Gp130 antigen-binding molecule

Abstract

Gp130 antigen-binding molecules are disclosed. Nucleic acids and expression vectors encoding the Gp130 antigen-binding molecules, compositions comprising the Gp130 antigen-binding molecules, and methods of using the Gp130 antigen-binding molecules are also disclosed.

Description

[Technical Field]

[0001] This application claims priority to GB 2218388.3, ​​filed December 7, 2022, the content and elements of which are incorporated herein by reference for all purposes.

[0002] The present disclosure relates to the field of molecular biology, and more particularly to antibody technology. The present disclosure also relates to methods of medical treatment and prophylaxis. [Background technology]

[0003] Gp130 is a component of the receptors for various cytokines, including IL-6, IL-11, OSM, LIF, CNTF, CT-1, CLC, IL-27, and IL-35, which are often collectively referred to as the IL-6 family of cytokines. Certain IL-6 family cytokines, such as IL-6 and IL-11, are involved in the pathology of a wide range of diseases / conditions characterized by inflammation and / or fibrosis (e.g., Rose-John, F1000 Res. (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. al., Cytokine (2022) 149:155750).

[0004] However, because gp130 is important for signaling mediated by such a range of different cytokines, it has been considered an unattractive target for therapeutic intervention in such diseases / conditions. For example, as a result of its role in promoting resistance to pathogens, it has been suggested that gp130-targeted therapies may leave patients susceptible to opportunistic infections. Furthermore, because signaling mediated by some IL-6 family cytokines may be beneficial in certain settings, drugs targeting gp130 may cause and / or exacerbate disease (see, e.g., Silver and Hunter, J Leukoc Biol. (2010) 88(6):1145-1156).

[0005] Monoclonal antibodies that bind to gp130 and antagonize gp130-mediated signaling have been described, including mAb16673, which was reported in WO2019 / 126071 A1 to inhibit signaling mediated by OSM, LIF, and CNTF. Summary of the Invention

[0006] In a first aspect, the present disclosure provides an optionally isolated antigen binding molecule that binds to gp130, wherein the antigen binding molecule inhibits signaling mediated by gp130:IL-6Rα and / or gp130:IL-11Rα, and the antigen binding molecule does not inhibit signaling mediated by one or more of gp130:OSMRβ, gp130:LIFRβ, gp130:LIFRβ:CNTFRα, gp130:IL-27Rα, and gp130:IL-12Rβ2.

[0007] In some embodiments, antigen binding inhibits signaling mediated by gp130:IL-6Rα and gp130:IL-11Rα.

[0008] In some embodiments, the antigen binding molecule does not inhibit signaling mediated by gp130:OSMRβ, does not inhibit signaling mediated by gp130:LIFRβ, and does not inhibit signaling mediated by gp130:LIFRβ:CNTFRα.

[0009] In some embodiments, the antigen binding molecule contacts the region of gp130 set forth in SEQ ID NO:386.

[0010] In some embodiments, the antigen binding molecule is: (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: 249 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: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 286; 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: 246 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: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 281; 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: 244 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: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 284; 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: 245 HC-CDR3 having the amino acid sequence of SEQ ID NO: 4; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 10 LC-CDR2 having the amino acid sequence of SEQ ID NO: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 281; or (e) (i) a heavy chain variable (VH) region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 62 HC-CDR2 having the amino acid sequence of SEQ ID NO: 63 HC-CDR3 having the amino acid sequence of SEQ ID NO: 64; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 65 LC-CDR2 having the amino acid sequence of SEQ ID NO: 66 LC-CDR3 having the amino acid sequence of SEQ ID NO: 67; or (f) (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: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 12; or (g) (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: 20; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 24 LC-CDR2 having the amino acid sequence of SEQ ID NO: 25 LC-CDR3 having the amino acid sequence of SEQ ID NO: 26; or (h) (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: 32; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 24 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 (i) (i) a heavy chain variable (VH) region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 37 HC-CDR2 having the amino acid sequence of SEQ ID NO: 38 HC-CDR3 having the amino acid sequence of SEQ ID NO: 39; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 45 LC-CDR2 having the amino acid sequence of SEQ ID NO: 46 LC-CDR3 having the amino acid sequence of SEQ ID NO: 47; or (j) (i) a heavy chain variable (VH) region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 52 HC-CDR2 having the amino acid sequence of SEQ ID NO: 53 HC-CDR3 having the amino acid sequence of SEQ ID NO: 54; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 24 LC-CDR2 having the amino acid sequence of SEQ ID NO: 11 It contains an LC-CDR3 having the amino acid sequence of SEQ ID NO:58.

[0011] In some embodiments, the antigen binding molecule is: a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 221, 241, 219, 239, 220, 240, 74, 106, 78, 80, 83, 1, 17, 31, 36, 51, 86, or 87; and and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 271, 274, 75, 110, 88, 91, 95, 98, 100, 9, 23, 34, 44, or 57.

[0012] In some embodiments, the antigen binding molecule is: a VH region having an amino acid sequence having at least 70% amino acid sequence identity to the amino acid sequence shown in column A of Table C; and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to an amino acid sequence set forth in column B of Table C; The sequences in columns A and B are selected from the same row of table C.

[0013] In some embodiments, the antigen binding molecule is a multispecific antigen binding molecule, and the antigen binding molecule further comprises an antigen binding domain that binds to an antigen other than gp130.

[0014] The present disclosure also provides a chimeric antigen receptor (CAR) comprising an antigen-binding molecule according to the present disclosure.

[0015] The present disclosure also provides an optionally isolated nucleic acid, or multiple nucleic acids, encoding an antigen-binding molecule or CAR according to the disclosure.

[0016] The present disclosure also provides an expression vector or expression vectors comprising a nucleic acid or nucleic acids according to the present disclosure.

[0017] The present disclosure also provides a cell comprising an antigen-binding molecule, a CAR, a nucleic acid or nucleic acids, or an expression vector or expression vectors according to the present disclosure.

[0018] 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.

[0019] The present disclosure also provides a composition comprising an antigen-binding molecule, a CAR, a nucleic acid or nucleic acids, an expression vector or expression vectors, or a cell according to the present disclosure, and a pharmaceutically acceptable carrier, diluent, excipient, or adjuvant.

[0020] The present disclosure also provides an antigen-binding molecule, a CAR, a nucleic acid or nucleic acids, an expression vector or expression vectors, a cell, or a composition according to the present disclosure for use in a method of medical treatment or prevention.

[0021] The present disclosure also provides an antigen-binding molecule, a CAR, a nucleic acid or nucleic acids, an expression vector or expression vectors, a cell, or a composition according to the present disclosure for use in a method of treating or preventing: pathological inflammation, fibrosis, a disease / condition characterized by inflammation, a disease / condition characterized by fibrosis, a disease / condition characterized by inflammation and fibrosis, a disease / condition in which signaling via gp130-containing complexes is pathologically implicated, a disease / condition in which cytokines that signal via gp130-containing complexes are pathologically implicated, an autoimmune disease, or a metabolic syndrome. Neurodegenerative diseases, chronic inflammatory diseases, arthritis, rheumatoid arthritis, juvenile arthritis, systemic juvenile idiopathic arthritis, lupus, systemic lupus erythematosus, pancreatitis, thyroiditis, periodontitis, rhinitis, allergic rhinitis, 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's 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, keloids, scleroderma, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, hippocampal atrophy, lung 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, clotting factor receptor β (CRβ) receptor β (β-glucan receptor β), cholangitis, ... Malignant leukemia, colitis, ulcerative colitis, endometriosis, stroke, ischemic stroke, nephropathy, kidney injury, acute kidney injury, nephrotoxicity, glomerulonephritis, chronic kidney disease, renal fibrosis, Alport syndrome, adult-onset Still's disease, Castleman's disease, cytokine release syndrome, sepsis, septic shock, retinal disorders, retinal fibrosis, age-related macular degeneration, wet age-related macular degeneration, retinitis pigmentosa, dry eye syndrome, COVID-19, Peutz-Jeghers syndrome, skeletal muscle diseases, muscular dystrophy, muscle atrophy, cachexia, endocrine disorders, polycystic ovary syndrome, cancer, malignant blood diseases, leukemia, plasmacytoma,Hodgkin's lymphoma, lung cancer, colorectal cancer, intestinal cancer, urinary tract cancer, bladder cancer, vulvar cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, osteosarcoma, glioblastoma, breast cancer, gastric cancer, kidney cancer, metastatic renal cell carcinoma, prostate cancer, skin cancer, melanoma, liver cancer, hepatocellular carcinoma, frailty, age-related increase in fat mass, sarcopenia, age-related dyslipidemia, age-related hypertriglyceridemia, age-related hypercholesterolemia, age-related fatty liver, age-related non-alcoholic fatty liver disease, age-related non-alcoholic steatohepatitis, age-related cardiovascular disease, age-related hypertension, age-related kidney disease, age-related skin disease, infectious diseases, viral diseases, viral hepatitis, hepatitis B, HIV infection, influenza infection, malaria, tuberculosis, allergic diseases, transplant rejection and graft-versus-host disease.

[0022] The present disclosure also provides an optionally isolated in vitro complex comprising an antigen-binding molecule of the present disclosure bound to gp130.

[0023] The present disclosure also provides a method for detecting gp130 in a sample, the method comprising contacting a sample containing or suspected of containing 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.

[0024] The present disclosure also provides a method for selecting or stratifying a subject for treatment with a gp130-targeting agent, the method comprising contacting a sample from the subject in vitro with an antigen-binding molecule according to the present disclosure, and detecting the formation of a complex of the antigen-binding molecule with gp130.

[0025] 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.

[0026] The present disclosure also provides antigen-binding molecules that bind to gp130 for use in methods for treating or preventing the following: pathological inflammation, fibrosis, diseases / conditions characterized by inflammation, diseases / conditions characterized by fibrosis, diseases / conditions characterized by inflammation and fibrosis, diseases / conditions in which signaling via gp130-containing complexes is pathologically implicated, diseases / conditions in which cytokines that signal via gp130-containing complexes are pathologically implicated, autoimmune diseases, metabolic syndrome, neurodegenerative diseases, chronic inflammatory diseases, arthritis, rheumatoid arthritis, juvenile arthritis, and systemic juvenile idiopathic rheumatoid arthritis. Arthritis, lupus, systemic lupus erythematosus, pancreatitis, thyroiditis, periodontitis, rhinitis, allergic rhinitis, 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's 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, Marfa Syndrome, systemic sclerosis, keloids, scleroderma, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, hippocampal atrophy, lung 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 injury, nephrotoxicity, glomerulonephritis, chronic kidney disease, renal fibrosis, Alport syndrome, adult-onset Still's disease, Castleman's disease, cytokine release syndrome, sepsis, septic shock, retinal disorders, retinal fibrosis, age-related macular degeneration, wet age-related macular degeneration, retinitis pigmentosa, dry eye syndrome, COVID-19, Peutz-Jeghers syndrome, skeletal muscle diseases, muscular dystrophy, muscle atrophy, cachexia, endocrine disorders, polycystic ovary syndrome, cancer, malignant hematological disorders, leukemia, plasmacytoma, Hodgkin's lymphoma, lung cancer, colorectal cancer, intestinal cancer, urinary tract cancer, bladder cancer, vulvar cancer, endometrial cancer, ovarian cancer,Prostate cancer, pancreatic cancer, osteosarcoma, glioblastoma, breast cancer, gastric cancer, kidney cancer, metastatic renal cell carcinoma, prostate cancer, skin cancer, melanoma, liver cancer, hepatocellular carcinoma, frailty, age-related increase in fat mass, sarcopenia, age-related dyslipidemia, age-related hypertriglyceridemia, age-related hypercholesterolemia, age-related fatty liver, age-related non-alcoholic fatty liver disease, age-related non-alcoholic steatohepatitis, age-related cardiovascular disease, age-related hypertension, age-related kidney disease, age-related skin disease, infectious diseases, viral diseases, viral liver disease inflammation, hepatitis B, HIV infection, influenza infection, malaria, tuberculosis, allergic diseases, transplant rejection and graft-versus-host disease; wherein the antigen-binding molecule inhibits signaling mediated by gp130:IL-6Rα and / or gp130:IL-11Rα, and the antigen-binding molecule does not inhibit signaling mediated by one or more of gp130:OSMRβ, gp130:LIFRβ, gp130:LIFRβ:CNTFRα, gp130:IL-27Rα and gp130:IL-12Rβ2.

[0027] The present disclosure also provides the use of an antigen binding molecule that binds to gp130 and inhibits IL-6-mediated signaling and / or IL-11-mediated signaling, wherein the antigen binding molecule inhibits signaling mediated by gp130:IL-6Rα and / or gp130:IL-11Rα, and the antigen binding molecule does not inhibit signaling mediated by one or more of gp130:OSMRβ, gp130:LIFRβ, gp130:LIFRβ:CNTFRα, gp130:IL-27Rα, and gp130:IL-12Rβ2.

[0028] The present disclosure also provides a method for inhibiting IL-6-mediated signaling and / or IL-11-mediated signaling, comprising contacting a cell capable of IL-6-mediated signaling and / or IL-11-mediated signaling with an antigen binding molecule that binds to gp130, wherein the antigen binding molecule inhibits signaling mediated by gp130:IL-6Rα and / or gp130:IL-11Rα, and the antigen binding molecule does not inhibit signaling mediated by one or more of gp130:OSMRβ, gp130:LIFRβ, gp130:LIFRβ:CNTFRα, gp130:IL-27Rα, and gp130:IL-12Rβ2.

[0029] The present disclosure also provides a method for inhibiting IL-6-mediated signaling and / or IL-11-mediated signaling in a subject, comprising administering to the subject an antigen binding molecule that binds to gp130, wherein the antigen binding molecule inhibits signaling mediated by gp130:IL-6Rα and / or gp130:IL-11Rα, and the antigen binding molecule does not inhibit signaling mediated by one or more of gp130:OSMRβ, gp130:LIFRβ, gp130:LIFRβ:CNTFRα, gp130:IL-27Rα, and gp130:IL-12Rβ2.

[0030] In some embodiments, the antigen binding molecule inhibits signal transduction mediated by gp130:IL-6Rα and gp130:IL-11Rα.

[0031] In some embodiments, the antigen binding molecule does not inhibit signaling mediated by gp130:OSMRβ, does not inhibit signaling mediated by gp130:LIFRβ, and does not inhibit signaling mediated by gp130:LIFRβ:CNTFRα.

[0032] In some embodiments, the antigen binding molecule contacts the region of gp130 set forth in SEQ ID NO:386.

[0033] In some embodiments, the antigen binding molecule is: (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: 249 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: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 286; 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: 246 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: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 281; 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: 244 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: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 284; 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: 245 HC-CDR3 having the amino acid sequence of SEQ ID NO: 4; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 10 LC-CDR2 having the amino acid sequence of SEQ ID NO: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 281; or (e) (i) a heavy chain variable (VH) region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 62 HC-CDR2 having the amino acid sequence of SEQ ID NO: 63 HC-CDR3 having the amino acid sequence of SEQ ID NO: 64; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 65 LC-CDR2 having the amino acid sequence of SEQ ID NO: 66 LC-CDR3 having the amino acid sequence of SEQ ID NO: 67; or (f) (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: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 12; or (g) (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: 20; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 24 LC-CDR2 having the amino acid sequence of SEQ ID NO: 25 LC-CDR3 having the amino acid sequence of SEQ ID NO: 26; or (h) (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: 32; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 24 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 (i) (i) a heavy chain variable (VH) region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 37 HC-CDR2 having the amino acid sequence of SEQ ID NO: 38 HC-CDR3 having the amino acid sequence of SEQ ID NO: 39; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 45 LC-CDR2 having the amino acid sequence of SEQ ID NO: 46 LC-CDR3 having the amino acid sequence of SEQ ID NO: 47; or (j) (i) a heavy chain variable (VH) region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 52 HC-CDR2 having the amino acid sequence of SEQ ID NO: 53 HC-CDR3 having the amino acid sequence of SEQ ID NO: 54; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 24 LC-CDR2 having the amino acid sequence of SEQ ID NO: 11 It contains an LC-CDR3 having the amino acid sequence of SEQ ID NO:58.

[0034] In some embodiments, the antigen binding molecule is: a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 221, 241, 219, 239, 220, 240, 74, 106, 78, 80, 83, 1, 17, 31, 36, 51, 86, or 87; and and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 271, 274, 75, 110, 88, 91, 95, 98, 100, 9, 23, 34, 44, or 57.

[0035] In some embodiments, the antigen binding molecule is: a VH region having an amino acid sequence having at least 70% amino acid sequence identity to the amino acid sequence shown in column A of Table C; and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to an amino acid sequence set forth in column B of Table C; The sequences in columns A and B are selected from the same row of table C.

[0036] In some embodiments, the antigen binding molecule is a multispecific antigen binding molecule, and the antigen binding molecule further comprises an antigen binding domain that binds to an antigen other than gp130.

[0037] explanation The present disclosure provides antigen-binding molecules that bind to gp130 and have novel biophysical and / or functional properties compared to antigen-binding molecules disclosed in the prior art.

[0038] In particular, the present disclosure relates to gp130-binding antigen-binding molecules that inhibit signaling mediated by IL-6 / gp130:IL-6Rα and IL-11 / gp130:IL-11Rα, but do not inhibit signaling mediated by other IL-6 family cytokines or other cytokine receptor complexes that contain gp130. That is, the present disclosure particularly relates to gp130-binding antigen-binding molecules that inhibit signaling mediated only by IL-6 / gp130:IL-6Rα and IL-11 / gp130:IL-11Rα.

[0039] The antigen binding molecules of the present disclosure are useful for inhibiting signaling mediated by the pro-fibrotic IL-6 / gp130:IL-6Rα and IL-11 / gp130:IL-11Rα signaling axes without substantially inhibiting signaling mediated by other IL-6 family cytokines.

[0040] The gp130-containing receptor complexes involved in the transduction of IL-11- and IL-6-mediated signaling are formed from heteromers containing gp130 and IL-11Rα or IL-6Rα molecules. In contrast, the gp130-containing receptor complexes involved in the transduction of signaling mediated by OSM, LIF, CNTF, CT-1, CLC, IL-27, and IL-35 contain a single gp130 molecule. Without wishing to be bound by any particular theory, the antigen-binding molecules of the present disclosure may selectively inhibit signaling mediated by IL-6 / gp130:IL-6Rα and IL-11 / gp130:IL-11Rα by inhibiting the formation of gp130-containing receptor complexes containing multiple gp130 molecules.

[0041] The gp130-binding antigen binding molecules disclosed herein that inhibit signal transduction mediated by IL-6 / gp130:IL-6Rα and IL-11 / gp130:IL-11Rα have also been shown to bind to the membrane proximal region of gp130.

[0042] Prior to the present disclosure, it was not appreciated that it would be possible to obtain antigen-binding molecules that inhibit signaling mediated by IL-6 / gp130:IL-6Rα and IL-11 / gp130:IL-11Rα (and that do not inhibit signaling mediated by other IL-6 family cytokines or other cytokine receptor complexes that contain gp130). Indeed, it was not clear whether targeting the membrane-proximal region of gp130 would enable selective inhibition of signaling mediated by IL-6 / gp130:IL-6Rα and IL-11 / gp130:IL-11Rα.

[0043] gp130 Human gp130 (also known as IL6ST, CD130) is a protein identified in UniProt P40189. The structure and function of gp130 are described, for example, 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 incorporated herein by reference in their entireties.

[0044] The canonical isoform of human gp130 (isoform 1) has the amino acid sequence set forth in SEQ ID NO: 129. Alternative splicing of the mRNA encoded by the human IL6ST gene results in three major gp130 isoforms: isoform 1 (SEQ ID NO: 129), isoform 2 (also known as gp130-RAPS; SEQ ID NO: 130), and isoform 3 (SEQ ID NO: 131). Isoform 2 differs from isoform 1 in that positions 325-329 of SEQ ID NO: 129 are different and positions 330-918 are absent. Positions 423-483 of SEQ ID NO: 129 are absent in isoform 3.

[0045] The canonical isoform of human gp130 contains an N-terminal signal peptide (SEQ ID NO: 132), followed by an extracellular domain (SEQ ID NO: 134), a single transmembrane domain (SEQ ID NO: 135), and a C-terminal cytoplasmic domain (SEQ ID NO: 136). The mature form of human gp130 isoform 1 is shown in SEQ ID NO: 133.

[0046] The extracellular domain contains an N-terminal Ig-like C2-type domain (SEQ ID NO: 137) followed by five fibronectin type III (FNIII) domains (set forth in SEQ ID NOs: 138, 139, 141, 142, and 143, respectively). The cytokine binding module (CBM) of gp130 is formed by the Ig-like C2-type domain and FNIII domains 1 and 2 (SEQ ID NO: 144). FNIII domain 2 contains the WSXWS motif set forth in SEQ ID NO: 140. The WSXWS motif is conserved among type I cytokine receptor polypeptides, and the WSXWS motif of gp130 is thought to be important for cytokine binding.

[0047] gp130 is a constituent polypeptide of all receptors in the IL-6 receptor family and mediates signal transduction. Two gp130 polypeptides associate with two IL-6Rα polypeptides to form the IL-6 receptor, and similarly, two gp130 polypeptides associate with two IL-11Rα polypeptides to form the IL-11 receptor. gp130 associates with OSMRβ to form the type II receptor for OSM, or with LIFRβ to form the type I receptor for OSM, which also functions as a receptor for LIF and CT-1. gp130 also associates with LIFRβ and CNTFRα to form the receptor for CNTF and CLC. gp130 associates with IL-27Rα to form the receptor for IL-27, and with IL-12Rβ2 to form the receptor for IL-35.

[0048] After forming a complex with its receptor-interacting partner(s) and cognate ligand, gp130 is phosphorylated on tyrosine residues in its cytoplasmic domain (particularly Y767, Y814, Y905, and Y915), triggering downstream signaling via the JAK / STAT and MAPK / ERK signaling pathways. gp130 can also trigger signaling via PI3K / AKT. Receptor binding leads to the phosphorylation and activation of JAK1 and JAK2, which subsequently phosphorylate STAT1, STAT3, and STAT5. Phosphorylation of tyrosine residues in gp130 also leads to the recruitment and activation of SHP2, which then activates signaling via the Ras-ERK1 / ERK2 MAPK and PI3K / AKT signaling pathways.

[0049] As used herein, "gp130" refers to gp130 from any species, including isoforms, fragments, variants, or homologs from any species. In some embodiments, the gp130 is gp130 from a mammal (e.g., a beast, a placental, an epithelial, a peptotherian, an archon, a primate (rhesus monkey, cynomolgus monkey, non-human primate, or human)). In some embodiments, the gp130 is human gp130, rhesus monkey gp130, mouse gp130, rat gp130, or dog gp130. In some embodiments, the gp130 is human gp130 or mouse gp130.

[0050] As used herein, an isoform, fragment, variant, or homolog of a given reference protein (e.g., gp130) may be characterized as having at least 70% sequence identity to the amino acid sequence of the reference protein, preferably one of ≧80%, ≧85%, ≧90%, ≧91%, ≧92%, ≧93%, ≧94%, ≧95%, ≧96%, ≧97%, ≧98%, ≧99%, or 100% amino acid sequence identity.

[0051] A "fragment" generally refers to a fragment of a reference protein. A "variant" generally refers to a protein having an amino acid sequence that contains one or more amino acid substitutions, insertions, deletions, or other modifications relative to the amino acid sequence of the reference protein, but retains a significant degree of sequence identity (e.g., at least 60%). An "isoform" generally refers to a variant of a reference protein that is expressed by the same species as the species of the reference protein. A "homolog" generally refers to a variant of a reference protein that is produced by a different species compared to the species of the reference protein. Homologs include orthologs. Homologs of human gp130 include, for example, mouse gp130 (UniProt Q00560) and rat gp130 (UniProt P40190).

[0052] An isoform, fragment, variant, or homologue of a given reference protein may optionally be characterized 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 the immature or mature (i.e., after processing to remove the signal peptide) form of a particular isoform of the related protein from a species such as, for example, human.

[0053] Isoforms, fragments, variants, or homologs of gp130 according to the present disclosure may optionally be characterized as having at least 70%, preferably 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.

[0054] The isoform, fragment, variant, or homolog may optionally be a functional isoform, fragment, variant, or homolog that has a functional property / activity of a reference gp130 (e.g., human gp130 isoform 1), e.g., as determined by analysis with a suitable assay for functional property / activity. For example, an isoform, fragment, variant, or homolog of gp130 may associate with IL-6Rα, IL-11Rα, OSMRβ, LIFRβ, and / or CNTFRα.

[0055] In some embodiments, gp130 comprises or consists of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 129, 130 or 131.

[0056] In some embodiments, gp130 comprises or consists of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 129 or 133.

[0057] A "fragment" of a reference protein may be of any length (by number of amino acids), but may optionally be at least 25% of the length of the reference protein (i.e., 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%.

[0058] 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 a maximum length of one of 20, 30, 40, 50, 100, 150, 200, 300, 400, 500, 600, 700, 800, or 900 amino acids.

[0059] In some embodiments, the fragment of gp130 comprises or consists of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 133.

[0060] In some embodiments, the fragment of gp130 comprises or consists of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 134.

[0061] In some embodiments, the fragment of gp130 comprises or consists of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO: 144.

[0062] As used herein, "gp130-mediated signal transduction" refers to signal transduction mediated by gp130 and / or a multimeric receptor complex containing gp130 (e.g., containing gp130 and another member of the IL-6 receptor family). "Signal transduction" refers to signal transduction and other cellular processes that govern cellular activity.

[0063] gp130-mediated signaling can be mediated by gp130-containing polypeptide complexes (i.e., polypeptide complexes comprising one or more gp130 polypeptides). Polypeptide complexes according to the present disclosure can be characterized by non-covalent protein:protein interactions between the constituent polypeptide(s) / peptide(s). In some embodiments, the association involves electrostatic interactions (e.g., ionic bonds, hydrogen bonds) and / or van der Waals forces.

[0064] The gp130-mediated signal transduction can be mediated by a heteromultimeric polypeptide complex comprising one or more gp130 polypeptides, and further comprising one or more polypeptides of one or more polypeptides of the IL-6 receptor family (e.g., selected from IL-6Rα, IL-11Rα, OSMRβ, LIFRβ, CNTFRα, IL-27Rα, and IL-12Rβ2).

[0065] In some embodiments, gp130-mediated signaling can be mediated by a polypeptide complex that forms a receptor for a cytokine of the IL-6 family, for example, gp130-mediated signaling can be mediated by a polypeptide complex that forms a receptor for IL-6, IL-11, OSM, LIF, CNTF, CT-1, CLC, IL-27, or IL-35.

[0066] In some embodiments, gp130-mediated signaling can be mediated by a polypeptide complex comprising gp130 and another polypeptide of the IL-6 receptor family (e.g., selected from IL-6Rα, IL-11Rα, OSMRβ, LIFRβ, CNTFRα, IL-27Rα, and IL-12Rβ2). In some embodiments, gp130-mediated signaling can be mediated by a polypeptide complex comprising gp130 and IL-6Rα (i.e., a gp130:IL-6Rα complex). In some embodiments, gp130-mediated signaling can be mediated by a polypeptide complex comprising gp130 and IL-11Rα (i.e., a gp130:IL-11Rα complex). In some embodiments, gp130-mediated signaling can be mediated by a polypeptide complex comprising gp130 and OSMRβ (i.e., a gp130:OSMRβ complex). In some embodiments, gp130-mediated signaling can be mediated by a polypeptide complex comprising gp130 and LIFRβ (i.e., a gp130:LIFRβ complex). In some embodiments, gp130-mediated signaling can be mediated by a polypeptide complex comprising gp130, LIFRβ, and CNTFRα (i.e., a gp130:LIFRβ:CNTFRα complex). In some embodiments, gp130-mediated signaling can be mediated by a polypeptide complex comprising gp130 and IL-27Rα (i.e., a gp130:IL-27Rα complex). In some embodiments, gp130-mediated signaling can be mediated by a polypeptide complex comprising gp130 and IL-12Rβ2 (i.e., a gp130:IL-12Rβ2 complex). In some embodiments, gp130-mediated signaling can be mediated by a polypeptide complex comprising multiple gp130 polypeptides. In some embodiments, gp130-mediated signaling can be mediated by a polypeptide complex comprising two gp130 polypeptides, hi some embodiments, gp130-mediated signaling can be mediated by a polypeptide complex comprising two gp130 polypeptides and IL-6Rα (i.e., a gp130:gp130:IL-6Rα complex).In some embodiments, gp130-mediated signaling can be mediated by a polypeptide complex comprising two gp130 polypeptides and IL-11Rα (ie, a gp130:gp130:IL-11Rα complex).

