complex, a gp130:OSMRp complex, a gp130:LIFRp complex, a gp130:LIFRp:CNTFRa complex, a gp130:IL-27Ra complex and a gp130:IL-12Rp2 complex), or of signalling mediated by a cytokine that signals through a gp130-containing complex (e.g. selected from IL- 6, IL-11 , OSM, LIF, CNTF, CT-1 , CLC, IL-27 and IL-35).

[0543] It will also be appreciated that the articles of the present disclosure may be used for the treatment / prevention of any disease / condition that would derive therapeutic or prophylactic benefit from a reduction in the number or activity of cells comprising / expressing gp130 or a gp130-containing complex (e.g. selected from a gp130:IL-6Ra complex, a gp130:l L-11Ra complex, a gp130:OSMRp complex, a gp130:LIFRp complex, a gp130:LIFRp:CNTFRa complex, a gp130:IL-27Ra complex and a gp130:IL- 12Rp2 complex).

[0544] For example, the disease / condition may be a disease / condition in which gp130, a gp130-containing complex and / or a cytokine that signals through a gp130-containing complex are pathologically-implicated, e.g. a disease / condition in which an increased level / activity of gp130, a gp130-containing complex and / or a cytokine that signals through a gp130-containing complex is positively-associated with the onset, development or progression of the disease / condition, and / or severity of one or more symptoms of the disease / condition. In some embodiments, an increased level / activity of gp130, a gp130-containing complex and / or a cytokine that signals through a gp130-containing complex may be a risk factor for the onset, development or progression of the disease / condition.

[0545] In some embodiments, the disease / condition to be treated / prevented in accordance with the present disclosure is a disease / condition characterised by an increase in the level of expression or activity of gp130, a gp130-containing complex and / or a cytokine that signals through a gp130-containing complex, e.g. as compared to the level of expression / activity in the absence of the disease / condition. In some embodiments, the disease / condition to be treated / prevented is a disease / condition characterised by an increase in the number / proportion / activity of cells expressing gp130, a gp130-containing complex and / or a cytokine that signals through a gp130-containing complex, e.g. as compared to the level / number / proportion / activity in the absence of the disease / condition (e.g. in a healthy subject, or in equivalent non-diseased tissue).

[0546] Where the disease / condition is a cancer, the level of expression or activity of gp130, a gp130-containing complex and / or a cytokine that signals through a gp130-containing complex may be greater than the level of expression or activity in equivalent non-cancerous cells / non-tumor tissue. A cancer / cell thereof may comprise one or more mutations (e.g. relative to equivalent non-cancerous cells / non-tumor tissue) causing upregulation of expression or activity of gp130, a gp130-containing complex and / or a cytokine that signals through a gp130-containing complex.

[0547] Treatment in accordance with the methods of the present disclosure may achieve a reduction in the activity of gp130, a gp130-containing complex and / or a cytokine that signals through a gp130-containing complex in a subject (compared to an equivalent untreated subject, or a subject treated with an appropriate control).

[0548] In some aspects and embodiments, the articles of the present disclosure are provided for the treatment / prevention of disease / condition selected from: a disease / condition in which gp130-mediated signalling is pathologically-implicated, a disease / condition in which signalling through a gp130-containing complex (e.g. a gp130:IL-6Ra complex, a gp130:IL-11 Ra complex, a gp130:OSMRp complex, a gp130:LIFRp complex, a gp130:LIFRp:CNTFRa complex, a gp130:IL-27Ra complex or a gp130:IL-12Rp2 complex) is pathologically implicated, a disease / condition in which signalling mediated by a cytokine that signals through a gp130-containing complex (e.g. IL-6, IL-11 , OSM, LIF, CNTF, CT-1 , CLC, IL-27 or IL- 35) is pathologically-implicated, pathological inflammation, fibrosis, a disease / condition characterised by inflammation or a disease / condition characterised by fibrosis.

[0549] In some aspects and embodiments, the articles of the present disclosure are provided for the treatment / prevention of inflammation, particularly pathological inflammation.

[0550] Inflammation and its role in heath and disease is reviewed e.g. in Chen et al., Oncotarget (2018) 9(6): 7204-7218, which is hereby incorporated by reference in its entirety. Inflammation refers to the bodily response to cellular / tissue injury, and is characterised by edema, erythema (redness), heat, pain, and loss of function (stiffness and immobility) resulting from local immune, vascular and inflammatory cell responses to infection or injury. The injury may result from e.g. of physical (e.g. mechanical) or chemical insult, trauma, infection, cancer or overactive / aberrant immune responses (e.g. autoimmune disease). Inflammation forms part of the innate immune response, and plays an important physiological role in wound healing and the control of infection, and contributes to the restoration of tissue homeostasis.

[0551] However, many diseases are associated with an overactive inflammatory response ( / .e. excessive inflammation and / or aberrantly activated inflammation), and / or chronic (prolonged) inflammation. Herein, excessive and / or chronic inflammation may be referred to as ‘pathological inflammation’. Pathological inflammation may refer to inflammation which is implicated in ( / .e. which positively contributes to) the pathology of a disease.

[0552] Inflammation to be treated / prevented in accordance with the present disclosure can be of any tissue / organ of the body. In some embodiments, the inflammation is of the lung (e.g. bronchioles, alveoli), airways (e.g. nasal cavity, oral cavity, pharynx, larynx, trachea, bronchi), heart, kidney, liver, skeletal muscle, blood vessels, eye, skin, pancreas, bowel, small intestine, large intestine, colon, joints, brain, or bone marrow. Inflammation may also occur in multiple tissues / organs at once.

[0553] In some embodiments, inflammation may be of an organ or tissue of the respiratory system, e.g. the lung (e.g. bronchioles, alveoli), or airways (e.g. nasal cavity, oral cavity, pharynx, larynx, trachea, bronchi). In some embodiments, inflammation may be of an organ or tissue of the cardiovascular system, e.g. the heart or blood vessels. In some embodiments, inflammation may be of an organ or tissue of the gastrointestinal system, e.g. of the liver, bowel, small intestine, large intestine, colon, or pancreas. In some embodiments, inflammation may be of the eye. In some embodiments, inflammation may be of the skin. In some embodiments, inflammation may be of an organ or tissue of the nervous system, e.g. the brain. In some embodiments, inflammation may be of the bone marrow. In some embodiments, inflammation may be of the joints. In some embodiments, inflammation may be of an organ or tissue of the urinary system, e.g. the kidneys. In some embodiments, inflammation may be of an organ or tissue of the musculoskeletal system, e.g. muscle tissue. In some embodiments, inflammation may be of an organ or tissue of one or more organ systems.

[0554] Inflammation can promote angiogenesis ( / .e. the growth and development of new blood vessels from existing vasculature), through multiple different pathways as described e.g. in Granger and Senchenkova, ‘Chapter 6: Angiogenesis’, in ‘Inflammation and the Microcirculation’, Morgan & Claypool Life Sciences; 2010. For example, inflammation can lead to hypoxic conditions in inflamed tissue, which in turn upregulates the expression of the potent angiogenic factor vascular endothelial growth factor (VEGF) which induces the growth of new blood vessels. Inflammatory cells such as macrophages, lymphocytes, mast cells and also fibroblasts produce angiogenic factors such as VEGF and FGF. Increased blood flow to inflamed tissue can stimulate angiogenesis through shear stresses on the endothelium of existing vessels, and extravasated plasma proteins, such as fibrinogen products, may also stimulate neovascularisation. In some embodiments, the disease / condition to be treated / prevented in accordance with the present disclosure is a disease / condition characterised by angiogenesis, e.g. a disease / condition characterised by inflammation-induced angiogenesis.

[0555] Angiogenesis is known to be dysregulated e.g. in systemic sclerosis, a chromic autoimmune connective tissue disease characterised by inflammation, vascular injury and fibrosis, and by an impaired angiogenesis response which cannot ensure efficient vascular recovery - reviewed e.g. in Cantatore et al., Biomed Res Int. (2017) 2017:5345673, which is incorporated herein by reference in its entirety. Vascular injury in systemic sclerosis induces hypoxia and tissue ischemia (which are usually primary triggers for angiogenesis) due to avascularisation of tissue, and causes vascular occlusion and thrombosis in larger vessels due to endothelial proliferation, fibrin disoposition and smooth muscle cell hypertrophy. However, when angiogenesis is dysregulated, compensatory angiogenesis is not induced and vascular damage may induce avascular areas or morphological changes in the vessel walls, such as fibrosis. Angiogenic cytokines, such as VEGF, TGFp and PDGF which are responsible for vessel formation and stabilisation, are also implicated in fibrosis, further contributing to vessel instability and loss of peripheral vascularisation. Inflammatory reactions play an important part in triggering fibrosis in many different organ systems. Inflammation can lead to excess in deposition of ECM components in the affected tissues. Low-grade but persistent inflammation is also thought to contribute to the progression of fibrosis in cardiovascular disease and hypertension. In many fibrotic disorders, a persistent inflammatory trigger is crucial to upregulation of production of growth factors, proteolytic enzymes, angiogenic factors and fibrogenic cytokines, which stimulate the deposition of connective tissue elements that progressively remodel and destroy normal tissue architecture.

[0556] In some aspects and embodiments, the articles of the present disclosure are provided for the treatment / prevention of fibrosis.

[0557] Fibrosis is a form of pathologic tissue remodelling characterised by the formation of excess connective tissue as a consequence of the excess deposition of extracellular matrix (ECM) components (including collagen). ‘Excess connective tissue’ refers to an amount of connective tissue at a given location (e.g. a given tissue / organ, or part of a given tissue / organ) which is greater than the amount of connective tissue present at that location under normal, non-pathological conditions. Similarly, ‘excess deposition of ECM components’ refers to a level of deposition of one or more ECM components which is greater than the level of deposition under normal, non-pathological conditions.