[0067] gp130-mediated signaling via the polypeptide complexes described in the preceding paragraph can be triggered by the binding of their cognate cytokine(s). That is, in some embodiments, gp130-mediated signaling via a polypeptide complex comprising (i) gp130 and (ii) another polypeptide of the IL-6 receptor family can be triggered by cytokine binding to the polypeptide complex formed by protein-protein interaction between (i) and (ii). In some embodiments, gp130-mediated signaling is triggered by IL-6 binding to a polypeptide complex comprising gp130 and IL-6Rα (i.e., a gp130:IL-6Rα complex). In some embodiments, gp130-mediated signaling is triggered by IL-11 binding to a polypeptide complex comprising gp130 and IL-11Rα (i.e., a gp130:IL-11Rα complex). In some embodiments, gp130-mediated signaling is induced by binding of OSM to a polypeptide complex comprising gp130 and OSM (i.e., a gp130:OSMRβ complex). In some embodiments, gp130-mediated signaling is induced by binding of OSM, LIF, or CT-1 to a polypeptide complex comprising gp130 and LIFRβ (i.e., a gp130:LIFRβ complex). In some embodiments, gp130-mediated signaling is induced by binding of CNTF or CLC to a polypeptide complex comprising gp130, LIFRβ, and CNTFRα (i.e., a gp130:LIFRβ:CNTFRα complex). In some embodiments, gp130-mediated signaling is induced by binding of IL-27 to a polypeptide complex comprising gp130 and IL-27Rα (i.e., a gp130:IL-27Rα complex). In some embodiments, gp130-mediated signaling is triggered by the binding of IL-35 to a polypeptide complex comprising gp130 and IL-12Rβ2 (ie, a gp130:IL-12Rβ2 complex).

[0068] antigen binding molecule The present disclosure provides antigen-binding molecules capable of binding to gp130. Antigen-binding molecules capable of binding to gp130 may also be described as antigen-binding molecules that bind to gp130.

[0069] An "antigen-binding molecule" refers to a molecule that binds to a given target antigen. Antigen-binding molecules include antibodies (i.e., immunoglobulins (Ig)) and antigen-binding fragments thereof. As used herein, "antibody" includes monoclonal antibodies, polyclonal antibodies, monospecific and multispecific (e.g., bispecific, trispecific, etc.) antibodies, as well as antigen-binding molecules derived from antibodies, such as scFv, scFab, diabodies, triabodies, scFv-Fc, minibodies, single-domain antibodies (e.g., VhH), etc. Antigen-binding fragments of antibodies include, for example, Fv, Fab, F(ab')2, and F(ab')2 fragments. In some embodiments, the antigen-binding molecule may be an antibody or an antigen-binding fragment thereof.

[0070] 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 Fab region of an antibody, or the entire antibody. For example, antigen-binding molecules according to the present disclosure include antibody-drug conjugates (ADCs) comprising a (cytotoxic) drug moiety (e.g., as described herein below). Antigen-binding molecules according to the present disclosure also include multispecific antigen-binding molecules such as (effector) immune cell engager molecules that contain domains for recruiting 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 incorporated herein by reference in their entireties), including BiTE, BiKE, and TriKE. Antigen-binding molecules according to the present disclosure also include chimeric antigen receptors (CARs), which are recombinant receptors that provide both antigen-binding and T cell activation functions (the structure, function, and technology of CARs are reviewed, for example, in Dotti et al., Immunol Rev (2014) 257(1) and Jayaraman et al., EBioMedicine (2020) 58:102931, both of which are incorporated herein by reference in their entireties).

[0071] The antigen-binding molecules of the present disclosure comprise a moiety(ies) 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 specifically binding to the target antigen. In some embodiments, the moiety capable of binding to a target antigen comprises or consists of an aptamer, e.g., a nucleic acid aptamer (reviewed, e.g., in Zhou and Rossi Nat Rev Drug Discov. 2017 16(3):181-202), capable of binding to the target antigen. In some embodiments, the moiety capable of binding to a target antigen comprises or consists of an antigen-binding peptide / polypeptide, such as a peptide aptamer, thioredoxin, monobody, anticalin, Kunitz domain, avimer, knottin, fynomer, atrimer, DARPin, affibody, nanobody (i.e., single domain antibody (sdAb)), affilin, armadillo repeat protein (ArmRP), OBody, or fibronectin - e.g., as reviewed in Reverdatto et al., Curr Top Med Chem. 2015;15(12):1082-1101, which is incorporated herein 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).

[0072] As used herein, "peptide" refers to a chain of two or more amino acid monomers linked by peptide bonds. Peptides typically range in length from about 2 to 50 amino acids. A "polypeptide" is a polymeric chain of two or more peptides. Polypeptides typically have a length greater than about 50 amino acids.

[0073] The antigen-binding molecules of the present disclosure generally comprise an antigen-binding domain comprising the VH and VL of an antibody capable of specifically binding to a target antigen. The antigen-binding domain formed by the VH and VL may also be referred to herein as an Fv region.

[0074] An antigen-binding molecule may be or comprise an antigen-binding polypeptide or an antigen-binding polypeptide complex. An antigen-binding molecule may comprise multiple polypeptides that together form an antigen-binding domain. The polypeptides may be covalently or non-covalently associated. In some embodiments, a polypeptide forms part of a larger polypeptide that comprises the polypeptide (e.g., in the case of an scFv comprising a VH and a VL, or in the case of an scFab comprising a VH-CH1 and a VL-CL).

[0075] An antigen-binding molecule can refer to a non-covalent or covalent complex of multiple polypeptides (e.g., 2, 3, 4, 6, or 8 polypeptides), for example, an IgG-like antigen-binding molecule comprising two heavy chain polypeptides and two light chain polypeptides.

[0076] The antigen-binding molecules of the present disclosure can be designed and prepared using the sequence of a monoclonal antibody (mAb) capable of binding to gp130. Antigen-binding regions of antibodies, such as single-chain variable fragments (scFv), Fab and F(ab')2 fragments, can also be used / provided. An "antigen-binding region" is any fragment of an antibody that binds to a specific target of a given antibody.

[0077] Antibodies generally contain 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. Together, the six CDRs define the paratope of the antibody, the portion of the antibody that binds to the target antigen.

[0078] The VH and VL regions comprise framework regions (FRs) flanking each CDR, which provide a framework for the CDRs. From N- to C-terminus, the VH region comprises the following structure: N-terminus-[HC-FR1]-[HC-CDR1]-[HC-FR2]-[HC-CDR2]-[HC-FR3]-[HC-CDR3]-[HC-FR4]-C-terminus; and the VL region comprises the following structure: N-terminus-[LC-FR1]-[LC-CDR1]-[LC-FR2]-[LC-CDR2]-[LC-FR3]-[LC-CDR3]-[LC-FR4]-C-terminus.

[0079] There are several different conventions for defining antibody CDRs and FRs, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991), Chothia et al., J. Mol. Biol. 196:901-917 (1987), and VBASE2, as described in Retter et al., Nucl. Acids Res. (2005) 33(suppl 1):D671-D674. The CDRs and FRs of the VH 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) using the IMGT V-DOMAIN numbering rules, as described in Lefranc et al., Dev. Comp. Immunol. (2003) 27: 55-77. In a preferred embodiment, the CDRs and FRs of the antigen-binding molecules referred to herein are defined according to the IMGT information system.

[0080] 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 FRs of an antigen binding molecule that binds to gp130. That is, in some embodiments, the antigen binding molecule comprises the VH region and VL region of an antigen binding molecule that binds to gp130.

[0081] In some embodiments, the antigen-binding molecule comprises the CDR, FR and / or VH and / or VL regions of a gp130-binding antibody described herein, or the CDR, FR and / or VH and / or VL regions of a gp130-binding antibody described herein derived therefrom. In some embodiments, the gp130-binding antibody is selected from the antibodies of Table C herein.

[0082] In some embodiments, the antigen binding molecule comprises a VH region according to one of the following: (1) a VH region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 62 HC-CDR2 having the amino acid sequence of SEQ ID NO: 63 HC-CDR3 having the amino acid sequence of SEQ ID NO: 64; or a variant thereof, in which one, two or three amino acids of HC-CDR1, and / or one, two or three amino acids of HC-CDR2, and / or one, two or three amino acids of HC-CDR3 are replaced with another amino acid.

[0083] (2) a 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: 249 HC-CDR3 having the amino acid sequence of SEQ ID NO: 4; or a variant thereof, in which one, two or three amino acids of HC-CDR1, and / or one, two or three amino acids of HC-CDR2, and / or one, two or three amino acids of HC-CDR3 are replaced with another amino acid.

[0084] (3) a 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; or a variant thereof, in which one, two or three amino acids of HC-CDR1, and / or one, two or three amino acids of HC-CDR2, and / or one, two or three amino acids of HC-CDR3 are replaced with another amino acid.

[0085] (4) A 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: 244 HC-CDR3 having the amino acid sequence of SEQ ID NO: 4; or a variant thereof, in which one, two or three amino acids of HC-CDR1, and / or one, two or three amino acids of HC-CDR2, and / or one, two or three amino acids of HC-CDR3 are replaced with another amino acid.

[0086] (5) A VH region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 2 HC-CDR2 having the amino acid sequence of SEQ ID NO: 245 HC-CDR3 having the amino acid sequence of SEQ ID NO: 4; or a variant thereof, in which one, two or three amino acids of HC-CDR1, and / or one, two or three amino acids of HC-CDR2, and / or one, two or three amino acids of HC-CDR3 are replaced with another amino acid.

[0087] (6) A 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: 246 HC-CDR3 having the amino acid sequence of SEQ ID NO: 4; or a variant thereof, in which one, two or three amino acids of HC-CDR1, and / or one, two or three amino acids of HC-CDR2, and / or one, two or three amino acids of HC-CDR3 are replaced with another amino acid.

[0088] (7) A 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: 247 HC-CDR3 having the amino acid sequence of SEQ ID NO: 4; or a variant thereof, in which one, two or three amino acids of HC-CDR1, and / or one, two or three amino acids of HC-CDR2, and / or one, two or three amino acids of HC-CDR3 are replaced with another amino acid.

[0089] (8) A 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: 248 HC-CDR3 having the amino acid sequence of SEQ ID NO: 4; or a variant thereof, in which one, two or three amino acids of HC-CDR1, and / or one, two or three amino acids of HC-CDR2, and / or one, two or three amino acids of HC-CDR3 are replaced with another amino acid.

[0090] (9) A 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 comprising the amino acid sequence of SEQ ID NO: 20; or a variant thereof, in which one, two or three amino acids of HC-CDR1, and / or one, two or three amino acids of HC-CDR2, and / or one, two or three amino acids of HC-CDR3 are replaced with another amino acid.

[0091] (10) A 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 comprising the amino acid sequence of SEQ ID NO: 32; or a variant thereof, in which one, two or three amino acids of HC-CDR1, and / or one, two or three amino acids of HC-CDR2, and / or one, two or three amino acids of HC-CDR3 are replaced with another amino acid.

[0092] (11) A VH region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 37 HC-CDR2 having the amino acid sequence of SEQ ID NO: 38 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39; or a variant thereof, in which one, two or three amino acids of HC-CDR1, and / or one, two or three amino acids of HC-CDR2, and / or one, two or three amino acids of HC-CDR3 are replaced with another amino acid.

[0093] (12) A VH region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 52 HC-CDR2 having the amino acid sequence of SEQ ID NO: 53 HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 54; or a variant thereof, in which one, two or three amino acids of HC-CDR1, and / or one, two or three amino acids of HC-CDR2, and / or one, two or three amino acids of HC-CDR3 are replaced with another amino acid.

[0094] In some embodiments, the antigen binding molecule comprises a VH region according to one of the following: (13) A VH region incorporating the following FR: HC-FR1 having the amino acid sequence of SEQ ID NO: 68 HC-FR2 having the amino acid sequence of SEQ ID NO: 6; HC-FR3 having the amino acid sequence of SEQ ID NO: 69 HC-FR4 having the amino acid sequence of SEQ ID NO: 8; or a variant thereof, in which one, two or three amino acids of HC-FR1, and / or one, two or three amino acids of HC-FR2, and / or one, two or three amino acids of HC-FR3, and / or one, two or three amino acids of HC-FR4 are substituted with another amino acid.

[0095] (14) A VH region incorporating the following FR: HC-FR1 having the amino acid sequence of SEQ ID NO: 103 HC-FR2 having the amino acid sequence of SEQ ID NO: 104 HC-FR3 having the amino acid sequence of SEQ ID NO: 105 HC-FR4 having the amino acid sequence of SEQ ID NO: 79; or a variant thereof, in which one, two or three amino acids of HC-FR1, and / or one, two or three amino acids of HC-FR2, and / or one, two or three amino acids of HC-FR3, and / or one, two or three amino acids of HC-FR4 are substituted with another amino acid.

[0096] (15) A VH region incorporating the following FR: HC-FR1 having the amino acid sequence of SEQ ID NO: 76 HC-FR2 having the amino acid sequence of SEQ ID NO: 6 HC-FR3 having the amino acid sequence of SEQ ID NO: 77 HC-FR4 having the amino acid sequence of SEQ ID NO: 79; or a variant thereof, in which one, two or three amino acids of HC-FR1, and / or one, two or three amino acids of HC-FR2, and / or one, two or three amino acids of HC-FR3, and / or one, two or three amino acids of HC-FR4 are substituted with another amino acid.

[0097] (16) A VH region incorporating the following FR: HC-FR1 having the amino acid sequence of SEQ ID NO: 76 HC-FR2 having the amino acid sequence of SEQ ID NO: 81 HC-FR3 having the amino acid sequence of SEQ ID NO: 82 HC-FR4 having the amino acid sequence of SEQ ID NO: 79; or a variant thereof, in which one, two or three amino acids of HC-FR1, and / or one, two or three amino acids of HC-FR2, and / or one, two or three amino acids of HC-FR3, and / or one, two or three amino acids of HC-FR4 are substituted with another amino acid.

[0098] (17) A VH region incorporating the following FR: HC-FR1 having the amino acid sequence of SEQ ID NO: 84 HC-FR2 having the amino acid sequence of SEQ ID NO: 81 HC-FR3 having the amino acid sequence of SEQ ID NO: 85 HC-FR4 having the amino acid sequence of SEQ ID NO: 79; or a variant thereof, in which one, two or three amino acids of HC-FR1, and / or one, two or three amino acids of HC-FR2, and / or one, two or three amino acids of HC-FR3, and / or one, two or three amino acids of HC-FR4 are substituted with another amino acid.

[0099] (18) A VH region incorporating the following FR: HC-FR1 having the amino acid sequence of SEQ ID NO: 76 HC-FR2 having the amino acid sequence of SEQ ID NO: 81 HC-FR3 having the amino acid sequence of SEQ ID NO: 77 HC-FR4 having the amino acid sequence of SEQ ID NO: 79; or a variant thereof, in which one, two or three amino acids of HC-FR1, and / or one, two or three amino acids of HC-FR2, and / or one, two or three amino acids of HC-FR3, and / or one, two or three amino acids of HC-FR4 are substituted with another amino acid.

[0100] (19) A VH region incorporating the following FR: HC-FR1 having the amino acid sequence of SEQ ID NO: 76 HC-FR2 having the amino acid sequence of SEQ ID NO: 6 HC-FR3 having the amino acid sequence of SEQ ID NO: 82 HC-FR4 having the amino acid sequence of SEQ ID NO: 79; or a variant thereof, in which one, two or three amino acids of HC-FR1, and / or one, two or three amino acids of HC-FR2, and / or one, two or three amino acids of HC-FR3, and / or one, two or three amino acids of HC-FR4 are substituted with another amino acid.

[0101] (20) A VH region incorporating the following FR: HC-FR1 having the amino acid sequence of SEQ ID NO:5 HC-FR2 having the amino acid sequence of SEQ ID NO: 6 HC-FR3 having the amino acid sequence of SEQ ID NO: 7 HC-FR4 having the amino acid sequence of SEQ ID NO: 8; or a variant thereof, in which one, two or three amino acids of HC-FR1, and / or one, two or three amino acids of HC-FR2, and / or one, two or three amino acids of HC-FR3, and / or one, two or three amino acids of HC-FR4 are substituted with another amino acid.

[0102] (21) A VH region incorporating the following FR: HC-FR1 having the amino acid sequence of SEQ ID NO: 21 HC-FR2 having the amino acid sequence of SEQ ID NO: 6 HC-FR3 having the amino acid sequence of SEQ ID NO: 22 HC-FR4 having the amino acid sequence of SEQ ID NO: 8; or a variant thereof, in which one, two or three amino acids of HC-FR1, and / or one, two or three amino acids of HC-FR2, and / or one, two or three amino acids of HC-FR3, and / or one, two or three amino acids of HC-FR4 are substituted with another amino acid.

[0103] (22) A VH region incorporating the following FR: HC-FR1 having the amino acid sequence of SEQ ID NO: 21 HC-FR2 having the amino acid sequence of SEQ ID NO: 6 HC-FR3 having the amino acid sequence of SEQ ID NO: 33 HC-FR4 having the amino acid sequence of SEQ ID NO: 8; or a variant thereof, in which one, two or three amino acids of HC-FR1, and / or one, two or three amino acids of HC-FR2, and / or one, two or three amino acids of HC-FR3, and / or one, two or three amino acids of HC-FR4 are substituted with another amino acid.

[0104] (23) A VH region incorporating the following FR: HC-FR1 having the amino acid sequence of SEQ ID NO: 40 HC-FR2 having the amino acid sequence of SEQ ID NO: 41 HC-FR3 having the amino acid sequence of SEQ ID NO: 42 HC-FR4 having the amino acid sequence of SEQ ID NO: 43; or a variant thereof, in which one, two or three amino acids of HC-FR1, and / or one, two or three amino acids of HC-FR2, and / or one, two or three amino acids of HC-FR3, and / or one, two or three amino acids of HC-FR4 are substituted with another amino acid.

[0105] (24) A VH region incorporating the following FR: HC-FR1 having the amino acid sequence of SEQ ID NO: 55 HC-FR2 having the amino acid sequence of SEQ ID NO: 41 HC-FR3 having the amino acid sequence of SEQ ID NO: 56 HC-FR4 having the amino acid sequence of SEQ ID NO: 43; or a variant thereof, in which one, two or three amino acids of HC-FR1, and / or one, two or three amino acids of HC-FR2, and / or one, two or three amino acids of HC-FR3, and / or one, two or three amino acids of HC-FR4 are substituted with another amino acid.

[0106] In some embodiments, the antigen-binding molecule comprises a VH region comprising a CDR according to one of (1) to (12) above and a FR according to any one of (13) to (24) above.

[0107] In some embodiments, the antigen binding molecule comprises a VH region according to one of the following: (25) A VH region comprising the CDR described in (1) and the FR described in (7).

[0108] (26) A VH region comprising the CDRs described in (2) and the FRs described in (7).

[0109] (27) A VH region comprising the CDR described in (3) and the FR described in (8).

[0110] (28) A VH region comprising the CDR described in (3) and the FR described in (9).

[0111] (29) A VH region comprising the CDRs described in (3) and the FRs described in (10).

[0112] (30) A VH region comprising the CDRs described in (3) and the FRs described in (11).

[0113] (31) A VH region comprising the CDRs described in (3) and the FRs described in (12).

[0114] (32) A VH region comprising the CDRs described in (3) and the FRs described in (13).

[0115] (33) A VH region comprising the CDR described in (3) and the FR described in (14).

[0116] (34) A VH region comprising the CDRs described in (4) and the FRs described in (8).

[0117] (35) A VH region comprising the CDRs described in (4) and the FRs described in (9).

[0118] (36) A VH region comprising the CDRs described in (4) and the FRs described in (10).

[0119] (37) A VH region comprising the CDRs described in (4) and the FRs described in (11).

[0120] (38) A VH region comprising the CDRs described in (4) and the FRs described in (12).

[0121] (39) A VH region comprising the CDRs described in (4) and the FRs described in (13).

[0122] (40) A VH region comprising the CDRs described in (4) and the FRs described in (14).

[0123] (41) A VH region comprising the CDRs described in (5) and the FRs described in (8).

[0124] (42) A VH region comprising the CDRs described in (5) and the FRs described in (9).

[0125] (43) A VH region comprising the CDRs described in (5) and the FRs described in (10).

[0126] (44) A VH region comprising the CDRs described in (5) and the FRs described in (11).

[0127] (45) A VH region comprising the CDRs described in (5) and the FRs described in (12).

[0128] (46) A VH region comprising the CDRs described in (5) and the FRs described in (13).

[0129] (47) A VH region comprising the CDRs described in (5) and the FRs described in (14).

[0130] (48) A VH region comprising the CDRs described in (6) and the FRs described in (8).

[0131] (49) A VH region comprising the CDRs described in (6) and the FRs described in (9).

[0132] (50) A VH region comprising the CDRs described in (6) and the FRs described in (10).

[0133] (51) A VH region comprising the CDRs described in (6) and the FRs described in (11).

[0134] (52) A VH region comprising the CDRs described in (6) and the FRs described in (12).

[0135] (53) A VH region comprising the CDRs described in (6) and the FRs described in (13).

[0136] (54) A VH region comprising the CDRs described in (6) and the FRs described in (14).

[0137] (55) A VH region comprising the CDRs described in (7) and the FRs described in (8).

[0138] (56) A VH region comprising the CDRs described in (7) and the FRs described in (9).

[0139] (57) A VH region comprising the CDRs described in (7) and the FRs described in (10).

[0140] (58) A VH region comprising the CDRs described in (7) and the FRs described in (11).

[0141] (59) A VH region comprising the CDRs described in (7) and the FRs described in (12).

[0142] (60) A VH region comprising the CDRs described in (7) and the FRs described in (13).

[0143] (61) A VH region comprising the CDRs described in (7) and the FRs described in (14).

[0144] (62) A VH region comprising the CDRs described in (8) and the FRs described in (8).

[0145] (63) A VH region comprising the CDRs described in (8) and the FRs described in (9).

[0146] (64) A VH region comprising the CDRs described in (8) and the FRs described in (10).

[0147] (65) A VH region comprising the CDRs described in (8) and the FRs described in (11).

[0148] (66) A VH region comprising the CDRs described in (8) and the FRs described in (12).

[0149] (67) A VH region comprising the CDRs described in (8) and the FRs described in (13).

[0150] (68) A VH region comprising the CDRs described in (8) and the FRs described in (14).

[0151] (69) A VH region comprising the CDRs described in (9) and the FRs described in (21).

[0152] (70) A VH region comprising the CDRs described in (10) and the FRs described in (22).

[0153] (71) A VH region comprising the CDRs described in (11) and the FRs described in (23).

[0154] (72) A VH region comprising the CDRs described in (12) and the FRs described in (24).

[0155] In some embodiments, the antigen binding molecule comprises a VH region according to one of the following: (73) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 74;

[0156] (74) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 106;

[0157] (75) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 250;

[0158] (76) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 78;

[0159] (77) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably 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: 80;

[0160] (78) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 83;

[0161] (79) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 1;

[0162] (80) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 214;

[0163] (81) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 215;

[0164] (82) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 216;

[0165] (83) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 217;

[0166] (84) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 218;

[0167] (85) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 219;

[0168] (86) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 220;

[0169] (87) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 221;

[0170] (88) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 222;

[0171] (89) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 223;

[0172] (90) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 224;

[0173] (91) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 225;

[0174] (92) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 226;

[0175] (93) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 227;

[0176] (94) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 228;

[0177] (95) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 229;

[0178] (96) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 230;

[0179] (97) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 231;

[0180] (98) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 232;

[0181] (99) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 233;

[0182] (100) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 234;

[0183] (101) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 235;

[0184] (102) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 236;

[0185] (103) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 237;

[0186] (104) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 238;

[0187] (105) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 239;

[0188] (106) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 240;

[0189] (107) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 241;

[0190] (108) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 242;

[0191] (109) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 243;

[0192] (110) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 17;

[0193] (111) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 31;

[0194] (112) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably 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;

[0195] (113) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably 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;

[0196] (114) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86;

[0197] (115) A VH region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 87.

[0198] In some embodiments, the antigen binding molecule comprises a VL region according to one of the following: (116) A VL region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 65 LC-CDR2 having the amino acid sequence of SEQ ID NO: 66 LC-CDR3 having the amino acid sequence of SEQ ID NO: 67; or a variant thereof, in which one, two or three amino acids of LC-CDR1, and / or one, two or three amino acids of LC-CDR2, and / or one, two or three amino acids of LC-CDR3 are replaced with another amino acid.

[0199] (117) A 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: 286; or a variant thereof, in which one, two or three amino acids of LC-CDR1, and / or one, two or three amino acids of LC-CDR2, and / or one, two or three amino acids of LC-CDR3 are replaced with another amino acid.

[0200] (118) A 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 a variant thereof, in which one, two or three amino acids of LC-CDR1, and / or one, two or three amino acids of LC-CDR2, and / or one, two or three amino acids of LC-CDR3 are replaced with another amino acid.

[0201] (119) A 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: 281; or a variant thereof, in which one, two or three amino acids of LC-CDR1, and / or one, two or three amino acids of LC-CDR2, and / or one, two or three amino acids of LC-CDR3 are replaced with another amino acid.

[0202] (120) A 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: 282; or a variant thereof, in which one, two or three amino acids of LC-CDR1, and / or one, two or three amino acids of LC-CDR2, and / or one, two or three amino acids of LC-CDR3 are replaced with another amino acid.

[0203] (121) A 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: 283; or a variant thereof, in which one, two or three amino acids of LC-CDR1, and / or one, two or three amino acids of LC-CDR2, and / or one, two or three amino acids of LC-CDR3 are replaced with another amino acid.

[0204] (122) A 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: 284; or a variant thereof, in which one, two or three amino acids of LC-CDR1, and / or one, two or three amino acids of LC-CDR2, and / or one, two or three amino acids of LC-CDR3 are replaced with another amino acid.

[0205] (123) A 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: 285; or a variant thereof, in which one, two or three amino acids of LC-CDR1, and / or one, two or three amino acids of LC-CDR2, and / or one, two or three amino acids of LC-CDR3 are replaced with another amino acid.

[0206] (124) A VL region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 24 LC-CDR2 having the amino acid sequence of SEQ ID NO: 25 LC-CDR3 having the amino acid sequence of SEQ ID NO: 26; or a variant thereof, in which one, two or three amino acids of LC-CDR1, and / or one, two or three amino acids of LC-CDR2, and / or one, two or three amino acids of LC-CDR3 are replaced with another amino acid.

[0207] (125) A VL region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 24 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 a variant thereof, in which one, two or three amino acids of LC-CDR1, and / or one, two or three amino acids of LC-CDR2, and / or one, two or three amino acids of LC-CDR3 are replaced with another amino acid.

[0208] (126) A VL region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 45 LC-CDR2 having the amino acid sequence of SEQ ID NO: 46 LC-CDR3 having the amino acid sequence of SEQ ID NO: 47; or a variant thereof, in which one, two or three amino acids of LC-CDR1, and / or one, two or three amino acids of LC-CDR2, and / or one, two or three amino acids of LC-CDR3 are replaced with another amino acid.

[0209] (127) A VL region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 24 LC-CDR2 having the amino acid sequence of SEQ ID NO: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 58; or a variant thereof, in which one, two or three amino acids of LC-CDR1, and / or one, two or three amino acids of LC-CDR2, and / or one, two or three amino acids of LC-CDR3 are replaced with another amino acid.

[0210] In some embodiments, the antigen binding molecule comprises a VL region according to one of the following: (128) A VL region incorporating the following FR: LC-FR1 having the amino acid sequence of SEQ ID NO: 70 LC-FR2 having the amino acid sequence of SEQ ID NO: 71 LC-FR3 having the amino acid sequence of SEQ ID NO: 72 LC-FR4 having the amino acid sequence of SEQ ID NO: 73; or a variant thereof, in which one, two or three amino acids of LC-FR1, and / or one, two or three amino acids of LC-FR2, and / or one, two or three amino acids of LC-FR3, and / or one, two or three amino acids of LC-FR4 are substituted with another amino acid.