[0558] The cellular and molecular mechanisms of fibrosis are described in Wynn, J. Pathol. (2008) 214(2): 199- 210, and Wynn and Ramalingam, Nature Medicine (2012) 18:1028-1040, both of which are hereby incorporated by reference in their entirety.

[0559] Damage to tissues can result from various stimuli, including infections, autoimmune reactions, toxins, radiation and mechanical injury. Repair typically involves replacement of injured cells by cells of the same type, and replacement of normal parenchymal tissue with connective tissue. Repair processes become pathologic when they are not controlled properly, resulting in excess deposition of ECM components in which normal parenchymal tissue is replaced with connective tissue. In diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, cardiovascular fibrosis, systemic sclerosis and nephritis, extensive tissue remodelling and fibrosis can ultimately lead to organ failure and death.

[0560] The main cellular effectors of fibrosis are myofibroblasts. In response to tissue injury, damaged cells and leukocytes produce pro-fibroinflammatory factors such as TGFp, IL-13 and PDGF, which activate fibroblasts (and other myofibroblast precursor cells) to become aSMA-ex pressing myofibroblasts, and recruit myofibroblasts to the site of injury. Myofibroblasts produce large amounts of extracellular matrix components such as collagen and periostin for wound contracture and closure, and also produce proinflammatory cytokines such as IL-6, and tissue remodelling factors such as MMP2 and TIMP1 . Persistent / chronic infection and / or inflammation can result in the generation of too many myofibroblasts, and consequently the over-production of extracellular matrix, resulting in fibrosis. In many diseases and conditions characterised by fibrosis, a persistent inflammatory trigger is crucial to upregulation of production of growth factors, proteolytic enzymes, angiogenic factors and fibrogenic cytokines, which stimulate the deposition of connective tissue elements that progressively remodel and destroy normal tissue architecture.

[0561] Fibrosis can be triggered by pathological conditions, e.g. conditions, infections or disease states that lead to production of pro-fibrotic factors (e.g. as TGFpl). Fibrosis may be caused by physical injury / stimuli, chemical injury / stimuli or environmental injury / stimuli. Physical injury / stimuli may occur during surgery, e.g. iatrogenic causes. Chemical injury / stimuli may include drug-induced fibrosis, e.g. following chronic administration of drugs such as bleomycin, cyclophosphamide, amiodarone, procainamide, penicillamine, gold and nitrofurantoin (Daba et al., Saudi Med J. (2004) 25(6): 700-706). Environmental injury / stimuli may include exposure to asbestos fibres or silica.

[0562] Fibrosis can be of any tissue / organ of the body. In some embodiments, fibrosis is of the lung (e.g. bronchioles, alveoli), airways (e.g. nasal cavity, oral cavity, pharynx, larynx, trachea, bronchi), heart, kidney, liver, skeletal muscle, blood vessels, eye, skin, pancreas, bowel, small intestine, large intestine, colon, joints, brain, or bone marrow. Fibrosis may also occur in multiple tissues / organs at once.

[0563] In some embodiments, fibrosis may be of an organ or tissue of the respiratory system, e.g. the lung (e.g. bronchioles, alveoli), or airways (e.g. nasal cavity, oral cavity, pharynx, larynx, trachea, bronchi). In some embodiments, fibrosis may be of an organ or tissue of the cardiovascular system, e.g. the heart or blood vessels. In some embodiments, fibrosis may be of an organ or tissue of the gastrointestinal system, e.g. of the liver, bowel, small intestine, large intestine, colon, or pancreas. In some embodiments, fibrosis may be of the eye. In some embodiments, fibrosis may be of the skin. In some embodiments, fibrosis may be of an organ or tissue of the nervous system, e.g. the brain. In some embodiments, fibrosis may be of the bone marrow. In some embodiments, fibrosis may be of the joints. In some embodiments, fibrosis may be of an organ or tissue of the urinary system, e.g. the kidneys. In some embodiments, fibrosis may be of an organ or tissue of the musculoskeletal system, e.g. muscle tissue. In some embodiments, fibrosis may be of an organ or tissue of one or more organ systems.

[0564] In some embodiments, the disease / condition to be treated in accordance with the present disclosure is a disease / condition characterised by inflammation. In some embodiments, the disease / condition is a disease / condition characterised by fibrosis. In some embodiments, the disease / condition is a disease / condition characterised by inflammation and fibrosis.

[0565] As used herein, a disease / condition which is ‘characterised by inflammation’ is a disease / condition in which fibrosis is a symptom of the disease / condition. Diseases / conditions characterised by inflammation include, but are not limited to:

[0566] Diseases / conditions affecting the respiratory system, such as sinusitis, rhinitis, pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonitis, pleuritis and mediastinitis;

[0567] Diseases / conditions affecting the accessory digestive organs such as hepatitis, ascending cholangitis, cholecystitis, pancreatitis and peritonitis; Diseases / conditions affecting the cardiovascular system such as carditis, endocarditis, myocarditis, pericarditis, vasculitis, arteritis, phlebitis, capillaritis and cardiogenic shock; Diseases / conditions affecting the urinary system such as nephritis, glomerulonephritis, pyelonephritis, ureteritis, cystitis and urethritis;

[0568] Diseases / conditions affecting the nervous system such as encephalitis, myelitis, meningitis, arachnoiditis and neuritis;

[0569] Diseases / conditions affecting the musculoskeletal system such as arthritis, dermatomyositis, soft tissue, myositis, synovitis / tenosynovitis, bursitis, enthesitis, fasciitis, capsulitis, epicondylitis, tendinitis, panniculitis, osteochondritis: osteitis / osteomyelitis, spondylitis, periostitis and chondritis;

[0570] Diseases / conditions affecting the oral cavity and throat such as stomatitis, gingivitis, gingivostomatitis, periodontitis, glossitis, tonsillitis, sialadenitis, parotitis, cheilitis, pulpitis and gnathitis;

[0571] Diseases / conditions affecting the gastrointestinal system such as esophagitis, gastritis, gastroenteritis, enteritis, colitis, enterocolitis, duodenitis, ileitis, caecitis, appendicitis, proctitis and Peutz- Jeghers syndrome;

[0572] Diseases / conditions affecting the skin such as dermatitis, folliculitis, cellulitis and hidradenitis;

[0573] Diseases / conditions affecting the eye such as dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis and dry eye syndrome;

[0574] Diseases / conditions affecting the ear such as otitis externa, otitis media, labyrinthitis and mastoiditis;

[0575] Diseases / conditions of the reproductive system such as oophoritis, salpingitis, endometritis, endometriosis, parametritis, cervicitis, vaginitis, vulvitis, mastitis, orchitis, epididymitis, prostatitis, seminal vesiculitis, balanitis, posthitis, balanoposthitis, chorioamnionitis, funisitis and omphalitis;

[0576] Diseases / conditions of the endocrine system such as insulitis, hypophysitis, thyroiditis, parathyroiditis and adrenalitis;

[0577] Diseases / conditions of the lymphatic system such as lymphangitis and lymphadenitis;

[0578] Cancers, including inflammation-induced and inflammation-associated cancers, such as lung cancer (e.g. lung adenocarcinoma, lung squamous cell carcinoma), prostate cancer, hematological malignancies (e.g. multiple myeloma), pancreatic cancer, cervical cancer, stomach cancer, oesophageal cancer, head and neck cancer, colorectal cancer, colon cancer, liver cancer (e.g. hepatocellular carcinoma) and bile duct cancer.

[0579] It will be appreciated that many of the diseases / conditions listed above are interrelated.

[0580] It will be appreciated that diseases / conditions characterised by inflammation may also exhibit further symptoms / pathologies. For example, a disease / condition characterised by inflammation may further be characterised by angiogenesis (e.g. inflammation-induced angiogenesis as described herein) and / or fibrosis (e.g. fibrosis as described herein). As used herein, a disease / condition which is ‘characterised by fibrosis’ is a disease / condition in which fibrosis is a symptom of the disease / condition. Diseases and conditions characterised by fibrosis include, but are not limited to:

[0581] Diseases / conditions affecting the respiratory system such as pulmonary fibrosis, fibrothorax, radiation-induced lung injury, interstitial lung disease (ILD), idiopathic interstitial pneumonia (IIP), idiopathic pulmonary fibrosis (IPF), cystic fibrosis, progressive massive fibrosis, scleroderma, obliterative bronchiolitis, Hermansky-Pudlak syndrome, asbestosis, silicosis, sarcoidosis, tumor stroma in lung disease, chronic obstructive pulmonary disease (COPD), emphysema, chronic bronchitis and asthma;

[0582] Diseases / conditions affecting the liver such as chronic liver disease, liver fibrosis, bridging fibrosis, cirrhosis, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), alcoholic fatty liver (AFL), alcoholic hepatitis, alcoholic steatohepatitis (ASH), primary biliary cirrhosis (PBC), schistosomal liver disease and hepatocellular carcinoma (HCC);

[0583] Diseases / conditions affecting the cardiovascular system such as hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), fibrosis of the atrium, atrial fibrillation, fibrosis of the ventricle, ventricular fibrillation, myocardial fibrosis, interstitial fibrosis, replacement fibrosis Brugada syndrome, myocarditis, endomyocardial fibrosis, myocardial infarction, fibrotic vascular disease, hypertension, hypertensive heart disease, arrhythmogenic right ventricular cardiomyopathy (ARVC), atherosclerosis, arterial stiffness, chronic pulmonary hypertension, AIDS-associated pulmonary hypertension, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), varicose veins and cerebral infarcts;