[0211] (129) A VL region incorporating the following FR: LC-FR1 having the amino acid sequence of SEQ ID NO: 107 LC-FR2 having the amino acid sequence of SEQ ID NO: 108 LC-FR3 having the amino acid sequence of SEQ ID NO: 109 LC-FR4 having the amino acid sequence of SEQ ID NO: 90; or a variant thereof, in which one, two or three amino acids of LC-FR1, and / or one, two or three amino acids of LC-FR2, and / or one, two or three amino acids of LC-FR3, and / or one, two or three amino acids of LC-FR4 are substituted with another amino acid.

[0212] (130) A VL region incorporating the following FR: LC-FR1 having the amino acid sequence of SEQ ID NO: 89 LC-FR2 having the amino acid sequence of SEQ ID NO: 14 LC-FR3 having the amino acid sequence of SEQ ID NO: 15 LC-FR4 having the amino acid sequence of SEQ ID NO: 90; or a variant thereof, in which one, two or three amino acids of LC-FR1, and / or one, two or three amino acids of LC-FR2, and / or one, two or three amino acids of LC-FR3, and / or one, two or three amino acids of LC-FR4 are substituted with another amino acid.

[0213] (131) A VL region incorporating the following FR: LC-FR1 having the amino acid sequence of SEQ ID NO: 92 LC-FR2 having the amino acid sequence of SEQ ID NO: 93 LC-FR3 having the amino acid sequence of SEQ ID NO: 15 LC-FR4 having the amino acid sequence of SEQ ID NO: 90; or a variant thereof, in which one, two or three amino acids of LC-FR1, and / or one, two or three amino acids of LC-FR2, and / or one, two or three amino acids of LC-FR3, and / or one, two or three amino acids of LC-FR4 are substituted with another amino acid.

[0214] (132) A VL region incorporating the following FR: LC-FR1 having the amino acid sequence of SEQ ID NO: 94 LC-FR2 having the amino acid sequence of SEQ ID NO: 93 LC-FR3 having the amino acid sequence of SEQ ID NO: 96 LC-FR4 having the amino acid sequence of SEQ ID NO: 90; or a variant thereof, in which one, two or three amino acids of LC-FR1, and / or one, two or three amino acids of LC-FR2, and / or one, two or three amino acids of LC-FR3, and / or one, two or three amino acids of LC-FR4 are substituted with another amino acid.

[0215] (133) A VL region incorporating the following FR: LC-FR1 having the amino acid sequence of SEQ ID NO: 97 LC-FR2 having the amino acid sequence of SEQ ID NO: 93 LC-FR3 having the amino acid sequence of SEQ ID NO: 99 LC-FR4 having the amino acid sequence of SEQ ID NO: 90; or a variant thereof, in which one, two or three amino acids of LC-FR1, and / or one, two or three amino acids of LC-FR2, and / or one, two or three amino acids of LC-FR3, and / or one, two or three amino acids of LC-FR4 are substituted with another amino acid.

[0216] (134) A VL region incorporating the following FR: LC-FR1 having the amino acid sequence of SEQ ID NO: 101 LC-FR2 having the amino acid sequence of SEQ ID NO: 93 LC-FR3 having the amino acid sequence of SEQ ID NO: 102 LC-FR4 having the amino acid sequence of SEQ ID NO: 90; or a variant thereof, in which one, two or three amino acids of LC-FR1, and / or one, two or three amino acids of LC-FR2, and / or one, two or three amino acids of LC-FR3, and / or one, two or three amino acids of LC-FR4 are substituted with another amino acid.

[0217] (135) A VL region incorporating the following FR: LC-FR1 having the amino acid sequence of SEQ ID NO: 13 LC-FR2 having the amino acid sequence of SEQ ID NO: 14 LC-FR3 having the amino acid sequence of SEQ ID NO: 15 LC-FR4 having the amino acid sequence of SEQ ID NO: 16; or a variant thereof, in which one, two or three amino acids of LC-FR1, and / or one, two or three amino acids of LC-FR2, and / or one, two or three amino acids of LC-FR3, and / or one, two or three amino acids of LC-FR4 are substituted with another amino acid.

[0218] (136) A VL region incorporating the following FR: LC-FR1 having the amino acid sequence of SEQ ID NO: 27 LC-FR2 having the amino acid sequence of SEQ ID NO: 28 LC-FR3 having the amino acid sequence of SEQ ID NO: 29 LC-FR4 having the amino acid sequence of SEQ ID NO: 30; or a variant thereof, in which one, two or three amino acids of LC-FR1, and / or one, two or three amino acids of LC-FR2, and / or one, two or three amino acids of LC-FR3, and / or one, two or three amino acids of LC-FR4 are substituted with another amino acid.

[0219] (137) A VL region incorporating the following FR: LC-FR1 having the amino acid sequence of SEQ ID NO: 27 LC-FR2 having the amino acid sequence of SEQ ID NO: 35 LC-FR3 having the amino acid sequence of SEQ ID NO: 29 LC-FR4 having the amino acid sequence of SEQ ID NO: 30; or a variant thereof, in which one, two or three amino acids of LC-FR1, and / or one, two or three amino acids of LC-FR2, and / or one, two or three amino acids of LC-FR3, and / or one, two or three amino acids of LC-FR4 are substituted with another amino acid.

[0220] (138) A VL region incorporating the following FR: LC-FR1 having the amino acid sequence of SEQ ID NO: 48 LC-FR2 having the amino acid sequence of SEQ ID NO: 49 LC-FR3 having the amino acid sequence of SEQ ID NO: 50 LC-FR4 having the amino acid sequence of SEQ ID NO: 30; or a variant thereof, in which one, two or three amino acids of LC-FR1, and / or one, two or three amino acids of LC-FR2, and / or one, two or three amino acids of LC-FR3, and / or one, two or three amino acids of LC-FR4 are substituted with another amino acid.

[0221] (139) A VL region incorporating the following FR: LC-FR1 having the amino acid sequence of SEQ ID NO: 13 LC-FR2 having the amino acid sequence of SEQ ID NO: 59 LC-FR3 having the amino acid sequence of SEQ ID NO: 60 LC-FR4 having the amino acid sequence of SEQ ID NO: 61; or a variant thereof, in which one, two or three amino acids of LC-FR1, and / or one, two or three amino acids of LC-FR2, and / or one, two or three amino acids of LC-FR3, and / or one, two or three amino acids of LC-FR4 are substituted with another amino acid.

[0222] In some embodiments, the antigen-binding molecule comprises a VL region comprising a CDR according to any one of (116) to (127) above and a FR according to any one of (128) to (139) above.

[0223] In some embodiments, the antigen binding molecule comprises a VL region according to one of the following: (140) A VL region comprising the CDRs described in (116) and the FRs described in (128).

[0224] (141) A VL region comprising the CDRs described in (117) and the FRs described in (128).

[0225] (142) A VL region comprising the CDRs described in (118) and the FRs described in (129).

[0226] (143) A VL region comprising the CDRs described in (118) and the FRs described in (130).

[0227] (144) A VL region comprising the CDRs described in (118) and the FRs described in (131).

[0228] (145) A VL region comprising the CDRs described in (118) and the FRs described in (132).

[0229] (146) A VL region comprising the CDRs described in (118) and the FRs described in (133).

[0230] (147) A VL region comprising the CDRs described in (118) and the FRs described in (134).

[0231] (148) A VL region comprising the CDRs described in (118) and the FRs described in (135).

[0232] (149) A VL region comprising the CDRs described in (119) and the FRs described in (129).

[0233] (150) A VL region comprising the CDRs described in (119) and the FRs described in (130).

[0234] (151) A VL region comprising the CDRs described in (119) and the FRs described in (131).

[0235] (152) A VL region comprising the CDRs described in (119) and the FRs described in (132).

[0236] (153) A VL region comprising the CDRs described in (119) and the FRs described in (133).

[0237] (154) A VL region comprising the CDRs described in (119) and the FRs described in (134).

[0238] (155) A VL region comprising the CDRs described in (119) and the FRs described in (135).

[0239] (156) A VL region comprising the CDRs described in (120) and the FRs described in (129).

[0240] (157) A VL region comprising the CDRs described in (120) and the FRs described in (130).

[0241] (158) A VL region comprising the CDRs described in (120) and the FRs described in (131).

[0242] (159) A VL region comprising the CDRs described in (120) and the FRs described in (132).

[0243] (160) A VL region comprising the CDRs described in (120) and the FRs described in (133).

[0244] (161) A VL region comprising the CDRs described in (120) and the FRs described in (134).

[0245] (162) A VL region comprising the CDRs described in (120) and the FRs described in (135).

[0246] (163) A VL region comprising the CDRs described in (121) and the FRs described in (129).

[0247] (164) A VL region comprising the CDRs described in (121) and the FRs described in (130).

[0248] (165) A VL region comprising the CDRs described in (121) and the FRs described in (131).

[0249] (166) A VL region comprising the CDRs described in (121) and the FRs described in (132).

[0250] (167) A VL region comprising the CDRs described in (121) and the FRs described in (133).

[0251] (168) A VL region comprising the CDRs described in (121) and the FRs described in (134).

[0252] (169) A VL region comprising the CDRs described in (121) and the FRs described in (135).

[0253] (170) A VL region comprising the CDRs described in (122) and the FRs described in (129).

[0254] (171) A VL region comprising the CDRs described in (122) and the FRs described in (130).

[0255] (172) A VL region comprising the CDRs described in (122) and the FRs described in (131).

[0256] (173) A VL region comprising the CDRs described in (122) and the FRs described in (132).

[0257] (174) A VL region comprising the CDRs described in (122) and the FRs described in (133).

[0258] (175) A VL region comprising the CDRs described in (122) and the FRs described in (134).

[0259] (176) A VL region comprising the CDRs described in (122) and the FRs described in (135).

[0260] (177) A VL region comprising the CDRs described in (123) and the FRs described in (129).

[0261] (178) A VL region comprising the CDRs described in (123) and the FRs described in (130).

[0262] (179) A VL region comprising the CDRs described in (123) and the FRs described in (131).

[0263] (180) A VL region comprising the CDRs described in (123) and the FRs described in (132).

[0264] (181) A VL region comprising the CDRs described in (123) and the FRs described in (133).

[0265] (182) A VL region comprising the CDRs described in (123) and the FRs described in (134).

[0266] (183) A VL region comprising the CDRs described in (123) and the FRs described in (135).

[0267] (184) A VL region comprising the CDRs described in (124) and the FRs described in (136).

[0268] (185) A VL region comprising the CDRs described in (125) and the FRs described in (137).

[0269] (186) A VL region comprising the CDRs described in (126) and the FRs described in (138).

[0270] (187) A VL region comprising the CDRs described in (122) and the FRs described in (139).

[0271] In some embodiments, the antigen binding molecule comprises a VL region according to one of the following: (188) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 75.

[0272] (189) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 110.

[0273] (190) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 88.

[0274] (191) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 91.

[0275] (192) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 95.

[0276] (193) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 98.

[0277] (194) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably 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: 100.

[0278] (195) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 9.

[0279] (196) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 251.

[0280] (197) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 252.

[0281] (198) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 253.

[0282] (199) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 254.

[0283] (200) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 255.

[0284] (201) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 256.

[0285] (202) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 257.

[0286] (203) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 258.

[0287] (204) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 259.

[0288] (205) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably 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: 260.

[0289] (206) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 261.

[0290] (207) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 262.

[0291] (208) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 263.

[0292] (209) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 264.

[0293] (210) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 265.

[0294] (211) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 266.

[0295] (212) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 267.

[0296] (213) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 268.

[0297] (214) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 269.

[0298] (215) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably 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: 270.

[0299] (216) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 271.

[0300] (217) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 272.

[0301] (218) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 273.

[0302] (219) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 274.

[0303] (220) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 275.

[0304] (221) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 276.

[0305] (222) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 277.

[0306] (223) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 278.

[0307] (224) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 279.

[0308] (225) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably 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: 280.

[0309] (226) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 23.

[0310] (227) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably 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.

[0311] (228) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably 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.

[0312] (229) A VL region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 57.

[0313] In some embodiments, the antigen-binding molecule comprises a VH region according to any one of (1) to (115) above and a VL region according to any one of (116) to (229) above.

[0314] In some embodiments, the VH according to any one of (73) to (109) comprises an amino acid other than "D" at a position corresponding to position 54 of SEQ ID NO: 1. In some embodiments, the amino acid other than "D" is selected from "G," "E," "Q," and "L." In some embodiments, the amino acid other than "D" is "G" or "Q."

[0315] In some embodiments, the VH according to any one of (73) to (109) comprises an amino acid other than "G" at a position corresponding to position 55 of SEQ ID NO: 1. In some embodiments, the amino acid other than "G" is selected from "G," "A," "L," and "T." In some embodiments, the amino acid other than "G" is "A."

[0316] In some embodiments, the VL according to any one of (73) to (109) comprises an amino acid other than "N" at a position corresponding to position 93 of SEQ ID NO: 9. In some embodiments, the amino acid other than "N" is selected from "G", "E", "Q", "L", and "T". In some embodiments, the amino acid other than "N" is selected from "G", "E", "Q", and "L". In some embodiments, the amino acid other than "N" is "Q" or "G".

[0317] In some embodiments, the VL according to any one of (73) to (109) comprises an amino acid other than "G" at a position corresponding to position 94 of SEQ ID NO: 9. In some embodiments, the amino acid other than "G" is "A" or "V." In some embodiments, the amino acid other than "G" is "A."

[0318] In embodiments according to the present disclosure, one or more amino acids are substituted with another amino acid. Substitutions include replacing an amino acid residue with a non-identical "replacement" amino acid residue. The replacement amino acid residue of a substitution according to the present disclosure can be a naturally occurring amino acid residue (i.e., encoded by the genetic code) that is not identical to the amino acid residue at the relevant position of the equivalent non-substituted amino acid selected from the following: alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine ​​(Cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), and valine (Val). In some embodiments, the substituted amino acid can be a non-naturally occurring amino acid residue, i.e., an amino acid residue other than those listed in the preceding sentence. Examples of non-naturally occurring amino acid residues include norleucine, ornithine, norvaline, homoserine, Aib, and other amino acid residue analogs such as those described in Ellman, et al., Meth. Enzym. 202 (1991) 301-336.

[0319] In some embodiments, substitutions can be biochemically conservative. In some embodiments, when a substituted amino acid is provided in one of rows 1-5 of the table below, the replacement amino acid for that substitution is another non-identical amino acid provided in the same row: [Table 1]

[0320] By way of example, in some embodiments where the substitution is of a Met residue, the replacement amino acid may be selected from Ala, Val, Leu, Ile, Trp, Tyr, Phe, and norleucine.

[0321] In some embodiments, the replacement amino acid in the substitution may have the same side chain polarity as the amino acid residue it replaces, In some embodiments, the replacement amino acid in the substitution may have the same side chain charge (at pH 7.4) as the amino acid residue it replaces. [Table 2]

[0322] 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 amino acid is substituted with another non-identical acidic polar amino acid; in some embodiments, a basic 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 positively charged amino acid is substituted with another non-identical positively charged amino acid; in some embodiments, a negatively charged amino acid is substituted with another non-identical negatively charged amino acid.

[0323] In some embodiments, the substitution(s) may be functionally conservative, i.e., in some embodiments, the substitution may not affect (or may not substantially affect) one or more functional properties (e.g., target binding) of an antigen-binding molecule comprising the substitution, compared to a comparable unsubstituted molecule.

[0324] The VH and VL regions of the antigen-binding region of an antibody together constitute an Fv region. In some embodiments, an 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 a single polypeptide, i.e., a single-chain Fv (scFv), linked by a linker sequence.

[0325] The VL and light chain constant (CL) regions, and the VH region and heavy chain constant 1 (CH1) region of the antigen-binding region of an antibody together constitute a Fab region. In some embodiments, the antigen-binding molecule comprises a Fab region comprising a VH, CH1, VL, and CL (e.g., CK or Cλ). In some embodiments, the Fab region comprises a polypeptide comprising a VH and CH1 (e.g., a VH-CH1 fusion polypeptide) and a polypeptide comprising a VL and CL (e.g., a VL-CL fusion polypeptide). In some embodiments, the Fab region comprises a polypeptide comprising a VH and CL (e.g., a VH-CL fusion polypeptide) and a polypeptide comprising a VL and CH (e.g., a VL-CH1 fusion polypeptide), i.e., in some embodiments, the Fab region is a CrossFab region. In some embodiments, the VH, CH1, VL, and CL regions of a Fab or CrossFab are provided as a single polypeptide linked by a linker region, i.e., as a single-chain Fab (scFab) or single-chain CrossFab (scCrossFab).

[0326] In some embodiments, the antigen-binding molecules described herein comprise or consist of a whole antibody that binds to gp130. As used herein, "whole antibody" refers to an antibody having a structure substantially similar to that of an immunoglobulin (Ig). Different types of immunoglobulins and their structures are described, for example, in Schroeder and Cavacini J Allergy Clin Immunol. (2010) 125(202):S41-S52, which is incorporated herein by reference in its entirety.

[0327] G-type immunoglobulins (i.e., IgG) are glycoproteins of approximately 150 kDa comprising two heavy chains and two light chains. From the N-terminus to the C-terminus, the heavy chain comprises a VH followed by a heavy chain constant region comprising three constant domains (CH1, CH2, and CH3); similarly, the light chain comprises a VL followed by a CL. Depending on the heavy chain, immunoglobulins can be classified as IgG (e.g., IgG1, IgG2, IgG3, IgG4), IgA (e.g., IgA1, IgA2), IgD, IgE, or IgM. The light chain can be kappa (κ) or lambda (λ).

[0328] Here, the term "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). Here, the term "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. Here, the term "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.

[0329] In some embodiments, the antigen binding molecules described herein comprise or consist of IgG (e.g., IgG1, IgG2, IgG3, IgG4), IgA (e.g., IgA1, IgA2), IgD, IgE, or IgM that binds to gp130.

[0330] 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., IgG1, IgG2, IgG3, IgG4), IgA (e.g., IgA1, IgA2), IgD, IgE, or IgM, such as human IgG (e.g., hIgG1, hIgG2, hIgG3, hIgG4), hIgA (e.g., hIgA1, hIgA2), hIgD, hIgE, or hIgM. In some embodiments, the immunoglobulin heavy chain constant sequence is or is derived from the heavy chain constant sequence of a human IgG1 allotype (e.g., G1m1, G1m2, G1m3, or G1m17).

[0331] In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, to the amino acid sequence of SEQ ID NO: 111 or 116. In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, to the amino acid sequence of SEQ ID NO: 192 or 193. In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 119 or 194.

[0332] In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, to the amino acid sequence of SEQ ID NO: 120, 121, 190, or 191. In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, to the amino acid sequence of SEQ ID NO: 122 or 201.

[0333] In some embodiments, the antigen-binding molecule comprises a CH1 region comprising an amino acid sequence having at least 70% sequence identity, more preferably 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: 112 or 117. In some embodiments, the antigen-binding molecule comprises a CH1 region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, to the amino acid sequence of SEQ ID NO: 195.

[0334] In some embodiments, the antigen-binding molecule comprises a hinge region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, to the amino acid sequence of SEQ ID NO: 113. In some embodiments, the antigen-binding molecule comprises a hinge region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, to the amino acid sequence of SEQ ID NO: 196 or 197.

[0335] In some embodiments, the antigen-binding molecule comprises a CH2 region comprising an amino acid sequence having at least 70% sequence identity, more preferably 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: 114 or 189. In some embodiments, the antigen-binding molecule comprises a CH2 region comprising an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, to the amino acid sequence of SEQ ID NO: 198 or 199.

[0336] In some embodiments, the antigen-binding molecule comprises a CH3 region comprising an amino acid sequence having at least 70% sequence identity, more preferably 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: 115 or 118. In some embodiments, the antigen-binding molecule comprises a CH2 region comprising an amino acid sequence having at least 70% sequence identity, more preferably 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: 200.

[0337] It will be understood that further substitutions may be provided in the CH2 and / or CH3 regions in accordance with the modifications to the Fc region of the antigen-binding molecules described herein.

[0338] 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 a human immunoglobulin kappa constant (IGKC; Cκ). In some embodiments, the immunoglobulin light chain constant sequence is a human immunoglobulin lambda constant (IGLC; Cλ), such as IGLC1, IGLC2, IGLC3, IGLC6, or IGLC7.

[0339] In some embodiments, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 123, 124, 125, 126, 127, or 128. In a preferred embodiment, the antigen-binding molecule comprises an amino acid sequence having at least 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 123.

[0340] In some embodiments, the antigen-binding molecule is or comprises a monoclonal antibody, or an antigen-binding fragment thereof.

[0341] 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 a human nucleic acid sequence(s). A fully human antibody / antibody fragment may lack non-human amino acid sequences. Commonly used techniques for producing fully human antibodies include (i) phage display, in which human antibody genes are expressed in a phage display library, and (ii) production of antibodies in transgenic mice engineered to carry human antibody genes (described in Park and Smolen, Advances in Protein Chemistry (2001) 56:369-421). Briefly, in human antibody gene phage display technology, genes encoding VH and VL chains are generated by PCR amplification and cloning from "naive" human lymphocytes, assembled into a library, from which they can be expressed as disulfide-linked Fab fragments or single-chain Fv (scFv) fragments. Genes encoding Fab or scFv are fused to surface coat proteins 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 used to enhance the affinity of the Fab / scFv fragments. In transgenic mouse technology, mice in which the endogenous mouse lg loci have been replaced with their human homologs by homologous recombination are immunized with antigen, and monoclonal antibodies are prepared by conventional hybridoma technology to obtain fully human monoclonal antibodies.

[0342] 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 by phage display using a human naive antibody gene library.

[0343] In some embodiments, the antigen-binding molecule is a mouse / human chimeric antigen-binding molecule (i.e., an antigen-binding molecule comprising a mouse antibody variable domain and a human antibody constant region). In some embodiments, the antigen-binding molecule is a humanized antigen-binding molecule comprising a mouse antibody variable domain and a human antibody constant region (i.e., an antigen-binding molecule comprising a variable domain obtained by humanizing the variable domain of an antibody derived from a non-human animal, for example, a mouse). In some embodiments, the antigen-binding molecule comprises the CDRs of a mouse antibody and the framework and constant regions of a human antibody.

[0344] Mouse / human chimeric antigen-binding molecules can be prepared from mouse antibodies by the chimerization process described, for example, 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.

[0345] Humanized antigen-binding molecules can be prepared from mouse antibodies by the chimerization process described, for example, 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'. Antibody humanization techniques are also described, for example, in Safdari et al., Biotechnol Genet Eng Rev (2013) 29:175-86.

[0346] Aspects of the present disclosure relate to multispecific antigen-binding molecules. "Multispecific" means that an antigen-binding molecule exhibits specific binding to multiple targets. In some embodiments, the antigen-binding molecule is a bispecific antigen-binding molecule. In some embodiments, the antigen-binding molecule comprises at least two different antigen-binding domains (i.e., at least two antigen-binding domains, e.g., non-identical VH and VL).

[0347] In some embodiments, the antigen-binding molecule is at least bispecific, as it binds to gp130 and another target (e.g., an antigen other than gp130). The term "bispecific" means that the antigen-binding molecule can specifically bind to at least two different antigenic determinants.

[0348] It will be understood that antigen-binding molecules (e.g., multispecific antigen-binding molecules) according to the present disclosure may include antigen-binding molecules capable of binding to specific targets. For example, antigen-binding molecules that bind to gp130 and antigens other than gp130 may include (i) antigen-binding molecules that bind to gp130 and (ii) antigen-binding molecules that bind to antigens other than gp130.

[0349] It will also be understood that an antigen-binding molecule (e.g., a multispecific antigen-binding molecule) according to the present disclosure may comprise an antigen-binding polypeptide or antigen-binding polypeptide complex capable of binding to a specific target.

[0350] 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, for example, as an "antigen-binding domain" or "antigen-binding region" of the larger antigen-binding molecule.

[0351] In some embodiments, the antigen other than gp130 in the 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 signaling molecule, e.g., a cytokine, chemokine, interferon, interleukin, or lymphokine. In some embodiments, the antigen is a growth factor or hormone.

[0352] In some embodiments, the antigen binding molecule is an immune cell engager. Immune cell engagers are reviewed, for example, in Goebeler and Bargou, Nat. Rev. Clin. Oncol. (2020) 17:418-434 and Ellerman, Methods (2019) 154:102-117, both of which are incorporated herein by reference in their entireties. Immune cell engager molecules include an antigen-binding region for a target antigen of interest and an antigen-binding region for recruiting / binding immune cells of interest. Immune cell engagers recruit / bind immune cells via an antigen-binding region specific for an immune cell surface molecule.

[0353] The most commonly studied immune cell engagers are bispecific T cell engagers (BiTEs), which contain a target antigen-binding domain and a CD3 polypeptide (usually CD3ε)-binding domain, through which BiTEs recruit T cells. Binding of a BiTE to its target antigen and to the CD3 polypeptide expressed by the T cell results in T cell activation, ultimately directing the effector activity of the T cell against cells expressing the target antigen. Other types of immune cell engagers are known in the art, including natural killer cell engagers, such as bispecific killer engagers (BiKEs), which recruit and activate NK cells.

[0354] In some embodiments, the immune cells engaged by the immune cell engager are T cells or NK cells, hi some embodiments, the immune cell engager is a T cell engager.

[0355] Multispecific antigen-binding molecules according to the present disclosure can be provided in any suitable format, such as those described in Brinkmann and Kontermann, MAbs (2017) 9(2): 182-212, which is incorporated herein 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., IgG2, F(ab')2, or CovX-Body; IgG or IgG-like molecules, e.g., IgG, chimeric IgG, κλ body common HC; CH1 / CL fusion proteins, e.g., scFv2-CH1 / CL, VHH2-CH1 / CL; and "variable domain only" bispecific antigen-binding molecules. , e.g., tandem scFv (taFv), triple body, diabody (Db), dsDb, Db(kih), DART, scDB, dsFv-dsFv, tandAb, triple head, tandem dAb / VHH, tetravalent dAb.VHH; non-Ig fusion proteins, e.g., scFv2-albumin, scDb-albumin, taFv-albumin, taFv-toxin, miniantibody, DNL-Fab2, DNL-Fab2-scFv, D NL-Fab2-IgG-cytokine 2, ImmTAC (TCR-scFv); modified Fc and CH3 fusion proteins, such as scFv-Fc(kih), scFv-Fc(CH3 charge pair), scFv-Fc(EW-RVT), scFv-fc(HA-TF), scFv-Fc(SEED body), taFv-Fc(kih), scFv-Fc(kih)-Fv, Fab-Fc(kih)-scFv, Fab-scFv-Fc(kih) , Fab-scFv-Fc (BEAT), Fab-scFv-Fc (SEED body), 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-Ig, scFv2-Fcab; CH3 fusions, e.g., di-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-Ig fusion proteins, e.g., DNL-Fab3, DNL-Fab2-scFv, DNL-Fab2-IgG-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-IgG(kih), Fab-scFab-IgG(kih), orthogonal Fab IgG(kih), DuetMab, CH3 charge pair + CH1 / CL charge pair, hinge / CH3 charge pair, SEED body, Duobody, four-in-one CrossMab(kih), LUZ-Y common LC; LUZ-Y scFab-IgG, FcFc*; IgG with added and Fc-modified, for example, IgG(kih)-Fv, IgG HA-TF-Fv, IgG(kih)scFab, scFab-Fc(kih)-scFv2, scFab-Fc(kih)-scFv, half DVD-Ig, DVI-Ig (four-in-one), CrossMab-Fab; modified Fc and CH3 fusion proteins, for example, Fab-Fc(kih)-scFv, Fab-scFv-Fc(kih), Fab-scFv-Fc(BEAT), Fab-scFv-Fc-SEED body, TriFab; IgG-HC fusions, for example, IgG-HC, scFv, IgG-dAb, IgG-taFV, IgG-crossFab, IgG-orthogonal Fab, IgG-(CαCβ)Fab, scFv-HC-IgG, tandem Fab-IgG (orthogonal Fab), Fab-IgG(CαCβFab), Fab-IgG(CR3), Fab-hinge-IgG(CR3); additional IgG-LC fusions, such as IgG-scFv(LC), scFv(LC)-IgG, dAb-IgG; additional IgG-HC and LC fusions, such as DVD-Ig, TVD-Ig, CODV-Ig, scFv4-IgG, Zybody; Fc fusions, such as Fab-scFv-Fc, scFv4-Ig; F(ab')2 fusions, such as F(ab')2-scFv2; CH1 / CL fusion proteins, such as scFv2-CH1-hinge / CL;Modified IgG, such as DAF (two-in-one IgG), DutaMab, Mab; 2 and non-Ig fusions, such as DNL-Fab4-IgG. Multispecific antigen-binding molecules can be readily designed and produced by those skilled in the art.