[0584] Diseases / conditions affecting the kidneys such as tubulointerstitial fibrosis, glomerular fibrosis, renal fibrosis, nephritic syndrome, Alport's syndrome, HIV-associated nephropathy, polycystic kidney disease, Fabry's disease, diabetic nephropathy, chronic glomerulonephritis and nephritis associated with systemic lupus;

[0585] Diseases / conditions affecting the pancreas such as pancreatic fibrosis, cystic fibrosis and chronic pancreatitis;

[0586] Diseases / conditions affecting the nervous system such as gliosis, Alzheimer's disease and multiple sclerosis;

[0587] Diseases / conditions affecting the musculoskeletal system such as muscular dystrophy, Duchenne muscular dystrophy (DMD), Becker’s muscular dystrophy (BMD) and fibrotic myopathy;

[0588] Diseases / conditions affecting the gastrointestinal system such as inflammatory bowel disease (IBD), Crohn’s disease, microscopic colitis and primary sclerosing cholangitis (PSC);

[0589] Diseases / conditions affecting the skin such as scleroderma, nephrogenic systemic fibrosis, Dupuytren’s contracture and cutis keloid;

[0590] Diseases / conditions affecting the eye such as Grave's opthalmopathy, epiretinal fibrosis, retinal fibrosis, subretinal fibrosis, subretinal fibrosis associated with macular degeneration (e.g. wet age-related macular degeneration (AMD)), diabetic retinopathy, glaucoma, corneal fibrosis, post-surgical fibrosis (e.g. of the posterior capsule following cataract surgery, or of the bleb following trabeculectomy for glaucoma), conjunctival fibrosis and subconjunctival fibrosis;

[0591] Diseases / conditions affecting the joints such as arthrofibrosis, arthritis and adhesive capsulitis; Diseases / conditions affecting multiple tissues / organ systems, including progressive systemic sclerosis (PSS), chronic graft versus host disease (GVHD); fibrotic pre-neoplastic and fibrotic neoplastic disease, and fibrosis induced by chemical or environmental insult (e.g., cancer chemotherapy, pesticides, radiation / cancer radiotherapy);

[0592] Cancers, such as hepatocellular carcinoma, gastric cancer, oesophageal cancer, head and neck cancer, colorectal cancer, pancreatic cancer, cervical cancer, and vulvar cancer;

[0593] Mediastinal fibrosis, retroperitoneal fibrosis, myelofibrosis and Peyronie’s disease.

[0594] In some embodiments, the disease / condition to be treated in accordance with the present disclosure is systemic sclerosis. In some embodiments, the disease / condition to be treated in accordance with the present disclosure is arthritis. In some embodiments, the disease / condition to be treated in accordance with the present disclosure is idiopathic pulmonary fibrosis (IPF). In some embodiments, the disease / condition to be treated in accordance with the present disclosure is COVID-19. In some embodiments, the disease / condition to be treated in accordance with the present disclosure is a cytokine storm syndrome (CSS), e.g. cytokine release syndrome (CRS). In some embodiments, the disease / condition to be treated in accordance with the present disclosure is kidney disease. In some embodiments, the disease / condition to be treated in accordance with the present disclosure is kidney disease sepsis or septic shock. In some embodiments, the disease / condition to be treated in accordance with the present disclosure is hypertrophic cardiomyopathy (HCM). In some embodiments, the disease / condition to be treated in accordance with the present disclosure is dilated cardiomyopathy (DCM). In some embodiments, the disease / condition to be treated in accordance with the present disclosure is cardiogenic shock. In some embodiments, the disease / condition to be treated in accordance with the present disclosure is chronic inflammation, for example, chronic inflammation associated with ageing. In some embodiments, the disease / condition to be treated in accordance with the present disclosure is cardiovascular disease.

[0595] In some embodiments, the disease / condition to be treated in accordance with the present disclosure is a disease / condition described in WO 2022 / 090509 A1 , which is hereby incorporated by reference in its entirety. In some embodiments, the disease / condition to be treated is an age-related diseases / condition. Age-related diseases / conditions as referred to herein are diseases / conditions having an incidence which increases with age. Age-related diseases and conditions are described e.g. in Franceschi et al., Front Med (Lausanne) (2018) 5: 61 and Jaul and Barron Front Public Health (2017) 5: 335, both of which are hereby incorporated by reference in their entirety.

[0596] Age-related diseases / conditions are typically characterised by progressive degeneration of tissue structure and / or the progressive decline of physiological tissue function. The molecular and cellular mechanisms underlying such diseases / conditions include one or more of deregulated autophagy, mitochondrial dysfunction, telomere shortening, oxidative stress, inflammation, metabolic dysfunction, and commonly cellular senescence. Aging is a major risk factor for many chronic diseases. In the liver, aging increases the susceptibility towards acute liver injury and hepatic fibrotic response (Kim et al., Curr Opin Gastroenterol (2015) 31 (3): 184-191 ; Hunt et al., Comput Struct Biotechnol J (2019) 17: 1151-1161 , Ferrucci et al., Aging Cell (2020) 19(2): e13080). Moreover, aging has been positively associated with increased risk and poor prognosis of various liver diseases including non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, hepatitis C, and negatively associated with hepatic regenerative capacity (Kim et al., Curr Opin Gastroenterol (2015) 31 (3): 184-191 ; Papatheodoridi et al., Hepatology (2020) 71 (1): 363-374).

[0597] As used herein, an “age-related” disease / condition or phenotype may also be referred to as being “aging- related” or “age / aging-associated”. In aspects and embodiments of the present disclosure, a disease / condition or phenotype which is described as being “age-related” may arise as a consequence of the age of the subject having the relevant disease / condition or phenotype, rather than another etiological cause. In some aspects and embodiments, a disease / condition or phenotype which is “age-related” may arise as a consequence of cellular senescence. By way of illustration, “age-related” changes in body composition may refer to changes in body composition arising as a consequence of aging of the subject and / or of cellular senescence, rather than the subject’s diet.

[0598] The accumulation of senescent cells is one of the hallmarks in aging (Hunt et al., Comput Struct Biotechnol J (2019) 17: 1151-1161). Cellular senescence is characterised by reduced replicative capacity and producing senescence-associated secretory phenotype (SASPs) proteins, resulting in a chronic, low- grade inflammatory environment for neighbouring cells (Hunt et al., Comput Struct Biotechnol J (2019) 17: 1151-1161 ; Borghesan et al., Trends Cell Biol. (2020) 30(10)777-791). Under pathological stress conditions, excessive accumulation of senescence cells in affected tissues adversely affects the tissue’s regenerative ability and chronic inflammation that can resemble various age-related disorders such as Alzheimer's disease, cancer, arthritis, cataracts, osteoporosis, atherosclerosis, hypertension, cardiovascular disease, type 2 diabetes, and chronic liver disorders (Baker and Haynes, Trends Biochem Sci (2011) 36(5): 254-261 ; Kim et al., Curr Opin Gastroenterol (2015) 31 (3): 184-191 ; Hernandez-Segura et al., Trends Cell Biol (2018) 28(6): 436-453; Stahl et al. Front Immunol (2018) 9: 2795; Belikov, Ageing Res Rev (2019) 49: 11-26; Campisi et al., Nature (2019) 571 (7764): 183-192;

[0599] Gorgoulis et al., Cell (2019) 179(4): 813-827; Schmeer et al., Cells (2019) 8(11); Papatheodoridi et al., Hepatology (2020) 71 (1): 363-374). Cellular senescence is therefore thought to be a key physiological process in the development and progression of age-related diseases (Borghesan et al., Trends Cell Biol. (2020) 30(10)777-791 ; Pignolo et al., Trends Mol Med (2020) 26(7): 630-638).

[0600] In some aspects and embodiments the present disclosure contemplates treatment / prevention of cellular senescence, and diseases / conditions characterised by cellular senescence. In some aspects and embodiments, the methods of the present disclosure comprise inhibiting cellular senescence. In some aspects and embodiments, the methods of the present disclosure comprise inhibiting senescent cells. In some aspects and embodiments, the methods comprise reducing the number of senescent cells and / or inhibiting the activity of senescent cells. In some embodiments, reducing the number of senescent cells comprises inhibiting the process of cellular senescence. That is, in some embodiments reducing the number of senescent cells comprises inhibiting the development of senescent cells from non-senescent precursor cells. In some embodiments, reducing the number of senescent cells comprises reversing the process of cellular senescence. That is, in some embodiments reducing the number of senescent cells comprises promoting reversion of senescent cells to a non-senescent phenotype. In some embodiments, reducing the number of senescent cells comprises depleting senescent cells.

[0601] Cellular senescence is described e.g. in Childs et al. Nat Med (2015) 21 (12):1424-1435 and van Deursen, Nature (2014) 509(7501): 439-446, both of which are hereby incorporated by reference in their entirety. Cellular senescence is characterised by cessation of cell division (associated with activation of p16INK4a, p21CIP1and p53), chromatin remodelling (including e.g. DNA damage response (DDR), formation of promyelocytic leukemia protein (PML) bodies and senescence as...

Claims

Claims:

1. An antigen-binding molecule, optionally isolated, which binds to gp130, wherein the antigen-binding molecule inhibits IL-6-mediated signalling, IL-11 -mediated signalling, OSM-mediated signalling, CNTF- mediated signalling, CT-1-mediated signalling, and LIF-mediated signalling.

2. The antigen-binding molecule according to claim 1 , wherein the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:89.