[0356] The present disclosure also provides chimeric antigen receptors (CARs). CARs are recombinant receptors that provide both antigen binding and T cell activation functions. CAR structure and modifications are outlined, for example, in Dotti et al., Immunol Rev (2014) 257(1), the entire contents of which are incorporated herein by reference. CARs comprise an antigen-binding region linked to a cell membrane anchor region and a signal transduction region. An optional hinge region may provide separation between the antigen-binding region and the cell membrane anchor region and may act as a flexible linker.

[0357] 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. Thus, a CAR according to the present disclosure comprises an antigen-binding molecule as described herein.

[0358] It will be understood that the antigen-binding molecules of the present disclosure form or are included in the antigen-binding domain of a CAR. Thus, in some embodiments, the antigen-binding molecules of the present disclosure are included in a CAR.

[0359] It will also be understood that the antigen-binding molecule of the present disclosure can be a CAR. A CAR having an antigen-binding domain comprising or consisting of an antigen-binding molecule of the present disclosure (e.g., gp130-binding Fv) is an antigen-binding molecule. The antigen-binding domain of the CAR of the present disclosure can be provided in any suitable format, such as scFv, scFab, etc.

[0360] The cell membrane anchor region is provided between the antigen binding region and the signaling region of the CAR, and serves to anchor the CAR to the cell membrane of a cell expressing the CAR, with the antigen binding region being in the extracellular space and the signaling region being intracellular. In some embodiments, the CAR comprises a cell membrane anchor region that comprises, consists of, or consists of an amino acid sequence that comprises, consists of, or is derived from the amino acid sequence of the transmembrane region of one of CD3-zeta, CD4, CD8, or CD28. As used herein, a region "derived from" a reference amino acid sequence comprises an amino acid sequence that has at least 60%, e.g., 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.

[0361] The signaling region of a CAR enables T cell activation. The CAR signaling region can include the amino acid sequence of the intracellular domain of CD3-zeta, which provides an immunoreceptor tyrosine-based activation motif (ITAM) for phosphorylation and activation of CAR-expressing T cells. Signaling regions containing sequences from other ITAM-containing proteins, such as FcγRI, have also been used in CARs (Haynes et al., 2001 J Immunol 166(1):182-187). The signaling region of a CAR can also include a costimulatory sequence derived from the signaling region of a costimulatory molecule to promote activation of CAR-expressing T cells upon binding to a target protein. Suitable costimulatory molecules include CD28, OX40, 4-1BB, ICOS, and CD27. In some cases, CARs are engineered to provide costimulation of different intracellular signaling pathways. For example, signaling associated with CD28 costimulation preferentially activates the phosphatidylinositol 3-kinase (PI3K) pathway, whereas 4-1BB-mediated signaling is via TNF receptor-associated factor (TRAF) adaptor proteins. Thus, the signaling region of a CAR can comprise costimulatory sequences derived from the signaling regions of multiple costimulatory molecules. In some embodiments, a CAR of the present disclosure comprises one or more costimulatory sequences that comprise, consist of, or are derived from the amino acid sequence of the intracellular domain of one or more of CD28, OX40, 4-1BB, ICOS, and CD27.

[0362] The optional hinge region may provide separation between the antigen-binding domain and the transmembrane domain and may act as a flexible linker. The hinge region may be derived from IgG1 or IgG4. In some embodiments, a CAR of the present disclosure comprises a hinge region that comprises, consists of, or is derived from the amino acid sequence of the hinge region of IgG1 or IgG4. In some embodiments, the hinge region of a CAR of the present disclosure comprises an amino acid sequence having at least about 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 113. In some embodiments, the hinge region of a CAR of the present disclosure comprises an amino acid sequence having at least about 70% sequence identity, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 196 or 197.

[0363] Also provided are cells comprising the CARs of the present disclosure.The CARs of the present disclosure can be used to generate CAR-expressing immune cells, such as CAR-T or CAR-NK cells.The manipulation of CARs into immune cells can be carried out during in vitro culture.

[0364] Fc area In some embodiments, an antigen binding molecule of the present disclosure comprises an Fc region.

[0365] As used herein, "Fc region" refers to the polypeptide complex formed by the interaction between two polypeptides, each of which contains the CH2-CH3 region of an immunoglobulin (Ig) heavy chain constant sequence.

[0366] Here, the term "CH2 region" refers to the 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. The term "CH3 region" refers to the 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. The term "CH2-CH3 region" refers to the 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.

[0367] In some embodiments, the CH2 region, CH3 region, and / or CH2-CH3 region of the present disclosure correspond to the CH2 region / CH3 region / CH2-CH3 region of IgG (e.g., IgG1, IgG2, IgG3, IgG4), IgA (e.g., IgA1, IgA2), IgD, IgE, or IgM. In some embodiments, the CH2 region, CH3 region, and / or CH2-CH3 region correspond to the CH2 region / CH3 region / CH2-CH3 region of human IgG (e.g., hIgG1, hIgG2, hIgG3, hIgG4), hIgA (e.g., hIgA1, hIgA2), hIgD, hIgE, or hIgM. In some embodiments, the CH2 region, CH3 region, and / or CH2-CH3 region correspond to the CH2 region / CH3 region / CH2-CH3 region of a human IgG1 allotype (e.g., G1m1, G1m2, G1m3, or G1m17).

[0368] The Fc region interacts with Fc receptors and other molecules of the immune system to produce functional effects. Fc-mediated effector functions are reviewed, for example, in Jefferis et al., Immunol Rev 1998 163:59-76 (incorporated herein by reference in its entirety), and include Fc-mediated immune cell recruitment and activation via interaction of the Fc region with Fc receptors expressed by immune cells (e.g., macrophages, dendritic cells, neutrophils, basophils, eosinophils, platelets, mast cells, NK cells, and T cells), recruitment of complement pathway components via binding of the Fc region to the 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.

[0369] Modifications to antibody Fc regions that affect Fc-mediated function are known in the art, such as those described in Wang et al., Protein Cell (2018) 9(1):63-73, which is incorporated herein by reference in its entirety. Exemplary Fc region modifications known to affect antibody effector function are summarized in Table 1 of Wang et al., Protein Cell (2018) 9(1):63-73. In some embodiments, the antigen-binding molecules of the present disclosure comprise an Fc region that includes a modification that increases or decreases an Fc-mediated function compared to an antigen-binding molecule comprising a corresponding unmodified Fc region.

[0370] When an Fc region / CH2 / CH3 is described as containing modification(s) "corresponding to" the reference substitution(s), the equivalent substitution(s) in the homologous Fc / CH2 / CH3 are contemplated. For example, the L234A / L235A substitutions in human IgG1 (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-2 A chain C region (UniProtKB: P01863-1, v1).

[0371] When an Fc region is described as comprising a modification, the modification can be present in one or both of the polypeptide chains that together form the Fc region.

[0372] In some embodiments, the antigen binding molecules of the present disclosure comprise an Fc region that comprises a modification, hi some embodiments, the antigen binding molecules of the present disclosure comprise an Fc region that comprises a modification in one or more of the CH2 and / or CH3 regions.

[0373] In some embodiments, the Fc region comprises a modification to increase an Fc-mediated function. In some embodiments, the Fc region comprises a modification to increase ADCC. In some embodiments, the Fc region comprises a modification to increase ADCP. In some embodiments, the Fc region comprises a modification to increase CDC. Antigen binding molecules comprising an Fc region comprising a modification to increase an Fc-mediated function (e.g., ADCC, ADCP, CDC) induce increased levels of the relevant effector function compared to an antigen binding molecule comprising a corresponding unmodified Fc region.

[0374] In some embodiments, the Fc region comprises a modification that increases binding to an Fc receptor. In some embodiments, the Fc region comprises a modification that increases binding to an Fcγ receptor. In some embodiments, the Fc region comprises a modification that increases binding to one or more of FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, and FcγRIIIb. In some embodiments, the Fc region comprises a modification that increases binding to FcγRIIIa. In some embodiments, the Fc region comprises a modification that increases binding to FcγRIIa. In some embodiments, the Fc region comprises a modification that increases binding to FcγRIIb. In some embodiments, the Fc region comprises a modification that increases binding to FcRn. In some embodiments, the Fc region comprises a modification that increases binding to a complement protein. In some embodiments, the Fc region comprises a modification that increases binding to C1q. In some embodiments, the Fc region comprises a modification to promote hexamerization of the antigen-binding molecule. In some embodiments, the Fc region comprises a modification to increase the half-life of the antigen-binding molecule. In some embodiments, the Fc region comprises modifications to increase simultaneous binding.

[0375] In some embodiments, the Fc region comprises modifications corresponding to the combination of substitutions F243L / R292P / Y300L / V305I / P396L, as described in Stavenhagen et al. Cancer Res. (2007) 67:8882-8890. In some embodiments, the Fc region comprises modifications 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 modifications 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 modifications to one of the heavy chain polypeptides corresponding to the combination of substitutions L234Y / L235Q / G236W / S239M / H268D / D270E / S298A, and modifications to the other heavy chain polypeptide corresponding to the combination of substitutions D270E / K326D / A330M / K334E, as described by Mimoto et al., MAbs. (2013):5:229-236. In some embodiments, the Fc region comprises modifications corresponding to the combination of substitutions G236A / S239D / I332E, as described by Richards et al., Mol Cancer Ther. (2008)7:2517-2527.

[0376] In some embodiments, the Fc region comprises modifications 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 modifications 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 modifications 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 modifications corresponding to the combination of substitutions E345R / E430G / S440Y as described in Diebolder et al. Science (2014) 343(6176):1260-3.

[0377] In some embodiments, the Fc region comprises modifications corresponding to the combination of substitutions M252Y / S254T / T256E, as described in Dall'Acqua et al. J Immunol. (2002) 169:5171-5180.

[0378] 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 the 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 specific 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 the CH2-CH3 region of a reference Fc region: M252Y, S254T, or T256E (according to the EU numbering system).

[0379] These so-called "YTE" modifications, located at the CH2-CH3 interface of the Fc region, have been shown to increase binding affinity at pH 6.0 to the MHC class I fetal Fc receptor (FcRn), which is localized within the acidic endosomes of endothelial and hematopoietic cells, thereby increasing the efficient recycling of administered mAbs and extending their plasma half-life.

[0380] In some embodiments, the Fc region comprises modifications corresponding to the combination of substitutions M428L / N434S, as described in Zalevsky et al. Nat Biotechnol. (2010) 28:157-159.

[0381] In some embodiments, the Fc region comprises modifications 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 modifications corresponding to the combination of substitutions N325S / L328F as described in Shang et al., Biol Chem. (2014) 289:15309-15318.

[0382] In some embodiments, the Fc region comprises a modification to reduce / prevent an Fc-mediated function. In some embodiments, the Fc region comprises a modification to reduce / prevent ADCC. In some embodiments, the Fc region comprises a modification to reduce / prevent ADCP. In some embodiments, the Fc region comprises a modification to reduce / prevent CDC. Antigen binding molecules comprising an Fc region comprising a modification to reduce / prevent an Fc-mediated function (e.g., ADCC, ADCP, CDC) induce a reduced level of the relevant effector function compared to an antigen binding molecule comprising a corresponding unmodified Fc region.

[0383] In some embodiments, the Fc region comprises a modification to reduce / prevent binding to an Fc receptor. In some embodiments, the Fc region comprises a modification to reduce / prevent binding to an Fcγ receptor. In some embodiments, the Fc region comprises a modification to reduce / prevent binding to one or more of FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, and FcγRIIIb. In some embodiments, the Fc region comprises a modification to reduce / prevent binding to FcγRIIIa. In some embodiments, the Fc region comprises a modification to reduce / prevent binding to FcγRIIa. In some embodiments, the Fc region comprises a modification to reduce / prevent binding to FcγRIIb. In some embodiments, the Fc region comprises a modification to reduce / prevent binding to complement proteins. In some embodiments, the Fc region comprises a modification to reduce / prevent binding to C1q. In some embodiments, the Fc region comprises a modification to reduce / prevent glycosylation of the amino acid residue corresponding to N297.

[0384] In some embodiments, the Fc region is unable to induce one or more Fc-mediated functions (i.e., lacks the ability to induce 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 lacking the relevant function(s).

[0385] In some embodiments, the Fc region is unable to induce ADCC. In some embodiments, the Fc region is unable to induce ADCP. In some embodiments, the Fc region is unable to induce CDC. In some embodiments, the Fc region is unable to induce ADCC and / or is unable to induce ADCP and / or is unable to induce CDC.

[0386] In some embodiments, the Fc region is unable to bind to an Fc receptor. In some embodiments, the Fc region is unable to bind to an Fcγ receptor. In some embodiments, the Fc region is unable to bind to one or more of FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, and FcγRIIIb. In some embodiments, the Fc region is unable to bind to FcγRIIIa. In some embodiments, the Fc region is unable to bind to FcγRIIa. In some embodiments, the Fc region is unable to bind to FcγRIIb. In some embodiments, the Fc region is unable to bind to FcRn. In some embodiments, the Fc region is unable to bind complement proteins. In some embodiments, the Fc region is unable to bind C1q. In some embodiments, the Fc region is not glycosylated at the amino acid residue corresponding to N297.

[0387] In some embodiments, the Fc region comprises a 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 a modification corresponding to L235E, as described in Alegre et al., J Immunol. (1992) 148:3461-3468. In some embodiments, the Fc region comprises a 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 a modification corresponding to P329A or P329G, as described in Schlothauer et al., Protein Engineering, Design and Selection (2016), 29(10):457-466. In some embodiments, the Fc region comprises modifications 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 modifications corresponding to the combination of substitutions as described in Rother et al., Nat Biotechnol. (2007) 25:1256-1264. In some embodiments, the Fc region comprises modifications 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 modifications 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 modifications corresponding to the combination of substitutions V234A / G237A / P238S / H268A / V309L / A330S / P331S, as described in Vafa et al., Methods. (2014) 65:114-126.In some embodiments, the Fc region comprises modifications corresponding to the combination of substitutions L234A / L235E / G237A / A330S / P331S, as described in US 2015 / 0044231 A1.

[0388] The combination of substitutions "L234A / L235A" and corresponding substitutions (e.g., F234A / L235A in human IgG4) is known to disrupt Fc binding to Fcγ receptors, inhibit ADCC, ADCP, and reduce C1q binding and, therefore, CDC (Schlothauer et al., Protein Engineering, Design and Selection (2016), 29(10):457-466, incorporated herein by reference in its entirety). The substitutions "P329G" and "P329A" reduce C1q binding (and thereby reduce CDC). Substitution of "N297" with "A," "G," or "Q" is known to eliminate glycosylation, thereby reducing Fc binding to C1q and Fcγ receptors, and, therefore, CDC and ADCC. Lo et al. J. Biol. Chem (2017) 292(9):3900-3908 (incorporated herein by reference in its entirety) report that the combination of substitutions L234A / L235A / P329G abrogates complement binding and fixation, as well as Fcγ receptor-dependent, antibody-dependent, cell-mediated cytotoxicity in both mouse IgG2a and human IgG1.

[0389] The combination of substitutions L234A / L235E / G237A / A330S / P331S in IgG1 Fc is disclosed in US2015 / 0044231 A1 to abolish the induction of phagocytosis, ADCC and CDC.

[0390] In some embodiments, the Fc region comprises a modification corresponding to the substitution S228P, as described in Silva et al., J Biol Chem. (2015) 290(9):5462-5469. The S228P substitution in an IgG4 Fc reduces Fab arm exchange, which may be undesirable.

[0391] In some embodiments, the Fc region comprises a modification corresponding to the combination of substitutions L234A / L235A. In some embodiments, the Fc region comprises a modification corresponding to substitution P329G. In some embodiments, the Fc region comprises a modification corresponding to substitution N297Q.

[0392] In some embodiments, the Fc region comprises modifications corresponding to the combination of substitutions L234A / L235A / P329G.

[0393] In some embodiments, the Fc region comprises modifications corresponding to the combination of substitutions L234A / L235A / P329G / N297Q.

[0394] In some embodiments, the Fc region comprises modifications corresponding to the combination of substitutions L234A / L235E / G237A / A330S / P331S.

[0395] In some embodiments, the Fc region comprises a modification corresponding to, for example, the substitution S228P in IgG4.

[0396] In some embodiments, particularly in embodiments in which the antigen-binding molecule is a multispecific (e.g., bispecific) antigen-binding molecule, the antigen-binding molecule comprises an Fc region containing modifications in one or more of the CH2 and CH3 regions that promote assembly of the Fc regions. Recombinant coexpression and subsequent assembly of the constituent polypeptides of an antigen-binding molecule results in several possible combinations. In recombinant production, to improve the yield of the desired combination of polypeptides in the antigen-binding molecule, it is advantageous to introduce modification(s) into the Fc region that promote assembly of the desired combination of heavy chain polypeptides. The modifications may, for example, promote hydrophobic and / or electrostatic interactions between the CH2 and / or CH3 regions of different polypeptide chains. Suitable modifications are described, for example, in Ha et al., Front. Immnol (2016) 7:394, the entire contents of which are incorporated herein by reference.

[0397] In some embodiments, an antigen binding molecule of the present disclosure comprises an Fc region, wherein the Fc region comprises paired substitutions in the CH3 region of the Rc region according to any of the following formats shown in Table 1 of Ha et al., Front: Immunol (2016) 7:394: KiH, KiH s-s , HA-TF, ZW1, 7.8.60, DD-KK, EW-RVT, EW-RVT s-s , SEED or A107.

[0398] Certain Exemplary Polypeptides and Antigen-Binding Molecules The present disclosure also provides polypeptide components of antigen-binding molecules. The polypeptides may be provided in isolated or substantially purified form.

[0399] The antigen-binding molecules of the present disclosure may be or may comprise a complex of polypeptides.

[0400] As used herein, it will be understood that when a polypeptide comprises multiple domains or regions, the multiple domains / regions are preferably present on the same polypeptide chain, i.e., a polypeptide comprising multiple domains or regions is a fusion polypeptide comprising the domains / regions.

[0401] In some embodiments, a polypeptide of the present disclosure comprises or consists of a VH described herein. In some embodiments, a polypeptide of the present disclosure comprises or consists of a VL described herein.

[0402] In some embodiments, the polypeptide further comprises one or more antibody heavy chain constant regions (CH). In some embodiments, the polypeptide further comprises one or more antibody light chain constant regions (CL). In some embodiments, the polypeptide comprises a CH1, CH2 and / or CH3 region of an immunoglobulin (Ig).

[0403] 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 described herein. In some embodiments, the polypeptide comprises a CH1-CH2 hinge region described herein. In some embodiments, the polypeptide comprises a CH2 region described herein. In some embodiments, the polypeptide comprises a CH3 region described herein.

[0404] In some embodiments, the polypeptide comprises one or more regions of an immunoglobulin light chain constant sequence, hi some embodiments, the polypeptide comprises a CL region as described herein.

[0405] In some embodiments, a polypeptide according to the present disclosure comprises an N-terminal to C-terminal structure according to one of the following: (i) VH (ii) VL (iii) VH-CH1 (iv) VL-CL (v) VL-CH1 (vi) VH-CL (vii) VH-CH1-CH2-CH3 (viii) VL-CL-CH2-CH3 (ix) VL-CH1-CH2-CH3 (x)VH-CL-CH2-CH3

[0406] Also provided by the present disclosure are antigen-binding molecules composed of the polypeptides of the present disclosure. In some embodiments, the antigen-binding molecules of the present disclosure comprise one of the following combinations of polypeptides: (A) VH + VL (B) VH-CH1 + VL-CL (C) VL-CH1 + VH-CL (D) VH-CH1-CH2-CH3 + VL-CL (E) VH-CL-CH2-CH3 + VL-CH1 (F) VL-CH1-CH2-CH3 + VH-CL (G) VL-CL-CH2-CH3 + VH-CH1 (H)VH-CH1-CH2-CH3 + VL-CL-CH2-CH3 (I)VH-CL-CH2-CH3 + VL-CH1-CH2-CH3

[0407] In some embodiments, the antigen-binding molecule comprises a plurality of polypeptides in the combinations shown in (A) to (I) above. For example, referring 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.

[0408] In some embodiments, the antigen binding molecules of the present disclosure comprise one of the following polypeptide combinations: (J) VH (anti-gp130) + VL (anti-gp130) (K)VH(anti-gp130)-CH1 + VL(anti-gp130)-CL (L)VL(anti-gp130)-CH1 + VH(anti-gp130)-CL (M)VH(anti-gp130)-CH1-CH2-CH3 + VL(anti-gp130)-CL (N)VH(anti-gp130)-CL-CH2-CH3 + VL(anti-gp130)-CH1 (O)VL(anti-gp130)-CH1-CH2-CH3 + VH(anti-gp130)-CL (P)VL(anti-gp130)-CL-CH2-CH3 + VH(anti-gp130)-CH1 (Q)VH(anti-gp130)-CH1-CH2-CH3 + VL(anti-gp130)-CL-CH2-CH3

[0409] In the formula, "VH(anti-gp130)" refers to the VH of an antigen-binding molecule capable of binding to gp130 described herein, for example, as defined in one of (1) to (115); and "VL(anti-gp130)" refers to the VL of an antigen-binding molecule capable of binding to gp130 described herein, for example, as defined in one of (116) to (229).

[0410] In some embodiments, the antigen binding molecule of the present disclosure is selected from the group consisting of SEQ ID NOs: 1, 17, 31, 36, 51, 74, 78, 80, 83, 106, 86, 87, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236 , 237, 238, 239, 240, 241, 242, 243 or 251, and polypeptides comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to , 237, 238, 239, 240, 241, 242, 243 or 251.

[0411] In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 221. In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 219. In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 241. In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 239. In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 220. In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 240.

[0412] In some embodiments, the antigen binding molecule of the present disclosure is selected from the group consisting of SEQ ID NOs: 9, 23, 34, 44, 57, 75, 88, 91, 95, 98, 100, 110, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 3 3, 274, 275, 276, 277, 278, 279, 280 or 287, and polypeptides comprising or consisting of an amino acid sequence having at least 70%, preferably 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 present invention.

[0413] In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 271. In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 269.

[0414] In some embodiments, the antigen binding molecule of the present disclosure is selected from the group consisting of SEQ ID NOs: 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, , 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348 or 349, or a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to

[0415] In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 295. In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 326. In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 315. In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 346. In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 293. In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 324.In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 313. In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 344. In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 294. In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 325. In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 314. In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 345.

[0416] In some embodiments, the antigen binding molecule of the present disclosure is selected from the group consisting of SEQ ID NOs: 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, ​​383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 71, 372, 373, 374, 375, 376, 377, 378, 379 or 380, or a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to 371, 372, 373, 374, 375, 376, 377, 378, 379 or 380.

[0417] In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 370. In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 373.

[0418] In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide(s) comprising a VH region comprising the heavy chain CDRs and a VL region comprising the light chain CDRs of an antibody selected from the antibodies set forth in Table A herein. That is, in some embodiments, the antigen-binding molecule comprises (i) a VH region comprising HC-CDR1, HC-CDR2, and HC-CDR3 set forth in column A of Table A, and (ii) a VL region comprising LC-CDR1, LC-CDR2, and LC-CDR3 set forth in column B of Table A, wherein the sequences in columns A and B are selected from the same row of Table A. In some embodiments, an antigen binding molecule of the disclosure comprises a polypeptide(s) comprising a VH region comprising the heavy chain CDRs and a VL region comprising the light chain CDRs of an antibody selected from 4D4CVH2_D53Q / 4D4GVL3_N93G, 4D4CVH2.2_D53Q / 4D4GVL3_N93G, 4D4CVH2_D53G / 4D4GVL3_N93Q, 4D4CVH2.2_D53G / 4D4GVL3_N93Q, 4D4CVH2_D53E / 4D4GVL3_N93G, and 4D4CVH2.2_D53E / 4D4GVL3_N93G (shown in Table A). In some embodiments, an antigen binding molecule of the disclosure comprises a polypeptide(s) comprising a VH region comprising the heavy chain CDRs and a VL region comprising the light chain CDRs of an antibody selected from 4D4CVH2_D53Q / 4D4GVL3_N93G, 4D4CVH2.2_D53Q / 4D4GVL3_N93G, 4D4CVH2_D53G / 4D4GVL3_N93Q, and 4D4CVH2.2_D53G / 4D4GVL3_N93Q (shown in Table A).

[0419] In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide(s) comprising a VH region comprising heavy chain FRs and a VL region comprising light chain FRs of an antibody selected from the antibodies set forth in Table B herein. That is, in some embodiments, the antigen-binding molecule comprises a polypeptide(s) comprising: (i) a VH region comprising HC-FR1, HC-FR2, HC-FR3, and HC-FR4 set forth in column A of Table B, and (ii) a VL region comprising a VL region comprising LC-FR1, LC-FR2, LC-FR3, and LC-FR4 set forth in column B of Table B, wherein the sequences in columns A and B are selected from the same row of Table B. In some embodiments, an antigen binding molecule of the disclosure comprises a polypeptide(s) comprising a VH region comprising a heavy chain FR and a VL region comprising a light chain FR of an antibody selected from 4D4CVH2_D53Q / 4D4GVL3_N93G, 4D4CVH2.2_D53Q / 4D4GVL3_N93G, 4D4CVH2_D53G / 4D4GVL3_N93Q, 4D4CVH2.2_D53G / 4D4GVL3_N93Q, 4D4CVH2_D53E / 4D4GVL3_N93G, and 4D4CVH2.2_D53E / 4D4GVL3_N93G (shown in Table B). In some embodiments, an antigen binding molecule of the disclosure comprises a polypeptide(s) comprising a VH region comprising a heavy chain FR and a VL region comprising a light chain FR of an antibody selected from 4D4CVH2_D53Q / 4D4GVL3_N93G, 4D4CVH2.2_D53Q / 4D4GVL3_N93G, 4D4CVH2_D53G / 4D4GVL3_N93Q, and 4D4CVH2.2_D53G / 4D4GVL3_N93Q (shown in Table B).

[0420] In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide(s) comprising: (i) an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to the amino acid sequence shown in column A of Table C; and (ii) an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to the amino acid sequence shown in column B of Table C, wherein the sequences in columns A and B are selected from the same row of Table C.

[0421] In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide(s) comprising the VH region and the VL region of an antibody clone selected from the antibodies shown in Table C herein. That is, in some embodiments, the antigen-binding molecule comprises a polypeptide(s) comprising (i) the amino acid sequence shown in column A of Table C, and (ii) the amino acid sequence shown in column B of Table C, wherein the sequences in columns A and B are selected from the same row of Table C. In some embodiments, an antigen binding molecule of the disclosure comprises a polypeptide(s) comprising the VH and VL regions of an antibody clone selected from 4D4CVH2_D53Q / 4D4GVL3_N93G, 4D4CVH2.2_D53Q / 4D4GVL3_N93G, 4D4CVH2_D53G / 4D4GVL3_N93Q, 4D4CVH2.2_D53G / 4D4GVL3_N93Q, 4D4CVH2_D53E / 4D4GVL3_N93G, and 4D4CVH2.2_D53E / 4D4GVL3_N93G (shown in Table C). In some embodiments, an antigen binding molecule of the disclosure comprises a polypeptide(s) comprising the VH and VL regions of an antibody clone selected from 4D4CVH2_D53Q / 4D4GVL3_N93G, 4D4CVH2.2_D53Q / 4D4GVL3_N93G, 4D4CVH2_D53G / 4D4GVL3_N93Q, and 4D4CVH2.2_D53G / 4D4GVL3_N93Q (shown in Table C).

[0422] In some embodiments, an antigen-binding molecule of the present disclosure comprises (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to the amino acid sequence shown in column A of Table D, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to the amino acid sequence shown in column B of Table D, wherein the sequences in columns A and B are selected from the same row of Table D.

[0423] In some embodiments, an antigen-binding molecule of the present disclosure comprises a polypeptide of an antigen-binding molecule according to Table D herein. That is, in some embodiments, the antigen-binding molecule comprises (i) a polypeptide comprising or consisting of an amino acid sequence set forth in column A of Table D, and (ii) a polypeptide comprising or consisting of an amino acid sequence set forth in column B of Table D, wherein the sequences in columns A and B are selected from the same row of Table D.

[0424] In some embodiments, the antigen-binding molecules of the present disclosure include (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 295, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 370. In some embodiments, the antigen-binding molecules of the present disclosure include (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 326, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 370.