3. The antigen-binding molecule according to claim 1 or claim 2, 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: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(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:185; 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:192 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 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:185; 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 NO:2HC-CDR2 having the amino acid sequence of SEQ ID NO:3HC-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:192 LC-CDR3 having the amino acid sequence of SEQ ID NO:12.

4. The antigen-binding molecule according to any one of claims 1 to 3, wherein the antigen-binding molecule comprises:(i) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to a VH sequence as indicated in Column A of row 68, 71 , 69, 72, 70, 73, 12, 13, 38-67, 3-11 or 1 of Table C, and(ii) a VL region having an amino acid sequence having at least 70% amino acid sequence identity to a VL sequence as indicated in Column B of row 68, 71 , 69, 72, 70, 73, 12, 13, 38-67, 3-11 or 1 of Table C, wherein the VH and VL sequences are selected from the same row of Table C.

5. The antigen-binding molecule according to claim 1 or claim 2, 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:18 HC-CDR2 having the amino acid sequence of SEQ ID NO:19 HC-CDR3 having the amino acid sequence of SEQ ID NO:218; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or(b)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:18 HC-CDR2 having the amino acid sequence of SEQ ID NO:19 HC-CDR3 having the amino acid sequence of SEQ ID NQ:204; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or(c)(i) a heavy chain variable (VH) region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO:18HC-CDR2 having the amino acid sequence of SEQ ID NO:19HC-CDR3 having the amino acid sequence of SEQ ID NO:20; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or(d)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:18 HC-CDR2 having the amino acid sequence of SEQ ID NO:19 HC-CDR3 having the amino acid sequence of SEQ ID NO:195; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or(e)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:18 HC-CDR2 having the amino acid sequence of SEQ ID NO:19 HC-CDR3 having the amino acid sequence of SEQ ID NO:214; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or(f)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:18 HC-CDR2 having the amino acid sequence of SEQ ID NO:19 HC-CDR3 having the amino acid sequence of SEQ ID NO:215; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28.

6. The antigen-binding molecule according to any one of claims 1 , 2 or 5, wherein the antigen-binding molecule comprises:(i) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to a VH sequence as indicated in Column A of row 89, 90, 80-88, 74-79 or 2 of Table C, and(ii) a VL region having an amino acid sequence having at least 70% amino acid sequence identity to a VL sequence as indicated in Column B of row 89, 90, 80-88, 74-79 or 2 of Table C, wherein the VH and VL sequences are selected from the same row of Table C.

7. The antigen-binding molecule according to any one of claims 1 to 6, 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.

8. A chimeric antigen receptor (CAR) comprising an antigen-binding molecule according to any one of claims 1 to 7.

9. A nucleic acid, or a plurality of nucleic acids, optionally isolated, encoding an antigen-binding molecule according to any one of claims 1 to 7, or a CAR according to claim 8.

10. An expression vector, or a plurality of expression vectors, comprising a nucleic acid or a plurality of nucleic acids according to claim 9.11 . A cell comprising an antigen-binding molecule according to any one of claims 1 to 7, a CAR according to claim 8, a nucleic acid or a plurality of nucleic acids according to claim 9, or an expression vector or a plurality of expression vectors according to claim 10.

12. A method comprising culturing a cell according to claim 11 under conditions suitable for expression of an antigen-binding molecule or CAR by the cell.

13. A composition comprising an antigen-binding molecule according to any one of claims 1 to 7, a CAR according to claim 8, a nucleic acid or a plurality of nucleic acids according to claim 9, an expression vector or a plurality of expression vectors according to claim 10, or a cell according to claim 11 , and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.

14. An antigen-binding molecule according to any one of claims 1 to 7, a CAR according to claim 8, a nucleic acid or a plurality of nucleic acids according to claim 9, an expression vector or a plurality of expression vectors according to claim 10, a cell according to claim 11 , or a composition according to claim 13, for use in a method of medical treatment or prophylaxis.

15. An antigen-binding molecule according to any one of claims 1 to 7, a CAR according to claim 8, a nucleic acid or a plurality of nucleic acids according to claim 9, an expression vector or a plurality of expression vectors according to claim 10, a cell according to claim 11 , or a composition according to claim 13, 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.

16. An in vitro complex, optionally isolated, comprising an antigen-binding molecule according to any one of claims 1 to 7 bound to gp130.

17. 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 7, and detecting the formation of a complex of the antigen-binding molecule with gp130.

18. 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 7, and detecting the formation of a complex of the antigen-binding molecule with gp130.

19. Use of an antigen-binding molecule according to any one of claims 1 to 7 as an in vitro or in vivo diagnostic or prognostic agent.

20. An antigen-binding molecule which binds to gp130 and inhibits IL-6-mediated signalling, IL-11 - mediated signalling, OSM-mediated signalling, CNTF-mediated signalling, CT-1-mediated signalling, and LIF-mediated signalling 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, wherein the antigenbinding molecule contacts the region of gp130 shown in SEQ ID NO:89.

21. Use of an antigen-binding molecule that binds to gp130 and that contacts the region of gp130 shown in SEQ ID NO:89 to inhibit IL-6-mediated signalling, IL-11 -mediated signalling, OSM-mediated signalling, CNTF-mediated signalling, CT-1-mediated signalling, and / or LIF-mediated signalling.

22. A method for inhibiting IL-6-mediated signalling, IL-11 -mediated signalling, OSM-mediated signalling, CNTF-mediated signalling, CT-1-mediated signalling, and / or LIF-mediated signalling, comprising contacting cells capable of IL-6-mediated signalling, IL-11 -mediated signalling, OSM-mediated signalling, CNTF-mediated signalling, CT-1-mediated signalling, and / or LIF-mediated signalling with an antigenbinding molecule that binds to gp130 and that contacts the region of gp130 shown in SEQ ID NO:89.

23. A method for inhibiting IL-6-mediated signalling, IL-11 -mediated signalling, OSM-mediated signalling, CNTF-mediated signalling, CT-1-mediated signalling, and LIF-mediated signalling in a subject, comprising administering to a subject an antigen-binding molecule that binds to gp130 and that contacts the region of gp130 shown in SEQ ID NO:89.

24. The antigen-binding molecule for use according to claim 20, the use according to claim 21 or the method according to claim 22 or claim 23, wherein the antigen-binding molecule comprises:(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(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:185; 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:192 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 NO:2 HC-CDR2 having the amino acid sequence of SEQ ID NO:3HC-CDR3 having the amino acid sequence of SEQ ID NO:185; 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: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 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:192 LC-CDR3 having the amino acid sequence of SEQ ID NO:12.

25. The antigen-binding molecule for use according to claim 20 or claim 24, the use according to claim 21 or claim 24, or the method according to any one of claims 22 to 24, wherein the antigen-binding molecule comprises:(i) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to a VH sequence as indicated in Column A of row 68, 71 , 69, 72, 70, 73, 12, 13, 38-67, 3-11 or 1 of Table C, and(ii) a VL region having an amino acid sequence having at least 70% amino acid sequence identity to a VL sequence as indicated in Column B of row 68, 71 , 69, 72, 70, 73, 12, 13, 38-67, 3-11 or 1 of Table C, wherein the VH and VL sequences are selected from the same row of Table C.

26. The antigen-binding molecule for use according to claim 20, the use according to claim 21 or the method according to claim 22 or claim 23, 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:18 HC-CDR2 having the amino acid sequence of SEQ ID NO:19 HC-CDR3 having the amino acid sequence of SEQ ID NO:218; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or(b)(i) a heavy chain variable (VH) region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO:18HC-CDR2 having the amino acid sequence of SEQ ID NO:19 HC-CDR3 having the amino acid sequence of SEQ ID NO:204; and(ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or(c)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:18 HC-CDR2 having the amino acid sequence of SEQ ID NO:19 HC-CDR3 having the amino acid sequence of SEQ ID NQ:20; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or(d)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:18 HC-CDR2 having the amino acid sequence of SEQ ID NO:19 HC-CDR3 having the amino acid sequence of SEQ ID NO:195; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or(e)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:18 HC-CDR2 having the amino acid sequence of SEQ ID NO:19 HC-CDR3 having the amino acid sequence of SEQ ID NO:214; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27 LC-CDR3 having the amino acid sequence of SEQ ID NO:28; or(f)(i) a heavy chain variable (VH) region incorporating the following CDRs:HC-CDR1 having the amino acid sequence of SEQ ID NO:18 HC-CDR2 having the amino acid sequence of SEQ ID NO:19 HC-CDR3 having the amino acid sequence of SEQ ID NO:215; and(ii) a light chain variable (VL) region incorporating the following CDRs:LC-CDR1 having the amino acid sequence of SEQ ID NO:26 LC-CDR2 having the amino acid sequence of SEQ ID NO:27LC-CDR3 having the amino acid sequence of SEQ ID NO:28.

27. The antigen-binding molecule for use according to claim 20 or claim 26, the use according to claim 21 or claim 26 or the method according to any one of claims 22, 23 or 26, wherein the antigen-binding molecule comprises:(i) a VH region having an amino acid sequence having at least 70% amino acid sequence identity to a VH sequence as indicated in Column A of row 89, 90, 80-88, 74-79 or 2 of Table C, and(ii) a VL region having an amino acid sequence having at least 70% amino acid sequence identity to a VL sequence as indicated in Column B of row 89, 90, 80-88, 74-79 or 2 of Table C, wherein the VH and VL sequences are selected from the same row of Table C.

28. The antigen-binding molecule for use according to any one of claims 20 or 24 to 27, the use according to any one of claims 21 or 24 to 27, or the method according to any one of claims 22 to 27, 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.

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