[0425] In some embodiments, the antigen-binding molecules of the present disclosure include (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 315, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 370. In some embodiments, the antigen-binding molecules of the present disclosure include (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 346, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 370.

[0426] In some embodiments, antigen-binding molecules of the present disclosure include (i) polypeptides comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 293, and (ii) polypeptides comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 373. In some embodiments, the antigen-binding molecules of the present disclosure include (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 324, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 373.

[0427] In some embodiments, antigen-binding molecules of the present disclosure include (i) polypeptides comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 313, and (ii) polypeptides comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 373. In some embodiments, the antigen-binding molecules of the present disclosure include (i) polypeptides comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 344, and (ii) polypeptides comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 373.

[0428] In some embodiments, antigen-binding molecules of the present disclosure include (i) polypeptides comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 294, and (ii) polypeptides comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 370. In some embodiments, antigen-binding molecules of the present disclosure include (i) polypeptides comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 325, and (ii) polypeptides comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 370.

[0429] In some embodiments, antigen-binding molecules of the present disclosure include (i) polypeptides comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 314, and (ii) polypeptides comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 370. In some embodiments, the antigen-binding molecules of the present disclosure include (i) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 345, and (ii) a polypeptide comprising or consisting of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity to SEQ ID NO: 370.

[0430] Functional properties of antigen-binding molecules The antigen-binding molecules described herein may be characterized by reference to certain functional properties. In some embodiments, the antigen-binding molecules described herein may have one or more of the following properties: binds to gp130 (e.g., human gp130, mouse gp130, rat gp130, and / or non-human primate gp130); binds to gp130-expressing cells; inhibits signal transduction mediated by gp130-containing receptors; inhibits signal transduction mediated by gp130:IL-6Rα and / or gp130:IL-11Rα; inhibits signal transduction mediated by cytokines binding to gp130-containing receptors; inhibiting IL-6 and / or IL-11-mediated signaling; does not inhibit signaling mediated by gp130:OSMRβ, gp130:LIFRβ, gp130:LIFRβ:CNTFRα, gp130:IL-27Rα, and / or gp130:IL-12Rβ2; does not inhibit OSM-, LIF-, CNTF-, CT-1-, CLC-, IL-27- and / or IL-35-mediated signaling; reducing inflammation and / or fibrosis; reducing the pathology of diseases / conditions characterized by inflammation and / or fibrosis; and / or Increased killing of cells expressing gp130.

[0431] It will be understood that a given antigen-binding molecule may exhibit more than one of the properties listed in the previous paragraph. A given antigen-binding molecule can be evaluated for the properties detailed in the preceding paragraph using an appropriate assay. For example, the assay may be, for example, an in vitro assay, optionally a cell-based assay or a cell-free assay. In some embodiments, the assay may be, for example, an in vivo assay, i.e., performed in a non-human animal. In some embodiments, the assay may be, for example, an ex vivo assay, i.e., an assay performed using cells / tissues / organs obtained from a subject.

[0432] When the assay is a cell-based assay, it may involve treating cells with a given antigen-binding molecule to determine whether the antigen-binding molecule exhibits one or more of the listed properties. The assay may use species labeled with a detectable substance to facilitate their detection. The assay may involve treating cells separately with a range of amounts / concentrations of the given antigen-binding molecule (e.g., a dilution series) and then evaluating the listed properties. It will be understood that the cells preferably express the target antigen (i.e., gp130) for the antigen-binding molecule.

[0433] Analysis of the results of such assays may include determining the concentration at which 50% of the maximal level of the relevant activity is achieved. The concentration of a given drug at which 50% of the maximal level of the relevant activity is achieved is sometimes referred to as the "half-maximal effective concentration" of the drug for the relevant activity, which is known as the "EC 50 For example, the EC of a given antigen-binding molecule for binding to human gp130 may be 50 may be the concentration of an antigen-binding molecule at which 50% of the maximal level of binding to human gp130 is achieved.

[0434] Depending on the characteristics, EC 50 is also known as the "half-maximal inhibitory concentration" or "IC 50 ", which is the concentration of an agent at which 50% of the maximal level of inhibition of a given property is observed.

[0435] The antigen binding molecules described herein bind to gp130. In some embodiments, the antigen binding 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 monkey gp130. In some embodiments, the antigen binding molecule binds to canine gp130. In some embodiments, the antigen binding molecule binds to human gp130 and mouse gp130. In some embodiments, the antigen binding molecule binds to human gp130 and rat gp130. In some embodiments, the antigen binding molecule binds to human gp130, mouse gp130, and rat gp130.

[0436] The antigen-binding molecules and antigen-binding domains described herein preferably exhibit specific binding to gp130. As used herein, "specific binding" refers to selective binding to an antigen, which can be distinguished from non-specific binding to non-target antigens. Antigen-binding molecules / domains that specifically bind to a target molecule preferably bind to the relevant target with higher affinity and / or longer duration than they bind to other non-target molecules.

[0437] The ability of a given polypeptide to specifically bind to a given molecule can be determined by analyzing according to methods known in the art, for example, by ELISA, surface plasmon resonance (SPR; see, e.g., Hardy et al., Methods Mol Biol (2012) 907:411-442), biolayer interferometry (BLI; see, e.g., Lad et al., (2015) J Biomol Screen 20(4):498-507), flow cytometry, or radiolabeled antigen binding assay (RIA) enzyme-linked immunosorbent assay. Such analysis can measure and quantitate binding to a given molecule. In some embodiments, binding can be a response detected in a given assay.

[0438] In some embodiments, the degree of binding of the antigen-binding molecule to the non-target molecule is less than about 10% of the binding of the antibody to the target molecule, as measured, for example, by ELISA, SPR, BLI, or RIA. Alternatively, binding specificity may be reflected in terms of binding affinity, where the K of the antigen-binding molecule to the non-target molecule is less than about 10% of the binding of the antibody to the target molecule, as measured, for example, by ELISA, SPR, BLI, or RIA. D at least 0.1 orders of magnitude (i.e., 0.1 × 10 n , where n is an integer representing the number of digits) D ), which may optionally be at least one of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, or 2.0.

[0439] The binding affinity of the antigen-binding molecules described herein to a given target antigen can be determined by SPR, for example, as described in the Examples of the present disclosure.

[0440] In some embodiments, the antigen binding molecules described herein have affinities in the micromolar range, i.e., K D =9.9×10 -4 ~1×10 -6In some embodiments, the antigen binding molecules described herein bind to gp130 with submicromolar affinity, i.e., K D <1×10 -6 In some embodiments, the antigen binding molecules described herein bind to gp130 with an affinity in the nanomolar range, i.e., K D =9.9×10 -7 ~1×10 -9 In some embodiments, the antigen binding molecules described herein bind to gp130 with subnanomolar affinity, i.e., K D <1×10 -9 In some embodiments, the antigen binding molecules described herein bind to gp130 with an affinity in the picomolar range, i.e., K D =9.9×10 -10 ~1×10 -12 In some embodiments, the antigen binding molecules described herein bind to gp130 with sub-picomolar affinity, i.e., K D <1×10 -12 Binds to gp130 at M.

[0441] In some embodiments, the antigen binding molecule described herein binds to human gp130 isoform 1 and binds to K D or less, preferably one of <5 μM, <2 μM, <1 μM, <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 (determined by analysis, for example, as described in Example 4 herein). In some embodiments, the antigen binding molecule described herein binds to human gp130 isoform 1 and binds to K DIn some embodiments, the antigen binding molecule described herein binds to human gp130 isoform 1 with a K 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 (determined by analysis, e.g., as described in Example 4 herein). D In some embodiments, the antigen binding molecules described herein bind to human gp130 isoform 1 with a K 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. D binds at 1 nM or less, preferably at one of ≦900 pM, ≦800 pM, ≦700 pM, ≦600 pM, ≦500 pM, ≦400 pM, ≦300 pM, ≦200 pM or ≦100 pM (as determined by analysis, e.g., as described in Examples 4 or 25 herein).

[0442] In some embodiments, the antigen binding molecules described herein bind to human gp130 isoform 1 and / or EC 50 or less, preferably one of ≦5 μM, ≦2 μM, ≦1 μM, ≦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.

[0443] The antigen-binding molecules of the present disclosure can bind to specific target regions of gp130. The antigen-binding molecules of the present disclosure can bind to linear epitopes of gp130 consisting of a continuous sequence of amino acids (i.e., a primary amino acid sequence). In some embodiments, the antigen-binding molecules can bind to conformational epitopes of gp130 consisting of a discontinuous sequence of amino acids in the amino acid sequence.

[0444] The region of a given target molecule to which an antigen-binding molecule binds can be determined by those skilled in the art using a variety of methods known in the art, including X-ray cocrystallography of antibody-antigen complexes, peptide scanning, mutagenesis mapping, mass spectrometric hydrogen-deuterium exchange analysis, phage display, competitive ELISA, and proteolysis-based "protection" methods. Such methods are described, for example, in Gershoni et al., BioDrugs, 2007, 21(3):145-156, the entire contents of which are incorporated herein by reference.

[0445] 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 a region of gp130 set forth in SEQ ID NO: 134. In some embodiments, the antigen binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 134.

[0446] In some embodiments, the antigen binding molecule of the present disclosure does not bind to the cytokine binding module of gp130. In some embodiments, the antigen binding molecule does not bind to the region of gp130 set forth in SEQ ID NO: 144. In some embodiments, the antigen binding molecule does not contact the region of gp130 set forth in SEQ ID NO: 144. In some embodiments, the antigen binding molecule does not bind to gp130 through contact with one or more amino acids in the region set forth in SEQ ID NO: 144. In some embodiments, the antigen binding molecule does not bind to a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 144.

[0447] In some embodiments, the antigen binding molecule of the present disclosure binds to the membrane proximal region of gp130. In some embodiments, the antigen binding molecule binds to the region of gp130 set forth in SEQ ID NO: 388. In some embodiments, the antigen binding molecule contacts the region of gp130 set forth in SEQ ID NO: 388. In some embodiments, the antigen binding molecule binds to gp130 through contact with one or more amino acids in the region set forth in SEQ ID NO: 388. In some embodiments, the antigen binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 388.

[0448] In some embodiments, the antigen binding molecule binds to a region of gp130 set forth in SEQ ID NO: 169, SEQ ID NO: 170, and / or SEQ ID NO: 171. In some embodiments, the antigen binding molecule contacts a region of gp130 set forth in SEQ ID NO: 169, SEQ ID NO: 170, and / or SEQ ID NO: 171. In some embodiments, the antigen binding molecule binds to gp130 through contact with one or more amino acids in the region set forth in SEQ ID NO: 169, SEQ ID NO: 170, and / or SEQ ID NO: 171. In some embodiments, the epitope of the antigen binding molecule comprises or consists of the amino acid sequence set forth in SEQ ID NO: 169, SEQ ID NO: 170, and / or SEQ ID NO: 171. In some embodiments, the antigen binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 169, SEQ ID NO: 170, and / or SEQ ID NO: 171. In some embodiments, the antigen binding molecule binds to a region of gp130 set forth in SEQ ID NO: 172. In some embodiments, the antigen binding molecule contacts a region of gp130 set forth in SEQ ID NO: 172. In some embodiments, the antigen-binding molecule binds to gp130 through contact with one or more amino acids in the region set forth in SEQ ID NO: 172. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence set forth in SEQ ID NO: 172. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 172.

[0449] In some embodiments, the antigen binding molecule binds to a region of gp130 set forth in SEQ ID NO: 173 and / or SEQ ID NO: 174. In some embodiments, the antigen binding molecule contacts a region of gp130 set forth in SEQ ID NO: 173 and / or SEQ ID NO: 174. In some embodiments, the antigen binding molecule binds to gp130 through contact with one or more amino acids in the region set forth in SEQ ID NO: 173 and / or SEQ ID NO: 174. In some embodiments, the epitope of the antigen binding molecule comprises or consists of the amino acid sequence set forth in SEQ ID NO: 173 and / or SEQ ID NO: 174. In some embodiments, the antigen binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 173 and / or SEQ ID NO: 174. In some embodiments, the antigen binding molecule binds to a region of gp130 set forth in SEQ ID NO: 175. In some embodiments, the antigen binding molecule contacts a region of gp130 set forth in SEQ ID NO: 175. In some embodiments, the antigen binding molecule binds to gp130 through contact with one or more amino acids in the region set forth in SEQ ID NO: 175. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence set forth in SEQ ID NO: 175. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 175.

[0450] In some embodiments, the antigen binding molecule binds to a region of gp130 set forth in SEQ ID NO: 176, SEQ ID NO: 177, and / or SEQ ID NO: 178. In some embodiments, the antigen binding molecule contacts a region of gp130 set forth in SEQ ID NO: 176, SEQ ID NO: 177, and / or SEQ ID NO: 178. In some embodiments, the antigen binding molecule binds to gp130 through contact with one or more amino acids in the region set forth in SEQ ID NO: 176, SEQ ID NO: 177, and / or SEQ ID NO: 178. In some embodiments, the epitope of the antigen binding molecule comprises or consists of the amino acid sequence set forth in SEQ ID NO: 176, SEQ ID NO: 177, and / or SEQ ID NO: 178. In some embodiments, the antigen binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 176, SEQ ID NO: 177, and / or SEQ ID NO: 178. In some embodiments, the antigen binding molecule binds to a region of gp130 set forth in SEQ ID NO: 179. In some embodiments, the antigen binding molecule contacts a region of gp130 set forth in SEQ ID NO: 179. In some embodiments, the antigen-binding molecule binds to gp130 through contact with one or more amino acids in the region set forth in SEQ ID NO: 179. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence set forth in SEQ ID NO: 179. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 179.

[0451] In some embodiments, the antigen binding molecule binds to a region of gp130 set forth in SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 382, ​​and / or SEQ ID NO: 385. In some embodiments, the antigen binding molecule contacts a region of gp130 set forth in SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 382, ​​and / or SEQ ID NO: 385. In some embodiments, the antigen binding molecule binds to gp130 through contact with one or more amino acids in the region set forth in SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 382, ​​and / or SEQ ID NO: 385. In some embodiments, the epitope of the antigen binding molecule comprises or consists of the amino acid sequence set forth in SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 382, ​​and / or SEQ ID NO: 385. In some embodiments, the antigen binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 382, ​​and / or SEQ ID NO: 385. In some embodiments, the antigen binding molecule binds to a region of gp130 set forth in SEQ ID NO: 182. In some embodiments, the antigen binding molecule contacts a region of gp130 set forth in SEQ ID NO: 182. In some embodiments, the antigen binding molecule binds to gp130 through contact with one or more amino acids in the region set forth in SEQ ID NO: 182. In some embodiments, the epitope of the antigen binding molecule comprises or consists of the amino acid sequence set forth in SEQ ID NO: 182. In some embodiments, the antigen binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 182. In some embodiments, the antigen binding molecule binds to a region of gp130 set forth in SEQ ID NO: 386. In some embodiments, the antigen binding molecule contacts a region of gp130 set forth in SEQ ID NO: 386. In some embodiments, the antigen binding molecule binds to gp130 through contact with one or more amino acids in the region set forth in SEQ ID NO: 386. In some embodiments, the epitope of the antigen binding molecule comprises or consists of the amino acid sequence set forth in SEQ ID NO: 386. In some embodiments, the antigen binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 386.

[0452] In some embodiments, the antigen binding molecule binds to a region of gp130 set forth in SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 381, and / or SEQ ID NO: 382. In some embodiments, the antigen binding molecule contacts a region of gp130 set forth in SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 381, and / or SEQ ID NO: 382. In some embodiments, the antigen binding molecule binds to gp130 through contact with one or more amino acids in the region set forth in SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 381, and / or SEQ ID NO: 382. In some embodiments, the epitope of the antigen binding molecule comprises or consists of the amino acid sequence set forth in SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 381, and / or SEQ ID NO: 382. In some embodiments, the antigen binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 381, and / or SEQ ID NO: 382. In some embodiments, the antigen binding molecule binds to a region of gp130 set forth in SEQ ID NO: 185. In some embodiments, the antigen binding molecule contacts a region of gp130 set forth in SEQ ID NO: 185. In some embodiments, the antigen binding molecule binds to gp130 through contact with one or more amino acids in the region set forth in SEQ ID NO: 185. In some embodiments, the epitope of the antigen binding molecule comprises or consists of the amino acid sequence set forth in SEQ ID NO: 185. In some embodiments, the antigen binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 185. In some embodiments, the antigen binding molecule binds to a region of gp130 set forth in SEQ ID NO: 383. In some embodiments, the antigen binding molecule contacts a region of gp130 set forth in SEQ ID NO: 383. In some embodiments, the antigen binding molecule binds to gp130 through contact with one or more amino acids in the region set forth in SEQ ID NO: 383. In some embodiments, the epitope of the antigen binding molecule comprises or consists of the amino acid sequence set forth in SEQ ID NO: 383. In some embodiments, the antigen binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 383.In some embodiments, the antigen binding molecule binds to a region of gp130 set forth in SEQ ID NO: 384. In some embodiments, the antigen binding molecule contacts a region of gp130 set forth in SEQ ID NO: 384. In some embodiments, the antigen binding molecule binds to gp130 through contact with one or more amino acids in the region set forth in SEQ ID NO: 384. In some embodiments, the epitope of the antigen binding molecule comprises or consists of the amino acid sequence set forth in SEQ ID NO: 384. In some embodiments, the antigen binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 384.

[0453] In some embodiments, the antigen binding molecule binds to a region of gp130 set forth in SEQ ID NO: 186 and / or SEQ ID NO: 187. In some embodiments, the antigen binding molecule contacts a region of gp130 set forth in SEQ ID NO: 186 and / or SEQ ID NO: 187. In some embodiments, the antigen binding molecule binds to gp130 through contact with one or more amino acids in the region set forth in SEQ ID NO: 186 and / or SEQ ID NO: 187. In some embodiments, the epitope of the antigen binding molecule comprises or consists of the amino acid sequence set forth in SEQ ID NO: 186 and / or SEQ ID NO: 187. In some embodiments, the antigen binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 186 and / or SEQ ID NO: 187. In some embodiments, the antigen binding molecule binds to a region of gp130 set forth in SEQ ID NO: 188. In some embodiments, the antigen binding molecule contacts a region of gp130 set forth in SEQ ID NO: 188. In some embodiments, the antigen binding molecule binds to gp130 through contact with one or more amino acids in the region set forth in SEQ ID NO: 188. In some embodiments, the epitope of the antigen-binding molecule comprises or consists of the amino acid sequence set forth in SEQ ID NO: 188. In some embodiments, the antigen-binding molecule binds to a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 188.

[0454] The ability of an antigen-binding molecule to bind to a given peptide / polypeptide can be analyzed by methods well known to those skilled in the art, including ELISA, immunoblot (e.g., Western blot), immunoprecipitation, SPR, and BLI analysis.

[0455] In some embodiments, the antigen binding molecule is capable of binding to a region of gp130 that is identical to, or an overlapping region of gp130, a region that binds to gp130 by an antibody comprising the VH and VL regions of the antibodies shown in Table C (see, e.g., Table C).

[0456] Whether a test antigen-binding molecule binds to the same or overlapping region as a given target as a reference antigen-binding molecule can be evaluated, for example, by analyzing (i) the interaction between the test antigen-binding molecule and the target in the absence of the reference antigen-binding molecule, and (ii) the interaction between the test antigen-binding molecule in the presence of the reference antigen-binding molecule, or the interaction after incubating the target with the reference antigen-binding molecule. A determination that the level of interaction between the test antigen-binding molecule and the target after analysis by (ii) is reduced compared to (i) may support the assumption that the test antigen-binding molecule and the reference antigen-binding molecule bind to the same or overlapping region as the target. Suitable assays for such analysis include, for example, competitive ELISA assays and epitope binning assays.

[0457] In some embodiments, the antigen binding molecule of the present disclosure binds to gp130 in a region accessible to antigen binding molecules (i.e., extracellular antigen binding molecules) when gp130 is expressed on the cell surface (i.e., in or on the cell membrane). In some embodiments, the antigen binding molecule binds to gp130 expressed on the cell surface of cells that express gp130. In some embodiments, the antigen binding molecule binds to gp130-expressing cells (e.g., fibroblasts). In some embodiments, the antigen binding molecule does not bind (i.e., does not substantially bind) to cells that lack surface expression of gp130.

[0458] The ability of an antigen-binding molecule to bind to a given cell type (e.g., a cell that expresses gp130 or a cell that does not express gp130) can be analyzed by contacting the cell with the antigen-binding molecule and detecting the antigen-binding molecule bound to the cell, for example, 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 analyzed by methods such as flow cytometry and immunofluorescence microscopy.

[0459] In some embodiments, the antigen binding molecules of the present disclosure inhibit signal transduction mediated by gp130-containing receptors. In some embodiments, the antigen binding molecules inhibit gp130-mediated signal transduction (e.g., gp130-mediated signal transduction described herein above). Signal transduction mediated by gp130 and / or by gp130-containing receptors can be analyzed using cells expressing gp130 / associated receptors, for example, using assays for detecting and / or quantitating gp130-mediated signal transduction. Suitable assays include, for example, assays for detecting the phosphorylation / activity / expression of factors that are phosphorylated / activated / expressed as a result of signal transduction via gp130 / gp130-containing receptors.

[0460] Such assays may involve contacting cells expressing a given cytokine receptor, including gp130, with an antigen binding molecule according to the present disclosure, for example, in the presence of a ligand for the cytokine receptor. By way of example, an assay to investigate the ability of an antigen binding molecule to inhibit IL-6-mediated signaling and / or the ability of an antigen binding molecule to inhibit signaling mediated by gp130:IL-6Rα may involve contacting cells expressing the gp130:IL-6Rα complex with an antigen binding molecule according to the present disclosure, for example, in the presence of IL-6. As a further example, an assay to investigate the ability of an antigen binding molecule to inhibit IL-11-mediated signaling and / or the ability of an antigen binding molecule to inhibit signaling mediated by gp130:IL-11Rα may involve contacting cells expressing the gp130:IL-11Rα complex with an antigen binding molecule according to the present disclosure, for example, in the presence of IL-11.

[0461] For example, gp130-mediated signaling can be investigated by assessing the phosphorylation of one or more signaling molecules in a signaling pathway (e.g., the JAK / STAT, MAPK / ERK, or PI3K / AKT pathway) triggered by signaling through a gp130 / gp130-containing cytokine receptor. For example, the level of gp130-mediated signaling can be analyzed by detecting and / or quantifying the phosphorylation level of JAK1, JAK2, STAT1, STAT3, STAT5, and / or ERK (e.g., STAT3 and / or ERK). By way of example, in the experimental examples of the present disclosure, gp130-mediated signaling (particularly, signaling mediated by gp130:IL-6Rα in response to stimulation with IL-6 and signaling mediated by gp130:IL-11Rα in response to stimulation with IL-11) is analyzed by assessing the phosphorylation of STAT3 or ERK1 / 2 by Western blot (see, in particular, Example 11).

[0462] The level of gp130-mediated signaling can also be assessed by analyzing one or more correlates of gp130-mediated signaling. For example, gp130-mediated signaling can be investigated by detecting and / or quantifying the expression or activity of factors whose expression / activity is upregulated or downregulated as a result of gp130-mediated signaling. In some embodiments, gp130-mediated signaling can be investigated by detecting and / or quantifying the expression of factors whose expression is upregulated as a result of gp130-mediated signaling, such as pro-inflammatory / pro-fibrotic / fibroinflammatory factors. By way of example, in the experimental examples of the present disclosure, gp130-mediated signaling (particularly signaling mediated by gp130:IL-11Rα in response to stimulation with IL-11) is analyzed by assessing the expression of αSMA and MMP2.

[0463] The level of gp130-mediated signaling can also be analyzed using reporter-based methods. For example, gp130-mediated signaling can be investigated using a reporter cell line stably expressing a luciferase reporter driven by gp130-mediated signaling. For example, in the experimental examples of the present disclosure, gp130-mediated signaling is investigated using a HEK293 reporter cell line containing a luciferase gene under the control of a STAT3 response element (STAT3 Reporter (Luc)-HEK293 Cell Line (Puromycin), BPS Bioscience).

[0464] In some embodiments, the antigen binding molecule is capable of inhibiting gp130-mediated signaling and / or signaling by a receptor comprising gp130 by less than 1-fold, e.g., ≦0.99-fold, ≦0.95-fold, ≦0.9-fold, ≦0.85-fold, ≦0.8-fold, ≦0.75-fold, ≦0.7-fold, ≦0.65-fold, ≦0.6-fold, ≦0.55-fold, ≦0.5-fold, ≦0.45-fold, ≦0.4-fold, ≦0.35-fold, ≦0.3-fold, ≦0.25-fold, ≦0.2-fold, ≦0.15-fold, ≦0.1-fold, ≦0.05-fold, or ≦0.01-fold, of the signaling level observed in the absence of the antigen binding molecule (or in the presence of a suitable control antigen binding molecule, e.g., an antigen binding molecule known to have no effect on gp130-mediated signaling and / or signaling by a receptor comprising gp130).

[0465] In some embodiments, the antigen binding molecule inhibits IL-6-mediated signaling. In some embodiments, the antigen binding molecule inhibits IL-11-mediated signaling. In some embodiments, the antigen binding molecule inhibits IL-6-mediated signaling and inhibits IL-11-mediated signaling.

[0466] In some embodiments, the antigen binding molecule inhibits signal transduction mediated by gp130:IL-6Rα. In some embodiments, the antigen binding molecule inhibits signal transduction mediated by gp130:IL-11Rα. In some embodiments, the antigen binding molecule inhibits signal transduction mediated by gp130:IL-6Rα and inhibits signal transduction mediated by gp130:IL-11Rα.

[0467] In some embodiments, the antigen binding molecule inhibits signaling mediated by IL-6 binding to cells expressing gp130:IL-6Rα. In some embodiments, the antigen binding molecule inhibits signaling mediated by IL-11 binding to cells expressing gp130:IL-11Rα. In some embodiments, the antigen binding molecule inhibits signaling mediated by IL-6 binding to cells expressing gp130:IL-6Rα and inhibits signaling mediated by IL-11 binding to cells expressing gp130:IL-11Rα.

[0468] In some embodiments, the antigen binding molecule inhibits IL-6-mediated signaling / gp130:IL-6Rα-mediated signaling / signaling mediated by IL-6 binding to cells expressing gp130:IL-6Rα in the absence of the antigen binding molecule (or an appropriate control antigen binding molecule, e.g., IL-6-mediated signaling / gp130:IL-6Rα-mediated signaling / signaling mediated by IL-6 binding to cells expressing gp130:IL-6Rα). In some embodiments, the signal transduction level can be inhibited by less than 1-fold, e.g., ≦0.99-fold, ≦0.95-fold, ≦0.9-fold, ≦0.85-fold, ≦0.8-fold, ≦0.75-fold, ≦0.7-fold, ≦0.65-fold, ≦0.6-fold, ≦0.55-fold, ≦0.5-fold, ≦0.45-fold, ≦0.4-fold, ≦0.35-fold, ≦0.3-fold, ≦0.25-fold, ≦0.2-fold, ≦0.15-fold, ≦0.1-fold, ≦0.05-fold, or ≦0.01-fold, of the level of signal transduction observed in the presence of an antigen-binding molecule known not to affect signal transduction mediated by the antibody.

[0469] In some embodiments, the antigen binding molecule inhibits the IL-6-mediated signaling / p130:IL-6Rα-mediated signaling observed in the absence of the antigen binding molecule (or in the presence of a suitable control antigen binding molecule, e.g., an antigen binding molecule known not to affect IL-6-mediated signaling / p130:IL-6Rα-mediated signaling / signaling mediated by IL-6 binding to cells expressing gp130:IL-6Rα). In some embodiments, the present invention can inhibit greater than 25%, e.g., ≥30%, ≥35%, ≥40%, ≥45%, ≥50%, ≥55%, ≥60%, ≥65%, ≥70%, ≥75%, ≥80%, ≥85%, ≥90%, ≥95%, ≥96%, ≥97%, ≥98%, or ≥99% of signal transduction mediated by IL-6 binding to cells expressing IL-6Rα, as determined, for example, in assays performed as described in Examples 1 and 11 herein.

[0470] In some embodiments, the antigen binding molecule inhibits IL-6-mediated signaling / signaling mediated by gp130:IL-6Rα / signaling mediated by IL-6 binding to cells expressing gp130:IL-6Rα, e.g., IC to determine the ability of the antigen binding molecule to inhibit such signaling in a suitable in vitro assay. 50 is less than 1 μM, 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.

[0471] In some embodiments, the antigen binding molecule inhibits IL-6-mediated signaling / signaling mediated by gp130:IL-6Rα / signaling mediated by IL-6 binding to cells expressing gp130:IL-6Rα, e.g., IC to determine the ability of the antigen binding molecule to inhibit such signaling in a suitable in vitro assay. 50 at an IC of less than 100 nM, preferably at one of ≦70 nM, ≦60 nM, ≦50 nM, ≦40 nM, ≦30 nM, ≦20 nM, ≦10 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. In some embodiments, the antigen binding molecule is capable of inhibiting IL-6-mediated signaling / gp130:IL-6Rα-mediated signaling / signaling mediated by binding of IL-6 to cells expressing gp130:IL-6Rα, e.g., to determine the ability of the antigen binding molecule to inhibit such signaling in a suitable in vitro assay. 50 is less than 15 μg / ml, preferably at one of < 11 μg / ml, < 10 μg / ml, < 9 μg / ml, < 8 μg / ml, < 7 μg / ml, < 6 μg / ml, < 5 μg / ml, < 4 μg / ml, < 3 μg / ml, < 2 μg / ml, < 1 μg / ml, < 0.9 μg / ml, < 0.8 μg / ml, < 0.7 μg / ml, < 0.6 μg / ml, < 0.5 μg / ml, < 0.4 μg / ml, < 0.3 μg / ml, < 0.2 μg / ml, < 0.1 μg / ml, < 0.09 μg / ml, < 0.8 μg / ml, < 0.07 μg / ml, < 0.06 μg / ml, or < 0.05 μg / ml.

[0472] In some embodiments, the antigen binding molecule inhibits IL-6-mediated signaling / gp130:IL-6Rα-mediated signaling / signaling mediated by IL-6 binding to cells expressing gp130:IL-6Rα, e.g., as determined by the assays described in Examples 2 or 34 herein, or by IC50 is less than 10 μg / ml, preferably at one of ≦5 μg / ml, ≦4 μg / ml, ≦3 μg / ml, ≦2 μg / ml, ≦1 μg / ml, ≦0.9 μg / ml, ≦0.8 μg / ml, ≦0.7 μg / ml, ≦0.6 μg / ml, or ≦0.5 μg / ml.

[0473] In some embodiments, the antigen binding molecule is capable of inhibiting IL-11-mediated signaling / gp130:IL-11Rα-mediated signaling / signaling mediated by IL-11 binding to cells expressing gp130:IL-11Rα in the absence of the antigen binding molecule (or a suitable control antigen binding molecule, e.g., IL-11-mediated signaling / gp130:IL-11Rα-mediated signaling / IL-11 binding to cells expressing gp130:IL-11Rα). In some embodiments, the signal transduction level can be inhibited by less than 1-fold, e.g., ≦0.99-fold, ≦0.95-fold, ≦0.9-fold, ≦0.85-fold, ≦0.8-fold, ≦0.75-fold, ≦0.7-fold, ≦0.65-fold, ≦0.6-fold, ≦0.55-fold, ≦0.5-fold, ≦0.45-fold, ≦0.4-fold, ≦0.35-fold, ≦0.3-fold, ≦0.25-fold, ≦0.2-fold, ≦0.15-fold, ≦0.1-fold, ≦0.05-fold, or ≦0.01-fold, of the level of signal transduction observed (in the presence of an antigen-binding molecule known not to affect signal transduction mediated by the antibody).

[0474] In some embodiments, the antigen binding molecule is capable of inhibiting more than 50%, e.g., ≥ 55%, ≥ 60%, ≥ 65%, ≥ 70%, ≥ 75%, ≥ 80%, ≥ 85%, ≥ 90%, ≥ 95%, ≥ 96%, ≥ 97%, ≥ 98%, or ≥ 99% of IL-11-mediated signaling / p130:IL-11Rα-mediated signaling / signaling mediated by IL-11 binding to cells expressing gp130:IL-11Rα) observed in the absence of the antigen binding molecule (or in the presence of a suitable control antigen binding molecule, e.g., an antigen binding molecule known to have no effect on IL-11-mediated signaling / p130:IL-11Rα-mediated signaling / signaling mediated by IL-11 binding to cells expressing gp130:IL-11Rα).

[0475] In some embodiments, the antigen binding molecule inhibits IL-6-mediated signaling / gp130:IL-6Rα-mediated signaling / signaling mediated by IL-6 binding to cells expressing gp130:IL-6Rα by less than 1-fold, e.g., ≦0.99-fold, ≦0.95-fold, ≦0.9-fold, ≦0.85-fold, ≦0.8-fold, ≦0.75-fold, ≦0.7-fold, ≦0.65-fold, ≦0.6-fold, ≦0.55-fold, ≦0.5-fold, ≦0.45-fold, ≦0.4-fold, ≦0.35-fold, ≦0.3-fold, ≦0.25-fold, ≦0.2-fold, ≦0.15-fold, ≦0.1-fold, ≦0.05-fold, or ≦0.01-fold the level of signaling observed in the absence of the antigen binding molecule (or in the presence of a suitable control antigen binding molecule). and capable of inhibiting IL-11-mediated signaling / gp130:IL-11Rα-mediated signaling / signaling mediated by IL-11 binding to cells expressing gp130:IL-11Rα by less than 1-fold, e.g., ≦0.99-fold, ≦0.95-fold, ≦0.9-fold, ≦0.85-fold, ≦0.8-fold, ≦0.75-fold, ≦0.7-fold, ≦0.65-fold, ≦0.6-fold, ≦0.55-fold, ≦0.5-fold, ≦0.45-fold, ≦0.4-fold, ≦0.35-fold, ≦0.3-fold, ≦0.25-fold, ≦0.2-fold, ≦0.15-fold, ≦0.1-fold, ≦0.05-fold, or ≦0.01-fold, of the signaling level observed in the absence of the antigen-binding molecule (or in the presence of a suitable control antigen-binding molecule).

[0476] In some embodiments, the antigen binding molecule inhibits IL-6-mediated signaling / gp130:IL-6Rα-mediated signaling observed in the absence of the antigen binding molecule (or in the presence of a suitable control antigen binding molecule, e.g., an antigen binding molecule known not to affect IL-6-mediated signaling / p130:IL-6Rα-mediated signaling / signaling mediated by IL-6 binding to cells expressing gp130:IL-6Rα). 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 signaling mediated by IL-6 binding to cells expressing gp130:IL-6Rα is determined, e.g., in assays performed as described in Examples 1 and 11 herein. and can inhibit more than 50%, e.g., ≥ 55%, ≥ 60%, ≥ 65%, ≥ 70%, ≥ 75%, ≥ 80%, ≥ 85%, ≥ 90%, ≥ 95%, ≥ 96%, ≥ 97%, ≥ 98%, or ≥ 99% of IL-11-mediated signaling / gp130:IL-11Rα-mediated signaling / signaling mediated by IL-11 binding to cells expressing gp130:IL-11Rα) observed in the absence of the antigen-binding molecule (or in the presence of a suitable control antigen-binding molecule, e.g., an antigen-binding molecule known not to affect IL-11-mediated signaling / p130:IL-11Rα-mediated signaling / signaling mediated by IL-11 binding to cells expressing gp130:IL-11Rα), as determined, for example, in assays performed as described in Examples 1 and 11 herein.

[0477] In some embodiments, the antigen binding molecule inhibits IL-11-mediated signaling / signaling mediated by gp130:IL-11Rα / signaling mediated by IL-11 binding to cells expressing gp130:IL-11Rα, e.g., IC, such that the ability of the antigen binding molecule to inhibit such signaling is determined in a suitable in vitro assay. 50 is less than 1 μM, 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. In some embodiments, the antigen binding molecule inhibits IL-11-mediated signaling / signaling mediated by gp130:IL-11Rα / signaling mediated by IL-11 binding to cells expressing gp130:IL-11Rα, e.g., IC, such that the ability of the antigen binding molecule to inhibit such signaling is determined in a suitable in vitro assay. 50 is less than 10 nM, preferably one of ≦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. In some embodiments, the antigen binding molecule is capable of inhibiting IL-11-mediated signaling / gp130:IL-11Rα-mediated signaling / signaling mediated by binding of IL-11 to cells expressing gp130:IL-11Rα, e.g., to determine the ability of the antigen binding molecule to inhibit such signaling in a suitable in vitro assay. 50is less than 1 μg / ml, preferably at one of ≦0.9 μg / ml, ≦0.8 μg / ml, ≦0.7 μg / ml, ≦0.6 μg / ml, ≦0.5 μg / ml, ≦0.4 μg / ml, ≦0.3 μg / ml, ≦0.2 μg / ml, ≦0.1 μg / ml, ≦0.09 μg / ml, ≦0.08 μg / ml, ≦0.07 μg / ml, ≦0.06 μg / ml, or ≦0.05 μg / ml.

[0478] In some embodiments, the antigen binding molecule inhibits IL-11-mediated signaling / signaling mediated by gp130:IL-11Rα / signaling mediated by IL-11 binding to cells expressing gp130:IL-11Rα, e.g., as determined by the assays described in Examples 2 or 34 herein, at an IC 50 is less than 10 μg / ml, preferably at one of ≦5 μg / ml, ≦4 μg / ml, ≦3 μg / ml, ≦2 μg / ml, ≦1 μg / ml, ≦0.9 μg / ml, ≦0.8 μg / ml, ≦0.7 μg / ml, ≦0.6 μg / ml or ≦0.5 μg / ml.

[0479] In some embodiments, the antigen binding molecule does not inhibit (i.e., does not substantially inhibit) OSM-mediated signaling. In some embodiments, the antigen binding molecule does not inhibit LIF-mediated signaling. In some embodiments, the antigen binding molecule does not inhibit CNTF-mediated signaling. In some embodiments, the antigen binding molecule does not inhibit CT-1-mediated signaling. In some embodiments, the antigen binding molecule does not inhibit CLC-mediated signaling. In some embodiments, the antigen binding molecule does not inhibit IL-27-mediated signaling. In some embodiments, the antigen binding molecule does not inhibit IL-35-mediated signaling. In some embodiments, the antigen binding molecule does not inhibit OSM-mediated signaling, does not inhibit LIF-mediated signaling, does not inhibit CNTF-mediated signaling, and does not inhibit CT-1-mediated signaling. In some embodiments, the antigen binding molecule does not inhibit OSM-mediated signaling, does not inhibit LIF-mediated signaling, does not inhibit CNTF-mediated signaling, does not inhibit CT-1-mediated signaling, does not inhibit IL-27-mediated signaling, and does not inhibit IL-35-mediated signaling. In some embodiments, the antigen binding molecule does not inhibit signaling mediated by cytokines other than IL-6 or IL-11.

[0480] In some embodiments, the antigen binding molecule does not inhibit (i.e., does not substantially inhibit) signaling mediated by gp130:OSMRβ. In some embodiments, the antigen binding molecule does not inhibit signaling mediated by gp130:LIFRβ. In some embodiments, the antigen binding molecule does not inhibit signaling mediated by gp130:LIFRβ:CNTFRα. In some embodiments, the antigen binding molecule does not inhibit signaling mediated by gp130:IL-27Rα. In some embodiments, the antigen binding molecule does not inhibit signaling mediated by gp130:IL-12Rβ2. In some embodiments, the antigen binding molecule does not inhibit signaling mediated by gp130:OSMRβ, does not inhibit signaling mediated by gp130:LIFRβ, and does not inhibit signaling mediated by gp130:LIFRβ:CNTFRα. In some embodiments, the antigen binding molecule does not inhibit signaling mediated by gp130:OSMRβ, does not inhibit signaling mediated by gp130:LIFRβ, does not inhibit signaling mediated by gp130:LIFRβ:CNTFRα, does not inhibit signaling mediated by gp130:IL-27Rα, or does not inhibit signaling mediated by gp130:IL-12Rβ2. In some embodiments, the antigen binding molecule does not inhibit signaling mediated by gp130-containing polypeptide complexes other than gp130:IL-6Rα or gp130:IL-11Rα.

[0481] In some embodiments, the antigen binding molecule does not inhibit (i.e., does not substantially inhibit) signaling mediated by binding of OSM to cells expressing gp130:OSMRβ. In some embodiments, the antigen binding molecule does not inhibit signaling mediated by binding of OSM, LIF, or CT-1 to cells expressing gp130:LIFRβ. In some embodiments, the antigen binding molecule does not inhibit signaling mediated by binding of CNTF or CLC to cells expressing gp130:LIFRβ:CNTFRα. In some embodiments, the antigen binding molecule does not inhibit signaling mediated by binding of IL-27 to cells expressing gp130:IL-27Rα. In some embodiments, the antigen binding molecule does not inhibit signaling mediated by binding of IL-35 to cells expressing gp130:IL-12Rβ2. In some embodiments, the antigen binding molecule does not inhibit signaling mediated by binding of OSM to cells expressing gp130:OSMRβ, does not inhibit signaling mediated by binding of OSM, LIF, or CT-1 to cells expressing gp130:LIFRβ, and does not inhibit signaling mediated by binding of CNTF or CLC to cells expressing gp130:LIFRβ:CNTFRα. In some embodiments, the antigen binding molecule does not inhibit signaling mediated by binding of OSM to cells expressing gp130:OSMRβ; does not inhibit signaling mediated by binding of OSM, LIF, or CT-1 to cells expressing gp130:LIFRβ; does not inhibit signaling mediated by binding of CNTF or CLC to cells expressing gp130:LIFRβ:CNTFRα; does not inhibit signaling mediated by binding of IL-27 to cells expressing gp130:LIFRβ:IL-27Rα; or does not inhibit signaling mediated by binding of IL-35 to cells expressing gp130:LIFRβ:IL-12Rβ2.

[0482] In an assay for the ability of an antigen-binding molecule to inhibit signal transduction mediated by binding of a given cytokine to a given cytokine / gp130-containing receptor complex / cells expressing a given gp130-containing receptor complex, an antigen-binding molecule that "does not inhibit" or "does not substantially inhibit" signal transduction can inhibit the relevant signal transduction with an IC50 of greater than 1 μM, preferably one of ≧5 μM, ≧10 μM, ≧20 μM, ≧50 μM, ≧100 μM, ≧500 μM, or ≧1 M.

[0483] In an assay for the ability of an antigen-binding molecule to inhibit signal transduction mediated by binding of a given cytokine to a given cytokine / gp130-containing receptor complex / cells expressing a given gp130-containing receptor complex, an antigen-binding molecule that "does not inhibit" or "does not substantially inhibit" signal transduction in the absence of the antigen-binding molecule (or in the absence of a suitable control antigen-binding molecule, e.g., a given cytokine / via a given gp130-containing receptor complex). may inhibit signal transduction by less than 0.8-fold the level observed (in the presence of an antigen-binding molecule known not to affect signal transduction), e.g., may inhibit the relevant level of signal transduction by ≦0.85-fold, ≦0.86-fold, ≦0.87-fold, ≦0.88-fold, ≦0.89-fold, ≦0.9-fold, ≦0.91-fold, ≦0.92-fold, ≦0.93-fold, ≦0.94-fold, ≦0.95-fold, ≦0.96-fold, ≦0.97-fold, ≦0.98-fold, ≦0.99-fold, or ≦1-fold.

[0484] In an assay for the ability of an antigen-binding molecule to inhibit signal transduction mediated by binding of a given cytokine to a gp130-containing receptor complex / cells expressing the gp130-containing receptor complex, the level of signal transduction observed in the presence of an antigen-binding molecule that "does not inhibit" or "does not substantially inhibit" signal transduction may be similar to the level of signal transduction observed in the absence of the antigen-binding molecule (or in the presence of a suitable control antigen-binding molecule, e.g., an antigen-binding molecule known not to affect signal transduction by the given cytokine / via the gp130-containing receptor complex). In some embodiments, a "similar" level of signal transduction according to the preceding sentence may be one of ≥ 0.5-fold and ≤ 2-fold the baseline level of signal transduction, e.g., ≥ 0.75-fold and ≤ 1.5-fold, ≥ 0.8-fold and ≤ 1.4-fold, ≥ 0.85-fold and ≤ 1.3-fold, ≥ 0.9-fold and ≤ 1.2-fold, or ≥ 0.95-fold and ≤ 1.1-fold.

[0485] In some embodiments, the antigen binding molecule inhibits less than 20%, e.g., ≦15%, ≦14%, ≦13%, ≦12%, ≦11%, ≦10%, ≦9%, ≦8%, ≦7%, ≦6%, ≦5%, ≦4%, ≦3%, ≦2%, or ≦1%, of LIF-mediated signaling / gp130:LIFRβ-mediated signaling / signaling mediated by LIF binding to cells expressing gp130:LIFRβ, observed in the absence of the antigen binding molecule (or in the presence of a suitable control antigen binding molecule, e.g., an antigen binding molecule known to have no effect on LIF-mediated signaling / signaling mediated by gp130:LIFRβ / signaling mediated by LIF binding to cells expressing gp130:LIFRβ), as determined, for example, in an assay performed as described in Examples 1 and 11 herein.

[0486] In some embodiments, the antigen binding molecule inhibits less than 20%, e.g., ≦15%, ≦14%, ≦13%, ≦12%, ≦11%, ≦10%, ≦9%, ≦8%, ≦7%, ≦6%, ≦5%, ≦4%, ≦3%, ≦2%, or ≦1%, of OSM-mediated signaling / gp130:OSMRβ- or gp130:LIFRβ-mediated signaling / signaling mediated by OSM binding to cells expressing gp130:OSMRβ, as determined, for example, in assays performed as described in Examples 1 and 11 herein.

[0487] In some embodiments, the antigen binding molecule is selected from the group consisting of: (i) IL-6-mediated signaling / gp130:IL-6Rα-mediated signaling observed in the absence of the antigen binding molecule (or in the presence of a suitable control antigen binding molecule, e.g., an antigen binding molecule known not to affect IL-6-mediated signaling / gp130:IL-6Rα-mediated signaling / signaling mediated by IL-6 binding to cells expressing gp130:IL-6Rα); signaling / gp130: capable of inhibiting more than 25%, e.g., ≥ 30%, ≥ 35%, ≥ 40%, ≥ 45%, ≥ 50%, ≥ 55%, ≥ 60%, ≥ 65%, ≥ 70%, ≥ 75%, ≥ 80%, ≥ 85%, ≥ 90%, ≥ 95%, ≥ 96%, ≥ 97%, ≥ 98%, or ≥ 99%, of signaling mediated by binding of IL-6 to cells expressing IL-6Rα, e.g., as determined in an assay performed as described in Examples 1 and 11 herein; (ii) IL-11-mediated signaling / gp130:IL-11Rα-mediated signaling / gp130:IL-11Rα-mediated signaling / gp130: observed in the absence of the antigen-binding molecule (or in the presence of a suitable control antigen-binding molecule, e.g., an antigen-binding molecule known not to affect IL-11-mediated signaling / gp130:IL-11Rα-mediated signaling / gp130:IL-11Rα-expressing cells). (iii) is capable of inhibiting more than 50%, e.g., ≥ 55%, ≥ 60%, ≥ 65%, ≥ 70%, ≥ 75%, ≥ 80%, ≥ 85%, ≥ 90%, ≥ 95%, ≥ 96%, ≥ 97%, ≥ 98%, or ≥ 99%, of signaling mediated by binding of IL-11 to cells expressing IL-11Rα, e.g., as determined in an assay performed as described in Examples 1 and 11 herein; and(iv) inhibits less than 20%, e.g., ≦15%, ≦14%, ≦13%, ≦12%, ≦11%, ≦10%, ≦9%, ≦8%, ≦7%, ≦6%, ≦5%, ≦4%, ≦3%, ≦2%, or ≦1% of LIF-mediated signaling / gp130:LIFRβ-mediated signaling / gp130:LIFRβ-mediated signaling / gp130:LIFRβ-mediated signaling observed in the presence of an antigen binding molecule known not to affect LIF-mediated signaling / gp130:LIFRβ-mediated signaling / gp130:LIFRβ-mediated signaling / gp130:LIFRβ-mediated signaling (as determined, e.g., in an assay performed as described in Examples 1 and 11 herein); The antibody inhibits less than 20%, e.g., ≦15%, ≦14%, ≦13%, ≦12%, ≦11%, ≦10%, ≦9%, ≦8%, ≦7%, ≦6%, ≦5%, ≦4%, ≦3%, ≦2%, or ≦1% of OSM-mediated signaling / gp130:OSMRβ or gp130:LIFRβ ...

[0488] In some embodiments, the antigen binding molecule inhibits less than 20%, e.g., ≦15%, ≦14%, ≦13%, ≦12%, ≦11%, ≦10%, ≦9%, ≦8%, ≦7%, ≦6%, ≦5%, ≦4%, ≦3%, ≦2%, or ≦1%, of CT-1-mediated signaling / gp130:LIFRβ-mediated signaling / signaling mediated by CT-1 binding to cells expressing gp130:LIFRβ, observed in the absence of the antigen binding molecule (or in the presence of a suitable control antigen binding molecule, e.g., an antigen binding molecule known to have no effect on CT-1-mediated signaling / gp130:LIFRβ-mediated signaling / signaling mediated by CT-1 binding to cells expressing gp130:LIFRβ), as determined, for example, in an assay performed as described in Examples 1 and 12 herein.

[0489] In some embodiments, the antigen binding molecule inhibits less than 20%, e.g., ≦15%, ≦14%, ≦13%, ≦12%, ≦11%, ≦10%, ≦9%, ≦8%, ≦7%, ≦6%, ≦5%, ≦4%, ≦3%, ≦2%, or ≦1%, of CNTF-mediated signaling / gp130:LIFRβ:CNTFRα-mediated signaling / signaling mediated by CNTF binding to cells expressing gp130:LIFRβ:CNTFRα, observed in the absence of the antigen binding molecule (or in the presence of a suitable control antigen binding molecule, e.g., an antigen binding molecule known to not affect CNTF-mediated signaling / gp130:LIFRβ:CNTFRα-mediated signaling / signaling mediated by CNTF binding to cells expressing gp130:LIFRβ:CNTFRα), as determined, for example, in an assay performed as described in Examples 1 and 12 herein.

[0490] In some embodiments, the antigen binding molecule is selected from the group consisting of: (i) IL-6-mediated signaling / gp130:IL-6Rα-mediated signaling observed in the absence of the antigen binding molecule (or in the presence of a suitable control antigen binding molecule, e.g., an antigen binding molecule known not to affect IL-6-mediated signaling / gp130:IL-6Rα-mediated signaling / signaling mediated by IL-6 binding to cells expressing gp130:IL-6Rα); signaling / gp130: capable of inhibiting more than 25%, e.g., ≥ 30%, ≥ 35%, ≥ 40%, ≥ 45%, ≥ 50%, ≥ 55%, ≥ 60%, ≥ 65%, ≥ 70%, ≥ 75%, ≥ 80%, ≥ 85%, ≥ 90%, ≥ 95%, ≥ 96%, ≥ 97%, ≥ 98%, or ≥ 99%, of signaling mediated by binding of IL-6 to cells expressing IL-6Rα, e.g., as determined in an assay performed as described in Examples 1 and 11 herein; (ii) IL-11-mediated signaling / gp130:IL-11Rα-mediated signaling / gp130:IL-11Rα-mediated signaling / gp130: observed in the absence of the antigen-binding molecule (or in the presence of a suitable control antigen-binding molecule, e.g., an antigen-binding molecule known not to affect IL-11-mediated signaling / gp130:IL-11Rα-mediated signaling / gp130:IL-11Rα-expressing cells). (iii) is capable of inhibiting more than 50%, e.g., ≥ 55%, ≥ 60%, ≥ 65%, ≥ 70%, ≥ 75%, ≥ 80%, ≥ 85%, ≥ 90%, ≥ 95%, ≥ 96%, ≥ 97%, ≥ 98%, or ≥ 99%, of signaling mediated by binding of IL-11 to cells expressing IL-11Rα, e.g., as determined in an assay performed as described in Examples 1 and 11 herein; andLess than 20%, e.g., ≦15%, ≦14%, ≦13%, ≦12%, ≦11%, ≦10%, ≦9%, ≦8%, ≦7% of the LIF-mediated signaling / gp130:LIFRβ-mediated signaling / signaling mediated by LIF binding to cells expressing gp130:LIFRβ observed in the presence of an antigen-binding molecule known not to affect LIF-mediated signaling / gp130:LIFRβ-mediated signaling / signaling mediated by LIF binding to cells expressing gp130:LIFRβ. , ≦6%, ≦5%, ≦4%, ≦3%, ≦2%, or ≦1%, as determined, for example, in assays performed as described in Examples 1 and 11 herein, and (iv) in the absence of the antigen-binding molecule (or in the presence of a suitable control antigen-binding molecule, for example an antigen-binding molecule known not to affect OSM-mediated signaling / signaling mediated by gp130:OSMRβ or gp130:LIFRβ / signaling mediated by binding of OSM to cells expressing gp130:OSMRβ or gp130:LIFRβ). (v) inhibits less than 20%, e.g., ≦15%, ≦14%, ≦13%, ≦12%, ≦11%, ≦10%, ≦9%, ≦8%, ≦7%, ≦6%, ≦5%, ≦4%, ≦3%, ≦2%, or ≦1% of OSM-mediated signaling observed in / mediated by gp130:OSMRβ or gp130:LIFRβ / mediated by binding of OSM to cells expressing gp130:OSMRβ or gp130:LIFRβ, as determined, for example, in an assay performed as described in Examples 1 and 11 herein; and less than 20%, e.g., ≦15%, ≦14%, of the CT-1-mediated signaling / gp130:LIFRβ-mediated signaling / signaling mediated by CT-1 binding to cells expressing gp130:LIFRβ observed in the absence of the molecule (or in the presence of a suitable control antigen-binding molecule, e.g., an antigen-binding molecule known to not affect CT-1-mediated signaling / gp130:LIFRβ-mediated signaling / signaling mediated by CT-1 binding to cells expressing gp130:LIFRβ);(vi) inhibits ≦13%, ≦12%, ≦11%, ≦10%, ≦9%, ≦8%, ≦7%, ≦6%, ≦5%, ≦4%, ≦3%, ≦2%, or ≦1%, as determined, for example, in assays performed as described in Examples 1 and 12 herein, and (vi) does not affect CNTF-mediated signaling / gp130:LIFRβ:CNTFRα-mediated signaling / signaling mediated by CNTF binding to cells expressing gp130:LIFRβ:CNTFRα in the absence of the antigen-binding molecule (or a suitable control antigen-binding molecule, e.g., CNTF-mediated signaling / gp130:LIFRβ:CNTFRα-mediated signaling / signaling mediated by CNTF binding to cells expressing gp130:LIFRβ:CNTFRα). The antibody inhibits less than 20%, e.g., ≦15%, ≦14%, ≦13%, ≦12%, ≦11%, ≦10%, ≦9%, ≦8%, ≦7%, ≦6%, ≦5%, ≦4%, ≦3%, ≦2%, or ≦1% of CNTF-mediated signaling / gp130:LIFRβ:CNTFRα-mediated signaling / gp130:LIFRβ:CNTFRα-mediated signaling / gp130:LIFRβ:CNTFRα-mediated signaling observed in a cell expressing gp130:LIFRβ:CNTFRα (in the presence of an antigen-binding molecule known to inhibit CNTF), as determined, for example, in assays performed as described in Examples 1 and 12 herein.

[0491] In some embodiments, antigen binding molecules according to the present disclosure reduce inflammation. In some embodiments, antigen binding molecules according to the present disclosure reduce fibrosis. In some embodiments, antigen binding molecules according to the present disclosure reduce inflammation and fibrosis.

[0492] The ability and extent of a given antigen-binding molecule to reduce inflammation and / or fibrosis can be assessed in a suitable in vitro or in vivo model of inflammation / fibrosis. For example, an in vitro method may involve contacting cells (e.g., gp130-expressing cells) with a pro-inflammatory, pro-fibrotic, or fibroinflammatory stimulus (e.g., IL-6, IL-11, TGFβ1, etc.) in the presence of the antigen-binding molecule, and subsequently assessing the cells to determine the level of one or more correlates of inflammation / fibrosis. For example, in an experimental example of the present disclosure, gp130-specific antigen-binding molecules are assessed for their ability to reduce fibrosis in an in vitro assay in which cells are stimulated with IL-6 or IL-11, and the fibrotic response is then analyzed by assessing the expression of αSMA and MMP2.

[0493] To analyze the ability and extent of a given antigen-binding molecule to reduce inflammation and / or fibrosis in vivo, non-human animal models of diseases characterized by inflammation and / or fibrosis can be used. Such models are also useful for evaluating the ability of an antigen-binding molecule to alleviate the pathology of a disease / condition characterized by inflammation and / or fibrosis. Such analyses may involve administering the antigen-binding molecule to a subject with a disease characterized by inflammation and / or fibrosis, and subsequently assessing the level of one or more correlations of inflammation / fibrosis in the subject. By way of example, in 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 mouse model of folic acid-induced acute kidney injury, for example, by assessing serum levels of IL-6, renal collagen content, and renal expression of pro-inflammatory genes (e.g., Ccl2, Ccl5, Il6, Tnfα, and Il1β), and pro-fibrotic genes (e.g., Col1a1, Col1a2, Col3a1, Fn, Acta2, and Il11).

[0494] In some embodiments, administration of an antigen-binding molecule according to the present disclosure may inhibit the development / progression of a disease / condition characterized by inflammation and / or fibrosis, or may reduce the severity of symptoms of a disease / condition characterized by inflammation and / or fibrosis, as determined, for example, in a suitable model.

[0495] In some embodiments, the antigen binding molecules of the present disclosure are capable of expressing the antigen at one level of more correlates of inflammation and / or fibrosis (e.g., in vitro models of inflammation / fibrosis, or in vivo models of diseases / conditions characterized by inflammation / fibrosis). It is possible to reduce the level of the antigen-binding molecule (e.g., IgG in vivo model) by less than 1-fold, e.g., ≦0.99-fold, ≦0.95-fold, ≦0.9-fold, ≦0.85-fold, ≦0.8-fold, ≦0.75-fold, ≦0.7-fold, ≦0.65-fold, ≦0.6-fold, ≦0.55-fold, ≦0.5-fold, ≦0.45-fold, ≦0.4-fold, ≦0.35-fold, ≦0.3-fold, ≦0.25-fold, ≦0.2-fold, ≦0.15-fold, ≦0.1-fold, ≦0.05-fold, or ≦0.01-fold, of the level observed in the absence of treatment with the antigen-binding molecule in a given assay (or treatment with a suitable control antigen-binding molecule known not to affect the level of the relevant correlation(s)).

[0496] The antigen-binding molecules of the present disclosure may comprise one or more moieties for promoting cell death of or reducing the number / proportion of gp130-expressing cells. For example, the antigen-binding molecules of the present disclosure may comprise, for example, an Fc region and / or a drug moiety.

[0497] In some embodiments, antigen binding molecules of the present disclosure may promote (i.e., upregulate, enhance) cell death of cells containing / expressing gp130. In some embodiments, antigen binding molecules do not promote (i.e., do not substantially promote) cell death of cells lacking surface expression of gp130.

[0498] Cell death can be determined, for example, using any of the methods outlined in Zaritskaya et al., Expert Rev Vaccines (2011), 9(6):601-616, which is incorporated herein by reference in its entirety. Examples of in vitro cytotoxicity / cell death assays include: 51 Examples of suitable release assays include Cr release assays, lactate dehydrogenase (LDH) release assays, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylbromide tetrazolium (MTT) release assays, and calcein-acetoxymethyl (calcein-AM) release assays. These assays measure cell death based on the detection of factors released from lysed cells. Cell death of a given test cell type caused by a given effector immune cell type can be analyzed, for example, by co-culturing the test cell with the effector immune cell and measuring the number / percentage of surviving / dead (e.g., lysed) test cells after an appropriate period of time. Other suitable assays include the xCELLigence real-time cytotoxicity in vitro potency assay described in Cerignoli et al., PLoS One. (2018) 13(3):e0193498 (incorporated herein by reference in its entirety).

[0499] In some embodiments, antigen binding molecules according to the present disclosure can reduce the number / proportion of cells that express gp130. In some embodiments, antigen binding molecules according to the present disclosure can reduce the number / proportion of cells that express gp130. In some embodiments, antigen binding molecules according to the present disclosure can deplete / enhance the depletion of such cells.

[0500] The Fc region provides interaction with Fc receptors and other molecules of the immune system to produce functional effects. IgG Fc-mediated effector functions are reviewed, for example, in Jefferis et al., Immunol Rev 1998 163:59-76 (incorporated herein by reference in its entirety), and are mediated by Fc-mediated immune cell recruitment and activation via interaction of the Fc region with Fc receptors expressed by immune cells (e.g., macrophages, dendritic cells, neutrophils, basophils, eosinophils, platelets, mast cells, NK cells, and T cells), recruitment of complement pathway components via binding of the Fc region to the 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.

[0501] In some embodiments, the antigen binding molecules of the present disclosure comprise an Fc region capable of enhancing / directing one or more of ADCC, ADCP, and CDC against cells expressing gp130 (e.g., cells expressing gp130 on their cell surface), and / or enhancing MAC formation on the cells or degranulation of the cells.

[0502] In some embodiments, the antigen binding molecules of the present disclosure are capable of enhancing / directing ADCC against cells expressing gp130.

[0503] The ability of a given antigen-binding molecule to induce ADCC of a given target cell type, and the extent to which it does so, can be determined, for example, according to the method described in Yamashita et al., Scientific Reports (2016) 6:19772 (incorporated herein by reference in its entirety), or, for example, according to the method described in Jedema et al., Blood (2004) 103:2677-82 (incorporated herein by reference in its entirety). 51The ability and extent of a given antigen-binding molecule to induce ADCP can be analyzed by Cr release assay. The ability and extent of a given antigen-binding molecule to induce CDC can be analyzed, for example, according to the method described in Kamen et al., J Immunol (2017) 198 (1 Supplement) 157.17 (incorporated herein by reference in its entirety). The ability and extent of a given antigen-binding molecule to induce CDC can be analyzed, for example, using a C1q binding assay, as described in Schlothauer et al., Protein Engineering, Design and Selection (2016), 29 (10): 457-466 (incorporated herein by reference in its entirety).

[0504] In some embodiments, the antigen-binding molecule of the present disclosure comprises a drug moiety. The antigen-binding molecule may be conjugated to a drug moiety. Antibody-drug conjugates are generally described, for example, in Parslow et al., Biomedicines. 2016 Sep;4(3):14 (incorporated herein by reference in its entirety). In some embodiments, the drug moiety is or comprises a cytotoxic agent such that the antigen-binding molecule exhibits cytotoxicity against cells expressing gp130 (e.g., cells expressing gp130 on their cell surface).

[0505] Linkers and Additional Sequences The antigen-binding molecules and polypeptides of the present disclosure may additionally comprise additional amino acids or amino acid sequences.

[0506] The antigen-binding molecules and polypeptides of the present disclosure may contain one or more linker sequences between amino acid sequences. For example, a linker sequence may be provided between the VH and VL sequences, thereby providing a bond between the VH and VL (e.g., as in an scFv molecule).

[0507] Linker sequences are known to those skilled in the art and are described, for example, in Chen et al., Adv Drug Deliv Rev (2013) 65(10):1357-1369, the entire contents of which are incorporated herein by reference. In some embodiments, the linker sequence may be a flexible linker sequence. A flexible linker sequence allows relative movement of the amino acid sequences connected by the linker sequence. Flexible linkers are known to those skilled in the art, and some are identified in Chen et al., Adv Drug Deliv Rev (2013) 65(10):1357-1369. Flexible linker sequences often contain a high proportion of glycine and / or serine residues.

[0508] 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, where 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)6. In some embodiments, the linker sequence has a length of 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 10, 1 to 15, 1 to 20, 1 to 25, or 1 to 30 amino acids.

[0509] The antigen-binding molecules and polypeptides of the present disclosure may comprise an amino acid sequence(s) that facilitates expression, folding, transport, processing, purification, or detection of the antigen-binding molecule / polypeptide. For example, the antigen-binding molecules and polypeptides of the present disclosure may further comprise a sequence of amino acids that forms a detectable moiety, for example, as described herein below.

[0510] The antigen-binding molecules and polypeptides of the present disclosure may further comprise a signal peptide (also known as a leader sequence or signal sequence). Signal peptides typically consist of a sequence of 5 to 30 hydrophobic amino acids that form a single alpha helix. Secreted proteins and proteins expressed on the cell surface often contain 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 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).

[0511] The signal peptide may be present at the N-terminus of the antigen-binding molecule / polypeptide or within a newly synthesized antigen-binding molecule / polypeptide. The signal peptide provides efficient transport of the antigen-binding molecule / polypeptide. In many cases, the signal peptide is removed by cleavage and is therefore not included in the mature antigen-binding molecule / polypeptide.

[0512] 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 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).

[0513] Labels and Conjugates In some embodiments, an antigen-binding molecule or polypeptide of the present disclosure comprises a detectable moiety.

[0514] In some embodiments, the detectable moiety is a fluorescent label, a phosphorescent label, a luminescent label, an immunodetectable label (e.g., an epitope tag), a radioactive label, a chemical label, a nucleic acid label, or an enzymatic label. The antigen-binding molecule or polypeptide may be covalently or non-covalently labeled with a detectable moiety.

[0515] Fluorescent labels include, for example, fluorescein, rhodamine, allophycocyanin, eosin, and NDB, green fluorescent protein (GFP), rare earth chelates such as europium (Eu), terbium (Tb), and samarium (Sm), tetramethylrhodamine, Texas Red, 4-methylumbelliferone, 7-amino-4-methylcoumarin, Cy3, and Cy5. Radioactive labels include hydrogen 3 ,sulfur 35 ,carbon 14 , Phosphorus 32 , iodine 123 , iodine 125 , iodine 126 , iodine 131 , iodine 133 ,bromine 77 ,technetium 99m ,indium 111 ,indium 113m ,gallium 67 ,gallium 68 ,ruthenium 95 ,ruthenium 97 ,ruthenium 103 ,ruthenium 105 ,mercury 207 ,mercury 203 ,rhenium 99m ,rhenium 101 ,rhenium 105 ,scandium 47 ,tellurium 121m ,tellurium 122m ,tellurium 125m ,thulium 165 ,thulium 167 ,thulium 168 ,copper 67, fluorine 18 ,yttrium 90 ,palladium 100 , bismuth 217 and antimony 211 Examples of suitable labels include radioisotopes such as fluoroisotopes, ...

[0516] In some embodiments, the antigen-binding molecule / polypeptide comprises an epitope tag, such as His, (e.g., 6XHis), FLAG, c-Myc, StrepTag, hemagglutinin, E, calmodulin-binding protein (CBP), glutathione-S-transferase (GST), maltose-binding protein (MBP), thioredoxin, S-peptide, T7 peptide, SH2 domain, avidin, streptavidin, and a hapten (e.g., biotin, digoxigenin, dinitrophenol), optionally at the N- or C-terminus of the antigen-binding molecule / polypeptide.

[0517] In some embodiments, the antigen-binding molecule / polypeptide comprises a moiety having a detectable activity, such as an enzymatic moiety, including, for example, luciferase, glucose oxidase, galactosidase (e.g., beta-galactosidase), glucorinidase, phosphatase (e.g., alkaline phosphatase), peroxidase (e.g., horseradish peroxidase), and cholinesterase.

[0518] In some embodiments, the antigen-binding molecules or polypeptides of the present disclosure comprise a chemical moiety. In some embodiments, the antigen-binding molecules / polypeptides of the present disclosure are conjugated to a chemical moiety.

[0519] The chemical moiety can be a moiety for providing a therapeutic effect, i.e., a drug moiety. The drug moiety can be a small molecule (e.g., an organic compound with a low molecular weight (<1000 daltons, typically about 300-700 daltons)). Drug moieties are described, for example, in Parslow et al., Biomedicines. 2016 Sep;4(3):14, incorporated herein by reference in its entirety. In some embodiments, the drug moiety can be or include a cytotoxic agent. In some embodiments, the drug moiety can be or include a chemotherapeutic agent. Drug moieties include, for example, calicheamicin, DM1, DM4, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), SN-38, doxorubicin, duocarmycin, D6.5, and PBD.

[0520] Nucleic acids and vectors The present disclosure provides a nucleic acid or 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.

[0521] Antigen-binding molecules or polypeptides according to the present disclosure can be produced intracellularly by translation of RNA encoding the polypeptide(s). Antigen-binding molecules or polypeptides according to the present disclosure can be produced intracellularly by transcription from a nucleic acid encoding the polypeptide(s) and subsequent translation of the transcribed RNA.

[0522] In some embodiments, the nucleic acid(s) may be or may be contained in a vector or multiple vectors. As used herein, a "vector" is a nucleic acid molecule used as a vehicle to transfer an exogenous nucleic acid into a cell.

[0523] Therefore, the present disclosure also provides a vector or vectors containing a nucleic acid or nucleic acids according to the present disclosure. The vector can facilitate the delivery of nucleic acid(s) encoding a polypeptide according to the present disclosure to a cell. The vector can be an expression vector containing elements necessary for expressing a polypeptide according to the present disclosure. The vector can also contain elements that facilitate the integration of nucleic acid(s) into the genomic DNA of a cell into which the vector is introduced.

[0524] The nucleic acids and vectors of the present disclosure can be provided in purified or isolated form, i.e., from other nucleic acids or naturally occurring biological materials.

[0525] The vector may be a vector for expressing a nucleic acid in a cell (i.e., an expression vector). Such a vector may comprise a promoter sequence operably linked to a nucleotide sequence encoding an antigen-binding molecule or polypeptide according to the present disclosure. The vector may also comprise a stop codon (i.e., 3' within the nucleotide sequence of the vector to the nucleotide sequence encoding the polypeptide(s)) and an expression enhancer. Any suitable vector, promoter, enhancer, and stop codon known in the art can be used to express a peptide or polypeptide from a vector according to the present disclosure.

[0526] The term "operably linked" can include a situation in which a nucleic acid encoding a polypeptide of the present disclosure and a regulatory nucleic acid sequence(s) (e.g., a promoter and / or enhancer) are covalently linked in such a way that expression of the nucleic acid encoding the polypeptide is under the influence or control of the regulatory nucleic acid sequence (thereby forming an expression cassette). Thus, a regulatory sequence is operably linked to a 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).

[0527] 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., gamma retroviral vectors (e.g., murine leukemia virus (MLV)-derived vectors, e.g., SFG vectors), lentiviral vectors, adeno-associated viral vectors, vaccinia viral vectors, and herpes viral vectors), transposon-based vectors, and artificial chromosomes (e.g., yeast artificial chromosomes), as described, for example, in Maus et al., Annu Rev Immunol (2014) 32:189-225 and Morgan and Boyerinas, Biomedicines (2016) 4:9, both of which are incorporated herein by reference in their entireties. In some embodiments, the vector of the present disclosure is a lentiviral vector.

[0528] In some embodiments, the vector can be a eukaryotic vector, i.e., a vector that contains elements necessary for protein expression from the vector in eukaryotic cells, hi some embodiments, the vector can be a mammalian vector, for example, containing a cytomegalovirus (CMV) or SV40 promoter driving protein expression.

[0529] The constituent polypeptides of an antigen-binding molecule according to the present disclosure may be encoded by different nucleic acids from the plurality of nucleic acids or by different vectors from the plurality of vectors.

[0530] Production of antigen-binding molecules and polypeptides The antigen-binding molecules and polypeptides of the present disclosure may be prepared according to methods for producing polypeptides known to those skilled in the art.

[0531] Antigen-binding molecules and polypeptides can be prepared by chemical synthesis, for example, liquid phase or solid phase synthesis. For example, peptides / polypeptides are described in, for example, Chandrudu et al., Molecules (2013), 18:4373-4388, the entire contents of which are incorporated herein by reference.

[0532] Alternatively, antigen-binding molecules and polypeptides can be produced by recombinant expression. Molecular biology techniques suitable for the recombinant production of polypeptides are well known in the art, such as those described in Green and Sambrook, Molecular Cloning: A Laboratory Manual (4th Edition), Cold Spring Harbor Press, 2012, and Nat Methods. (2008); 5(2): 135-146, both of which are incorporated herein 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 incorporated herein by reference in their entirety.

[0533] In some cases, the antigen-binding molecules of the present disclosure are composed of multiple polypeptide chains. In such cases, production of the antigen-binding molecule may involve transcription and translation of multiple polypeptides, and then assembly of the polypeptide chains to form the antigen-binding molecule.

[0534] For recombinant production according to the present disclosure, any cell suitable for expression of a polypeptide can be used. The cell can be a prokaryotic or eukaryotic cell. In some embodiments, the cell is a prokaryotic cell, such as an archaeal or bacterial cell. In some embodiments, the bacterium can be a gram-negative bacterium from the family Enterobacteriaceae, e.g., Escherichia coli. In some embodiments, the cell is a eukaryotic cell, such as a yeast cell, a plant cell, an insect cell, or a mammalian cell, e.g., a cell described herein.

[0535] In some cases, the cells are not prokaryotic because some prokaryotic cells do not allow the same folding or post-translational modifications as eukaryotic cells. Furthermore, much higher expression levels are possible in eukaryotic organisms, and proteins may be easier to purify from eukaryotic organisms using appropriate tags. Specific plasmids that enhance protein secretion into the culture medium may also be utilized.

[0536] In some embodiments, polypeptides can be prepared by cell-free protein synthesis (CFPS), for example, according to the system described in Zemella et al. Chembiochem (2015) 16(17):2420-2431, the entire contents of which are incorporated herein by reference.

[0537] Production may involve the culture or fermentation of eukaryotic cells engineered to express the polypeptide(s) of interest. The culture or fermentation may be carried out in a bioreactor appropriately provided with nutrients, air / oxygen, and / or growth factors. Secreted proteins may be recovered by partitioning the culture medium / fermentation broth from the cells, extracting the protein content, and separating the individual proteins to isolate the 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 herein by reference above).

[0538] A bioreactor contains one or more vessels in which cells can be cultured. Cultivation in a bioreactor can be continuous, with a continuous inflow of reactants into the reactor and a continuous inflow of cultured cells from the reactor. Alternatively, cultivation can be performed in batches. Bioreactors monitor and control environmental conditions, such as pH, oxygen, flow rates to and from the vessel, and agitation within the vessel, to provide optimal conditions for the cells being cultured.

[0539] After culturing cells expressing a polypeptide(s), the polypeptide(s) of interest can be isolated. Any suitable method known in the art for separating proteins from cells may be used. To isolate the polypeptide, it may be necessary to separate the cells from the nutrient medium. If the polypeptide(s) are secreted from the cells, the cells can be separated from the culture medium containing the secreted polypeptide(s) of interest by centrifugation. If the polypeptide(s) of interest are collected intracellularly, protein isolation may include centrifugation to separate the cells from the cell medium, treatment of the cell pellet with a lysis buffer, and cell disruption, for example, by sonication, rapid freeze-thawing, or osmotic lysis.

[0540] It may then be desirable to isolate the polypeptide(s) of interest from the supernatant or medium, which may contain other proteins and non-protein components. A common approach to separating protein components from the supernatant or medium is by precipitation. Proteins of different solubilities are precipitated in different concentrations of a precipitant (such as ammonium sulfate). For example, low concentrations of the precipitant extract water-soluble proteins. Thus, by adding increasing concentrations of the precipitant, proteins of different solubilities can be differentiated. Dialysis may then be used to remove ammonium sulfate from the separated proteins.

[0541] Other methods for distinguishing different proteins are known in the art, such as ion exchange chromatography and size chromatography, which may be used instead of or may follow precipitation.

[0542] After isolating the polypeptide(s) of interest from the culture, it may be desirable or necessary to concentrate the polypeptide(s). Several methods for concentrating proteins are known in the art, such as ultrafiltration or lyophilization.

[0543] Cells containing / expressing antigen-binding molecules and polypeptides The present disclosure also provides a cell comprising or expressing an antigen-binding molecule or polypeptide according to the present disclosure, as well as a cell comprising or expressing a nucleic acid, nucleic acids, vector, or vectors according to the present disclosure.

[0544] It will be understood that where a cell is referred to herein in the singular (ie, "a / the cell"), the plural / populations of such cells is also contemplated.

[0545] The cell can be a eukaryotic cell, e.g., a mammalian cell. The mammal can be a primate (rhesus monkey, cynomolgus monkey, non-human primate, or human), or a non-human mammal (e.g., rabbit, guinea pig, rat, mouse, or other rodent (including any animal of the order Rodentia), cat, dog, pig, sheep, goat, cattle (including cattle such as dairy cows, or any animal of the order Bos), horse (including any animal of the order Equidae), donkey, and non-human primate).

[0546] In some embodiments, the cells are or are derived from cell types commonly used for expression of polypeptides for therapeutic use in humans. Exemplary cells are described, for example, in Kunert and Reinhart, Appl Microbiol Biotechnol. (2016) 100:3451-3461 (incorporated herein by reference in its entirety), and include, for example, CHO, HEK293, PER.C6, NS0, and BHK cells. In a preferred embodiment, the cells are or are derived from CHO cells.

[0547] The present disclosure also provides methods for producing a cell comprising a nucleic acid(s) or vector(s) according to the present disclosure, the method comprising introducing into the cell a nucleic acid, a plurality of nucleic acids, a vector, or a plurality of vectors according to the present disclosure. In some embodiments, introducing into the cell the isolated nucleic acid(s) or vector(s) according to the present disclosure comprises transformation, transfection, electroporation, or transduction (e.g., retroviral transduction).

[0548] The present disclosure also provides a method for producing a cell that expresses / contains an antigen-binding molecule or polypeptide according to the present disclosure, the method comprising introducing into the cell a nucleic acid, a plurality of nucleic acids, a vector, or a plurality of vectors according to the present disclosure. In some embodiments, the method further comprises culturing the cell under conditions suitable for expression of the nucleic acid(s) or vector(s) by the cell. In some embodiments, the method is performed in vitro.

[0549] The present disclosure also provides cells obtained or obtainable by the methods of the present disclosure.

[0550] composition The present disclosure also provides compositions comprising the antigen-binding molecules, polypeptides, nucleic acids, expression vectors and / or cells described herein.

[0551] 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 contain pharmaceutically acceptable carriers, diluents, excipients, or adjuvants. Accordingly, the present disclosure also provides pharmaceutical compositions / medicaments comprising the antigen-binding molecules, polypeptides, nucleic acids / nucleic acids, expression vectors / expression vectors, or cells described herein.

[0552] The compositions of the present disclosure may be formulated in a pharmaceutical composition containing one or more pharmaceutically acceptable carriers (e.g., liposomes, micelles, microspheres, nanoparticles), diluents / excipients (e.g., starch, cellulose, cellulose derivatives, polyols, 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, methylparaben, propylparaben), antioxidants, or the like. (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), stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, or colorants (e.g., titanium oxide).

[0553] As used herein, the term "pharmaceutically acceptable" refers to a compound, ingredient, material, composition, dosage form, etc., that is suitable, within the scope of sound medical judgment, for use in contact with the tissues of a subject (e.g., a human subject) without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, diluent, excipient, adjuvant, filler, buffer, preservative, antioxidant, lubricant, binder, stabilizer, solubilizer, surfactant, masking agent, colorant, flavorant, or sweetener of a composition of 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, antioxidants, lubricants, binders, stabilizers, solubilizers, surfactants, masking agents, colorants, flavorings, 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.

[0554] The composition may be formulated for topical, parenteral, systemic, intracavitary, intravenous, intraarterial, intramuscular, intrathecal, intraocular, intraconjunctival, intratumoral, subcutaneous, intradermal, intrathecal, oral, or transdermal administration. In some embodiments, the pharmaceutical composition / medicament may be formulated for administration by injection or infusion, or by oral ingestion.

[0555] Suitable formulations may include the relevant items in a sterile or isotonic medium. Drugs and pharmaceutical compositions may be formulated in fluid form, including gels. Fluid formulations may be formulated for administration by injection or infusion (e.g., via a catheter) to a selected area of ​​the human or animal body.

[0556] In some embodiments, the compositions are formulated for injection or infusion, for example, into a blood vessel, a tissue / organ of interest, or a tumor.

[0557] The present disclosure also provides methods for producing pharmaceutically useful compositions and medicaments. Such methods may include one or more steps selected from the following: producing an antigen-binding molecule, polypeptide, nucleic acid(s), expression vector(s), or cell described herein; isolating an antigen-binding molecule, polypeptide, nucleic acid(s), expression vector(s), or cell described herein; and / or mixing an antigen-binding molecule, polypeptide, nucleic acid(s), expression vector(s), or cell described herein with a pharmaceutically acceptable carrier, adjuvant, excipient, or diluent.

[0558] 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 treating a disease / condition (e.g., a disease / condition described herein), the method comprising formulating the pharmaceutical composition or medicament by mixing an antigen-binding molecule, polypeptide, nucleic acid(s), expression vector(s), or cell described herein with a pharmaceutically acceptable carrier, adjuvant, excipient, or diluent.

[0559] Therapeutic and preventive applications The antigen-binding molecules, polypeptides, nucleic acids, expression vectors, cells, and compositions described herein are used in therapeutic and prophylactic methods.

[0560] The present disclosure provides antigen-binding molecules, polypeptides, nucleic acids(s), expression vectors(s), cells, or compositions described herein for use in methods of medical treatment or prevention. Also provided are antigen-binding molecules, polypeptides, nucleic acids(s), expression vectors(s), cells, or compositions described herein for use in methods of treating or preventing the diseases or conditions described herein. Also provided is the use of antigen-binding molecules, polypeptides, nucleic acids(s), expression vectors(s), cells, or compositions described herein in the manufacture of a medicament for treating or preventing the diseases or conditions described herein. Also provided are methods of treating or preventing the diseases or conditions described herein, comprising administering a therapeutically or prophylactically effective amount of an antigen-binding molecule, polypeptide, nucleic acid(s), expression vector(s), cell, or composition described herein to a subject.

[0561] The method may be effective in reducing the development or progression of a disease / condition, alleviating symptoms of a disease / condition, or reducing the pathology of a disease / condition. The method may be effective to prevent the progression of a disease / condition, for example, to prevent the disease / condition from worsening or to slow its rate of progression. In some embodiments, the method may cause an improvement in the disease / condition, for example, a reduction in symptoms of the disease / condition, or a reduction in some other associated factor of the severity / activity of the disease / condition. In some embodiments, the method may prevent the disease / condition from progressing to a later stage (e.g., chronic or metastatic).

[0562] It will be understood that the articles of the present disclosure may be used in the treatment / prevention of any disease / condition in which a therapeutic or prophylactic benefit would be derived from a reduction in the level / activity of signaling mediated by gp130, IL-6, gp130:IL-6Rα, IL-11 and / or gp130:IL-11Rα, or a reduction in the number or activity of cells containing / expressing gp130, gp130:IL-6Rα, and / or gp130:IL-11Rα.

[0563] For example, the disease / condition can be one in which gp130, IL-6, gp130:IL-6Rα, IL-11 and / or gp130:IL-11Rα, or cells containing / expressing gp130, IL-6, gp130:IL-6Rα, IL-11 and / or gp130:IL-11Rα are pathologically involved, e.g., an increase in the level / activity of gp130, IL-6, gp130:IL-6Rα, IL-11 and / or gp130:IL-11Rα, or an increase in the number / proportion of cells containing / expressing gp130, IL-6, gp130:IL-6Rα, IL-11 and / or gp130:IL-11Rα, positively correlates with the onset, development or progression of the disease / condition and / or the severity of one or more symptoms of the disease / condition. In some embodiments, an increase in the level / activity of gp130, IL-6, gp130:IL-6Rα, IL-11 and / or gp130:IL-11Rα, or an increase in the number / proportion of cells containing / expressing gp130, IL-6, gp130:IL-6Rα, IL-11, and / or gp130:IL-11Rα may be a risk factor for the onset, development, or progression of a disease / condition.

[0564] In some embodiments, the disease / condition treated / prevented in accordance with the present disclosure is one characterized by an elevated level of expression or activity of gp130, IL-6, gp130:IL-6Rα, IL-11, and / or gp130:IL-11Rα, e.g., when compared to the level of expression / activity in the absence of the disease / condition. In some embodiments, the disease / condition treated / prevented is one characterized by an elevated number / proportion / activity of cells expressing gp130, IL-6, gp130:IL-6Rα, IL-11, and / or gp130:IL-11Rα, e.g., when compared to the level / number / proportion / activity in the absence of the disease / condition (e.g., in a healthy subject, or in a comparable non-diseased tissue).

[0565] If the disease / condition is cancer, the levels of expression or activity of gp130, IL-6, gp130:IL-6Rα, IL-11, and / or gp130:IL-11Rα may be higher than the levels of gp130, IL-6, gp130:IL-6Rα, IL-11, and / or gp130:IL-11Rα in comparable non-cancer cells / non-tumor tissue. The cancer / its cells may contain one or more mutations (e.g., compared to comparable non-cancer cells / non-tumor tissue) that result in upregulation of gp130, IL-6, gp130:IL-6Rα, IL-11, and / or gp130:IL-11Rα expression or activity.

[0566] Treatment with the methods of the present disclosure may achieve a decrease in the activity of gp130, IL-6, gp130:IL-6Rα, IL-11, and / or gp130:IL-11Rα in a subject (compared to an equivalent untreated subject, or a subject treated with an appropriate control).

[0567] In some aspects and embodiments, articles of the present disclosure are provided for the treatment / prevention of a disease / condition selected from the following: a disease / condition in which IL-6-mediated signaling is pathologically implicated, a disease / condition in which gp130:IL-6Rα-mediated signaling is pathologically implicated, a disease / condition in which IL-11-mediated signaling is pathologically implicated, a disease / condition in which gp130:IL-11Rα-mediated signaling is pathologically implicated, pathological inflammation, fibrosis, a disease / condition characterized by inflammation, a disease / condition characterized by fibrosis, or systemic sclerosis.

[0568] In some embodiments, the disease / condition treated / prevented in accordance with the present disclosure is systemic sclerosis.

[0569] In some aspects and embodiments, articles of the present disclosure are provided for the treatment / prevention of inflammation, particularly pathological inflammation.

[0570] Inflammation and its role in health and disease are reviewed, for example, in Chen et al., Oncotarget (2018) 9(6):7204-7218, which is incorporated herein by reference in its entirety. Inflammation refers to the body's response to cell / tissue injury and is characterized 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. Injury can result from, for example, physical (e.g., mechanical) or chemical injury, trauma, infection, cancer, or an exaggerated / abnormal immune response (e.g., autoimmune disease). Inflammation forms part of the innate immune response and plays an important physiological role in wound healing and infection control, contributing to the restoration of tissue homeostasis.

[0571] However, many diseases are associated with an excessive inflammatory response (i.e., excessive inflammation and / or abnormally activated inflammation) and / or chronic (long-term) inflammation. As used herein, excessive and / or chronic inflammation may be referred to as "pathological inflammation." Pathological inflammation may refer to inflammation that is involved in (i.e., actively contributes to) the pathology of a disease.

[0572] The inflammation to be treated / prevented according to the present disclosure may occur in any tissue / organ of the body. In some embodiments, the inflammation is in the lungs (e.g., bronchioles, alveoli), airways (e.g., nasal cavity, oral cavity, pharynx, larynx, trachea, bronchi), heart, kidneys, liver, skeletal muscles, blood vessels, eyes, skin, pancreas, intestines, small intestine, large intestine, colon, joints, brain, or bone marrow. Inflammation may also occur in multiple tissues / organs simultaneously.

[0573] In some embodiments, the inflammation can be inflammation of an organ or tissue of the respiratory system, e.g., the lungs (e.g., bronchioles, alveoli), or the airways (e.g., nasal cavity, oral cavity, pharynx, larynx, trachea, bronchi). In some embodiments, the inflammation can be inflammation of an organ or tissue of the cardiovascular system, e.g., the heart or blood vessels. In some embodiments, the inflammation can be inflammation of an organ or tissue of the gastrointestinal system, e.g., the liver, intestine, small intestine, large intestine, colon, or pancreas. In some embodiments, the inflammation can be inflammation of the eye. In some embodiments, the inflammation can be inflammation of the skin. In some embodiments, the inflammation can be inflammation of an organ or tissue of the nervous system, e.g., the brain. In some embodiments, the inflammation can be inflammation of the bone marrow. In some embodiments, the inflammation can be inflammation of a joint. In some embodiments, the inflammation can be inflammation of an organ or tissue of the urinary system, e.g., the kidney. In some embodiments, the inflammation can be inflammation of an organ or tissue of the musculoskeletal system, e.g., muscle tissue. In some embodiments, the inflammation can be inflammation of an organ or tissue of one or more organ systems.

[0574] Inflammation can promote angiogenesis (i.e., the growth and development of new blood vessels from existing vasculature) through several different pathways, as described, for example, in Granger and Senchenkova, "Chapter 6: Angiogenesis," in "Inflammation and the Microcirculation," Morgan & Claypool Life Sciences; 2010. For example, inflammation can cause hypoxia in inflamed tissue, which upregulates the expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, which induces the growth of new blood vessels. Inflammatory cells such as macrophages, lymphocytes, mast cells, and fibroblasts also produce angiogenic factors such as VEGF and FGF. Increased blood flow to inflamed tissues can stimulate angiogenesis through shear stress on the endothelium of existing blood vessels, and extravasated plasma proteins such as fibrinogen preparations can also stimulate angiogenesis. In some embodiments, the disease / condition treated / prevented in accordance with the present disclosure is a disease / condition characterized by angiogenesis, for example, a disease / condition characterized by inflammation-induced angiogenesis.

[0575] Angiogenesis is known to be dysregulated, for example, in systemic sclerosis, a chronic autoimmune connective tissue disease characterized by inflammation, vascular injury and fibrosis, and an impaired angiogenic response that fails to ensure efficient vascular recovery—reviewed, for example, in Cantatore et al., Biomed Res Int. (2017) 2017:5345673, incorporated herein by reference in its entirety. Vascular injury in systemic sclerosis induces hypoxia and tissue ischemia (which are normally the primary triggers for angiogenesis) through tissue angiogenesis, leading to vascular occlusion and thrombosis in larger blood vessels through endothelial proliferation, fibrin deposition, and smooth muscle cell hypertrophy. However, when angiogenesis is dysregulated, compensatory angiogenesis is not induced, and vascular injury can induce morphological changes in the vascular wall, such as non-vascularized areas or fibrosis. Angiogenic cytokines such as VEGF, TGFβ and PDGF, which are responsible for the formation and stabilization of blood vessels, are also involved in fibrosis, further contributing to vascular instability and loss of peripheral vascularization.

[0576] Inflammatory responses play a key role in causing fibrosis in many different organ systems. Inflammation can lead to excessive deposition of ECM components in 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, persistent inflammatory triggers are essential for upregulating the 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.

[0577] In some aspects and embodiments, articles of the present disclosure are provided for the treatment / prevention of fibrosis.

[0578] Fibrosis is a form of pathological tissue remodeling characterized by the formation of excess connective tissue as a result of excessive deposition of extracellular matrix (ECM) components (including collagen). "Excess connective tissue" refers to the amount of connective tissue in a given location (e.g., a given tissue / organ, or part of a given tissue / organ) that is greater than the amount of connective tissue present in the same location under normal, non-pathological conditions. Similarly, "excessive deposition of ECM components" refers to a deposition level of one or more ECM components that is higher than the deposition level under normal, non-pathological conditions.

[0579] 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 incorporated herein by reference in their entireties.

[0580] Tissue damage can result from a variety of stimuli, including infection, autoimmune reactions, toxins, radiation, and mechanical injury. Repair typically involves the replacement of damaged cells with allogeneic cells and the replacement of normal parenchymal tissue with connective tissue. If the repair process is not properly regulated, it can become pathological, resulting in excessive deposition of ECM components, replacing normal parenchymal tissue with connective tissue. In diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, cardiovascular fibrosis, systemic sclerosis, and nephritis, extensive tissue remodeling and fibrosis can ultimately lead to organ failure and death.

[0581] The primary cellular effector of fibrosis is the myofibroblast. In response to tissue injury, injured cells and leukocytes produce pro-fibroinflammatory factors, such as TGFβ, IL-13, and PDGF, which activate fibroblasts (and other myofibroblast precursor cells) to become αSMA-expressing myofibroblasts and recruit myofibroblasts to the injury site. Myofibroblasts produce large amounts of extracellular matrix components, such as collagen and periostin, for wound contraction and closure, as well as inflammatory cytokines, such as IL-6, and tissue remodeling factors, such as MMP2 and TIMP1. Persistent / chronic infection and / or inflammation can lead to the excessive production of myofibroblasts, resulting in excessive production of extracellular matrix and fibrosis. In many diseases and conditions characterized by fibrosis, persistent inflammatory triggers are essential for the up-regulation of the 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.

[0582] Fibrosis can be caused by pathological conditions, such as conditions, infections, or disease states, which result in the production of profibrotic factors (e.g., TGFβ1). Fibrosis can be caused by physical damage / irritation, chemical damage / irritation, or environmental damage / irritation. Physical damage / irritation can occur during surgery, for example, due to iatrogenic causes. Chemical damage / irritation can include drug-induced fibrosis, such as fibrosis after long-term 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 damage / irritation can include exposure to asbestos fibers or silica.

[0583] Fibrosis can be in any tissue / organ in the body. In some embodiments, fibrosis is inflammation in the lungs (e.g., bronchioles, alveoli), airways (e.g., nasal cavity, oral cavity, pharynx, larynx, trachea, bronchi), heart, kidneys, liver, skeletal muscle, blood vessels, eyes, skin, pancreas, intestines, small intestine, large intestine, colon, joints, brain, or bone marrow. Fibrosis can also occur in multiple tissues / organs simultaneously.

[0584] In some embodiments, the fibrosis can be inflammation of an organ or tissue of the respiratory system, e.g., the lungs (e.g., bronchioles, alveoli), or the airways (e.g., nasal cavity, oral cavity, pharynx, larynx, trachea, bronchi). In some embodiments, the fibrosis can be inflammation of an organ or tissue of the cardiovascular system, e.g., the heart or blood vessels. In some embodiments, the fibrosis can be inflammation of an organ or tissue of the gastrointestinal system, e.g., the liver, intestine, small intestine, large intestine, colon, or pancreas. In some embodiments, the fibrosis can be inflammation of the eye. In some embodiments, the fibrosis can be inflammation of the skin. In some embodiments, the fibrosis can be inflammation of an organ or tissue of the nervous system, e.g., the brain. In some embodiments, the fibrosis can be inflammation of the bone marrow. In some embodiments, the fibrosis can be inflammation of a joint. In some embodiments, the fibrosis can be inflammation of an organ or tissue of the urinary system, e.g., the kidney. In some embodiments, the fibrosis can be inflammation of an organ or tissue of the musculoskeletal system, e.g., muscle tissue. In some embodiments, the fibrosis can be inflammation of an organ or tissue of one or more organ systems.

[0585] In some embodiments, the disease / condition treated in accordance with the present disclosure is a disease / condition characterized by inflammation. In some embodiments, the disease / condition is a disease / condition characterized by fibrosis. In some embodiments, the disease / condition is a disease / condition characterized by inflammation and fibrosis.

[0586] As used herein, a disease / condition "characterized by inflammation" is a disease / condition in which inflammation is a symptom of the disease / condition. Diseases / conditions characterized by inflammation include, but are not limited to: Diseases / conditions affecting the respiratory system, such as sinusitis, rhinitis, pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonia, pleuritis, and mediastinitis; 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, cardiogenic shock, pericarditis, vasculitis, arteritis, phlebitis and capillitis; Diseases / conditions affecting the urinary system, such as nephritis, glomerulonephritis, pyelonephritis, ureteritis, cystitis and urethritis; Diseases / conditions affecting the nervous system, such as encephalitis, osteomyelitis, meningitis, arachnoiditis, and neuritis; Diseases / conditions affecting the musculoskeletal system, such as arthritis, dermatomyositis, soft tissue, myositis, synovitis / tenosynovitis, bursitis, enthesitis, fasciitis, capsulitis, humeral osteitis, tendonitis, panniculitis, osteochondritis: osteitis / osteomyelitis, spondylitis, periostitis and chondritis; Diseases / conditions affecting the mouth and throat, such as stomatitis, gingivitis, gingivostomatitis, periodontitis, glossitis, tonsillitis, sialadenitis, parotitis, cheilitis, pulpitis and jaw inflammation; Diseases / conditions affecting the gastrointestinal system, such as esophagitis, gastritis, gastroenteritis, enteritis, colitis, enterocolitis, duodenitis, ileitis, appendicitis, proctitis and Peutz-Jeghers syndrome; Diseases / conditions affecting the skin, such as dermatitis, folliculitis, cellulitis and hidradenitis; Diseases / conditions affecting the eyes, such as dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis and uveitis; Diseases / conditions affecting the ear, such as otitis externa, otitis media, labyrinthitis and mastoiditis; Diseases / conditions of the reproductive system such as oophoritis, salpingitis, endometritis, endometriosis, parametritis, cervicitis, vaginitis, vulvitis, mastitis, orchitis, epididymitis, prostatitis, seminal vesiculitis, balanitis, presitis, balanoposthitis, chorioamnionitis, omphalitis and omphalitis; Diseases / conditions of the endocrine system such as insulitis, hypophysitis, thyroiditis, parathyroiditis and adrenalitis; Diseases / conditions of the lymphatic system such as lymphangitis and lymphadenitis; 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, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, colon cancer, liver cancer (e.g., hepatocellular carcinoma), and cholangiocarcinoma.

[0587] As used herein, a disea...

Claims

1. An optionally isolated antigen binding molecule that binds to gp130, wherein the antigen binding molecule inhibits signaling mediated by gp130:IL-6Rα and / or gp130:IL-11Rα, and the antigen binding molecule does not inhibit signaling mediated by one or more of gp130:OSMRβ, gp130:LIFRβ, gp130:LIFRβ:CNTFRα, gp130:IL-27Rα, and gp130:IL-12Rβ2.

2. The antigen-binding molecule of claim 1, wherein the antigen binding inhibits signal transduction mediated by gp130:IL-6Rα and gp130:IL-11Rα.

3. The antigen-binding molecule of claim 1 or claim 2, wherein the antigen-binding molecule does not inhibit signal transduction mediated by gp130:OSMRβ, does not inhibit signal transduction mediated by gp130:LIFRβ, and does not inhibit signal transduction mediated by gp130:LIFRβ:CNTFRα.

4. The antigen-binding molecule of any one of claims 1 to 3, wherein the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:

386.

5. The antigen-binding molecule of any one of claims 1 to 4, comprising: (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: 249 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: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 286; 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: 246 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: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 281; 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: 244 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: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 284; 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: 245 HC-CDR3 having the amino acid sequence of SEQ ID NO:4; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 10 LC-CDR2 having the amino acid sequence of SEQ ID NO: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 281; or (e) (i) a heavy chain variable (VH) region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 62 HC-CDR2 having the amino acid sequence of SEQ ID NO: 63 HC-CDR3 having the amino acid sequence of SEQ ID NO: 64; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 65 LC-CDR2 having the amino acid sequence of SEQ ID NO: 66 LC-CDR3 having the amino acid sequence of SEQ ID NO: 67; or (f) (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: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 12; or (g) (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: 20; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 24 LC-CDR2 having the amino acid sequence of SEQ ID NO: 25 LC-CDR3 having the amino acid sequence of SEQ ID NO: 26; or (h) (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: 32; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 24 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 (i) (i) a heavy chain variable (VH) region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 37 HC-CDR2 having the amino acid sequence of SEQ ID NO: 38 HC-CDR3 having the amino acid sequence of SEQ ID NO: 39; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 45 LC-CDR2 having the amino acid sequence of SEQ ID NO: 46 LC-CDR3 having the amino acid sequence of SEQ ID NO: 47; or (j) (i) a heavy chain variable (VH) region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 52 HC-CDR2 having the amino acid sequence of SEQ ID NO:53 HC-CDR3 having the amino acid sequence of SEQ ID NO:54; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 24 LC-CDR2 having the amino acid sequence of SEQ ID NO: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO:

58.

6. The antigen-binding molecule of any one of claims 1 to 5, comprising: a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 221, 241, 219, 239, 220, 240, 74, 106, 78, 80, 83, 1, 17, 31, 36, 51, 86, or 87; and A VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 271, 274, 75, 110, 88, 91, 95, 98, 100, 9, 23, 34, 44, or 57.

7. The antigen-binding molecule comprises: a VH region having an amino acid sequence having at least 70% amino acid sequence identity to the amino acid sequence shown in column A of Table C; and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to an amino acid sequence shown in column B of Table C; The antigen-binding molecule of any one of claims 1 to 6, wherein the sequences in columns A and B are selected from the same row of Table C.

8. The antigen-binding molecule of any one of claims 1 to 7, wherein the antigen-binding molecule is a multispecific antigen-binding molecule and further comprises an antigen-binding domain that binds to an antigen other than gp130.

9. A chimeric antigen receptor (CAR) comprising the antigen-binding molecule of any one of claims 1 to 8.

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

11. An expression vector or a plurality of expression vectors comprising the nucleic acid or nucleic acids of claim 9.

12. A cell comprising the antigen-binding molecule of any one of claims 1 to 8, the CAR of claim 9, the nucleic acid or multiple nucleic acids of claim 10, or the expression vector or multiple expression vectors of claim 11.

13. 13. A method according to claim 12, comprising culturing cells under conditions suitable for expression of the antigen-binding molecule or CAR by the cells.

14. A composition comprising the antigen-binding molecule of any one of claims 1 to 8, the CAR of claim 9, the nucleic acid or nucleic acids of claim 10, the expression vector or expression vectors of claim 11, or the cell of claim 12, and a pharmaceutically acceptable carrier, diluent, excipient, or adjuvant.

15. The antigen-binding molecule of any one of claims 1 to 8, the CAR of claim 9, the nucleic acid or nucleic acids of claim 10, the expression vector or expression vectors of claim 11, the cell of claim 12, or the composition of claim 14 for use in a method of treatment or prevention.

16. The antigen-binding molecule according to any one of claims 1 to 8, the CAR according to claim 9, the nucleic acid or nucleic acids according to claim 10, the expression vector or expression vectors according to claim 11, the cell according to claim 12, or the composition according to claim 14, for use in a method for treating or preventing the following: pathological inflammation, fibrosis, a disease / condition characterized by inflammation, a disease / condition characterized by fibrosis, a disease / condition characterized by inflammation and fibrosis, a disease / condition in which signaling via gp130-containing complexes is pathologically involved, or signaling via gp130-containing complexes. Diseases / conditions in which cytokines are pathologically involved, autoimmune diseases, metabolic syndrome, neurodegenerative diseases, chronic inflammatory diseases, arthritis, rheumatoid arthritis, juvenile arthritis, systemic juvenile idiopathic arthritis, lupus, systemic lupus erythematosus, pancreatitis, thyroiditis, periodontitis, rhinitis, allergic rhinitis, 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's arteritis, cardiovascular diseases, 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, keloids, scleroderma, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, hippocampal atrophy, lung 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, renal fibrosis, Alport syndrome, adult-onset Still's disease, Castleman's disease, cytokine release syndrome, sepsis, septic shock, retinal disorders, retinal fibrosis, age-related macular degeneration, wet age-related macular degeneration, retinitis pigmentosa, dry eye syndrome, COVID-19, Peutz-Jeghers syndrome, skeletal muscle diseases, muscular dystrophy, muscle atrophy,Cachexia, endocrine disorders, polycystic ovary syndrome, cancer, malignant hematological disorders, leukemia, plasmacytoma, Hodgkin's lymphoma, lung cancer, colorectal cancer, intestinal cancer, urinary tract cancer, bladder cancer, vulvar cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, osteosarcoma, glioblastoma, breast cancer, gastric cancer, kidney cancer, metastatic renal cell carcinoma, prostate cancer, skin cancer, melanoma, liver cancer, hepatocellular carcinoma, frailty, age-related increase in fat mass, sarcopenia, age-related dyslipidemia, age-related hypertriglyceridemia Choleridemia, age-related hypercholesterolemia, age-related fatty liver, 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 kidney disease, age-related skin disease, infectious diseases, viral diseases, viral hepatitis, hepatitis B, HIV infection, influenza infection, malaria, tuberculosis, allergic diseases, transplant rejection and graft-versus-host disease.

17. An in vitro complex, optionally isolated, comprising the antigen-binding molecule of any one of claims 1 to 8 bound to gp130.

18. A method for detecting gp130 in a sample, the method comprising contacting a sample containing or suspected of containing gp130 with the antigen-binding molecule of any one of claims 1 to 8, and detecting the formation of a complex between the antigen-binding molecule and gp130.

19. A method for selecting or stratifying a subject for treatment with a gp130-targeting drug, the method comprising contacting a sample from the subject in vitro with the antigen-binding molecule of any one of claims 1 to 8, and detecting the formation of a complex between the antigen-binding molecule and gp130.

20. Use of the antigen-binding molecule of any one of claims 1 to 8 as an in vitro or in vivo diagnostic or prognostic agent.

21. An antigen-binding molecule that binds to gp130 for use in a method for treating or preventing the following: pathological inflammation, fibrosis, diseases / conditions characterized by inflammation, diseases / conditions characterized by fibrosis, diseases / conditions characterized by inflammation and fibrosis, diseases / conditions in which signaling via gp130-containing complexes is pathologically implicated, diseases / conditions in which cytokines that signal via gp130-containing complexes are pathologically implicated, autoimmune diseases, metabolic syndrome, neurodegenerative diseases, chronic inflammatory diseases, arthritis, rheumatoid arthritis, juvenile arthritis, systemic juvenile idiopathic arthritis, loop inflammatory diseases, and rheumatoid arthritis. rhinitis, systemic lupus erythematosus, pancreatitis, thyroiditis, periodontitis, rhinitis, allergic rhinitis, 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's 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, lung 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 Nephritis, chronic kidney disease, renal fibrosis, Alport syndrome, adult-onset Still's disease, Castleman's disease, cytokine release syndrome, sepsis, septic shock, retinopathy, retinal fibrosis, age-related macular degeneration, wet age-related macular degeneration, retinitis pigmentosa, dry eye syndrome, COVID-19, Peutz-Jeghers syndrome, skeletal muscle disease, muscular dystrophy, muscle atrophy, cachexia, endocrine disorders, polycystic ovary syndrome, cancer, malignant blood disorders, leukemia, plasmacytoma, Hodgkin's lymphoma, lung cancer, colorectal cancer, intestinal cancer, urinary tract cancer, bladder cancer, vulvar cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer,Osteosarcoma, glioblastoma, breast cancer, gastric cancer, kidney cancer, metastatic renal cell carcinoma, prostate cancer, skin cancer, melanoma, liver cancer, hepatocellular carcinoma, frailty, age-related increase in fat mass, sarcopenia, age-related dyslipidemia, age-related hypertriglyceridemia, age-related hypercholesterolemia, age-related fatty liver, age-related non-alcoholic fatty liver disease, age-related non-alcoholic steatohepatitis, age-related cardiovascular disease, age-related hypertension, age-related kidney disease, age-related skin disease, infectious diseases, viral diseases, viral hepatitis, hepatitis B, HIV infection diseases, influenza infection, malaria, tuberculosis, allergic diseases, transplant rejection and graft-versus-host disease, wherein the antigen-binding molecule inhibits signaling mediated by gp130:IL-6Rα and / or gp130:IL-11Rα, and does not inhibit signaling mediated by one or more of gp130:OSMRβ, gp130:LIFRβ, gp130:LIFRβ:CNTFRα, gp130:IL-27Rα and gp130:IL-12Rβ2.

22. Use of an antigen binding molecule that binds to gp130 and inhibits IL-6-mediated signaling and / or IL-11-mediated signaling, wherein the antigen binding molecule inhibits signaling mediated by gp130:IL-6Rα and / or gp130:IL-11Rα, and the antigen binding molecule does not inhibit signaling mediated by one or more of gp130:OSMRβ, gp130:LIFRβ, gp130:LIFRβ:CNTFRα, gp130:IL-27Rα, and gp130:IL-12Rβ2.

23. 1. A method for inhibiting IL-6-mediated signaling and / or IL-11-mediated signaling, comprising contacting a cell capable of IL-6-mediated signaling and / or IL-11-mediated signaling with an antigen binding molecule that binds to gp130, wherein the antigen binding molecule inhibits signaling mediated by gp130:IL-6Rα and / or gp130:IL-11Rα, and the antigen binding molecule does not inhibit signaling mediated by one or more of gp130:OSMRβ, gp130:LIFRβ, gp130:LIFRβ:CNTFRα, gp130:IL-27Rα, and gp130:IL-12Rβ2.

24. 1. A method for inhibiting IL-6-mediated signaling and / or IL-11-mediated signaling in a subject, comprising administering to the subject an antigen-binding molecule that binds to gp130, wherein the antigen-binding molecule inhibits signaling mediated by gp130:IL-6Rα and / or gp130:IL-11Rα, and the antigen-binding molecule does not inhibit signaling mediated by one or more of gp130:OSMRβ, gp130:LIFRβ, gp130:LIFRβ:CNTFRα, gp130:IL-27Rα, and gp130:IL-12Rβ2.

25. An antigen-binding molecule for use according to claim 21, the use according to claim 22, or the method according to claim 23 or 24, wherein the antigen-binding molecule inhibits signal transduction mediated by gp130:IL-6Rα and gp130:IL-11Rα.

26. An antigen binding for use according to claim 21 or claim 25, a use according to claim 22 or claim 25, or a method according to any one of claims 23 to 25, wherein the antigen binding molecule does not inhibit signaling mediated by gp130:OSMRβ, does not inhibit signaling mediated by gp130:LIFRβ, and does not inhibit signaling mediated by gp130:LIFRβ:CNTFRα.

27. The antigen binding for the use according to any one of claims 21, 25, or 26, the use according to any one of claims 22, 25, or 26, or the method according to any one of claims 23 to 26, wherein the antigen-binding molecule contacts the region of gp130 shown in SEQ ID NO:

386.

28. Antigen binding for use according to any one of claims 21 or 25 to 27, the use according to any one of claims 22, 25 to 27, or the method according to any one of claims 23 to 27, 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: 249 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: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 286; 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: 246 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: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 281; 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: 244 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: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 284; 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: 245 HC-CDR3 having the amino acid sequence of SEQ ID NO:4; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 10 LC-CDR2 having the amino acid sequence of SEQ ID NO: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 281; or (e) (i) a heavy chain variable (VH) region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 62 HC-CDR2 having the amino acid sequence of SEQ ID NO: 63 HC-CDR3 having the amino acid sequence of SEQ ID NO: 64; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 65 LC-CDR2 having the amino acid sequence of SEQ ID NO: 66 LC-CDR3 having the amino acid sequence of SEQ ID NO: 67; or (f) (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: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO: 12; or (g) (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: 20; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 24 LC-CDR2 having the amino acid sequence of SEQ ID NO: 25 LC-CDR3 having the amino acid sequence of SEQ ID NO: 26; or (h) (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: 32; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 24 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 (i) (i) a heavy chain variable (VH) region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 37 HC-CDR2 having the amino acid sequence of SEQ ID NO: 38 HC-CDR3 having the amino acid sequence of SEQ ID NO: 39; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 45 LC-CDR2 having the amino acid sequence of SEQ ID NO: 46 LC-CDR3 having the amino acid sequence of SEQ ID NO: 47; or (j) (i) a heavy chain variable (VH) region incorporating the following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 52 HC-CDR2 having the amino acid sequence of SEQ ID NO:53 HC-CDR3 having the amino acid sequence of SEQ ID NO:54; and (ii) a light chain variable (VL) region incorporating the following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 24 LC-CDR2 having the amino acid sequence of SEQ ID NO: 11 LC-CDR3 having the amino acid sequence of SEQ ID NO:

58.

29. 29. An antigen binding for use according to any one of claims 21 or 25 to 28, a use according to any one of claims 22, 25 to 28, or a method according to any one of claims 23 to 28, wherein the antigen binding molecule comprises: a VH region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 221, 241, 219, 239, 220, 240, 74, 106, 78, 80, 83, 1, 17, 31, 36, 51, 86, or 87; and A VL region having an amino acid sequence having at least 70% amino acid sequence identity to SEQ ID NO: 271, 274, 75, 110, 88, 91, 95, 98, 100, 9, 23, 34, 44, or 57.

30. 30. An antigen binding for use according to any one of claims 21 or 25 to 29, a use according to any one of claims 22, 25 to 29, or a method according to any one of claims 23 to 29, wherein the antigen binding molecule comprises: a VH region having an amino acid sequence having at least 70% amino acid sequence identity to the amino acid sequence shown in column A of Table C; and a VL region having an amino acid sequence having at least 70% amino acid sequence identity to an amino acid sequence shown in column B of Table C; Here, the sequences in columns A and B are selected from the same row of table C.

31. The antigen binding for the use according to any one of claims 21 or 25 to 30, the use according to any one of claims 22, 25 to 30, or the method according to any one of claims 23 to 30, wherein the antigen-binding molecule is a multispecific antigen-binding molecule, and the antigen-binding molecule further comprises an antigen-binding domain that binds to an antigen other than gp130.

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