Antibodies that Bind to OX40 and Their Uses

Abstract

The present invention relates to antagonist antibodies or fragments thereof that bind to human OX40. More specifically, the present invention relates to an antagonist antibody or fragment thereof that binds to human OX40 comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 1, and/or a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and/or a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 3; and/or comprising a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 4, and/or a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 5 and/or a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 6.

1 - 73 . (canceled) 
     
     
         74 . A method for treating an OX40-mediated disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an antagonistic antibody or fragment thereof that binds to human OX40, wherein said antibody comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 3; and/or comprising a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 5 and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 6. 
     
     
         75 . The method of  claim 74 , wherein the antibody or fragment thereof is a murine antibody, chimeric antibody or a humanized antibody. 
     
     
         76 . The method of  claim 74 , wherein the antibody or fragment thereof is a humanized antibody. 
     
     
         77 . The method of  claim 74 , wherein the antibody or fragment thereof comprises a heavy chain variable region sequence comprising the amino acid sequence of SEQ ID NO:  7 . 
     
     
         78 . The method of  claim 74 , wherein the antibody or fragment thereof comprises a non-CDR region of a heavy chain variable region sequence which is at least 80% identical to the non-CDR region of the heavy chain variable region sequence of SEQ ID NO: 7. 
     
     
         79 . The method of  claim 74 , wherein the heavy chain sequence comprises a non-CDR region which is at least 80% identical to the non-CDR region of the heavy chain variable region sequence of the heavy chain sequence selected from the group consisting of SEQ ID NOS: 35, 36, 37 or 38. 
     
     
         80 . The method of  claim 79 , wherein the antibody or fragment thereof comprises a heavy chain sequence comprising the amino acid sequence selected from the group consisting of SEQ ID NOS: 35, 36, 37 and 38. 
     
     
         81 . The method of  claim 74 , wherein the antibody or fragment thereof comprises a heavy chain variable region sequence comprising the amino acid sequence selected from the group consisting of SEQ ID NOS: 58, 59, 79 and 80. 
     
     
         82 . The method of  claim 74 , wherein the antibody or fragment thereof comprises a non-CDR region of a heavy chain variable region sequence which is at least 80% identical to the non-CDR region of the heavy chain variable region sequence selected from the group consisting of SEQ ID NOS: 58, 59, 79 and 80. 
     
     
         83 . The method of  claim 74 , wherein the antibody or fragment thereof comprises a heavy chain variable framework region that is the product of a human gene selected from the group consisting of IGHV2-70*10 (SEQ ID NO: 19), IGHV2-70*01 (SEQ ID NO: 20), IGHV2-70*13 (SEQ ID NO: 21), IGHV2-5*09 (SEQ ID NO: 22), and IGHV2-70* 11 (SEQ ID NO: 23). 
     
     
         84 . The method of  claim 74 , wherein the antibody or fragment thereof comprises a heavy chain variable framework region that is the product of human gene IGHV2-70* 10 (SEQ ID NO: 19) and wherein the heavy chain variable framework region comprises at least one amino acid modification, wherein the amino acid modification comprises an amino acid substitution from the corresponding heavy chain variable framework region of the corresponding murine antibody of SEQ ID NO: 7 or wherein the antibody or fragment thereof comprises a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 32 and wherein the heavy chain variable framework region comprises at least one amino acid modification, wherein the amino acid modification comprises an amino acid substitution from the corresponding heavy chain variable framework region of the corresponding murine antibody of SEQ ID NO: 7. 
     
     
         85 . The method of  claim 84 , wherein the amino acid substitution is at an amino acid position selected from the group consisting of 23, 35, 48, 50, 60 and 62, wherein the amino acid position of each group member is indicated according to the Kabat numbering. 
     
     
         86 . The method of  claim 84 , wherein the amino acid substitution is selected from the group consisting of 23S, 35G, 48L, 50H, 60N, and 62A, wherein the amino acid position of each group member is indicated according to the Kabat numbering. 
     
     
         87 . The method of  claim 74 , wherein the antibody or fragment thereof comprises a light chain variable region sequence comprising the amino acid sequence of SEQ ID NO: 8, wherein the antibody or fragment thereof comprises a non-CDR region of a light chain variable region sequence which is at least 80% identical to the non-CDR region of the light chain variable region sequence of SEQ ID NO: 8, and/or wherein the light chain sequence comprises a non-CDR region which is at least 80% identical to the non-CDR region of the light chain variable region sequence of the light chain sequence selected from the group consisting of SEQ ID NOS: 45, 46, 47 and 49. 
     
     
         88 . The method of  claim 87 , wherein the antibody or fragment thereof comprises a light chain sequence comprising the amino acid sequence selected from the group consisting of SEQ ID NOS: 45, 46, 47 and 49. 
     
     
         89 . The method of  claim 74 , wherein the antibody or fragment thereof comprises a light chain variable region sequence comprising the amino acid sequence selected from the group consisting of SEQ ID NOS: 60, 86, 87 and 89, wherein the antibody or fragment thereof comprises a non-CDR region of a light chain variable region sequence which is at least 80% identical to the non-CDR region of the light chain variable region sequence selected from the group consisting of SEQ ID NOS: 60, 86, 87 and 89 and/or wherein the antibody or fragment thereof comprises a light chain variable framework region that is the product of a human gene selected from the group consisting of IGKV3-11*01 (SEQ ID NO: 24), IGKV1-39*01 (SEQ ID NO: 25), IGKV1D-39*01 (SEQ ID NO: 26), IGKV3-11*02 (SEQ ID NO: 27) and IGKV3-20*01 (SEQ ID NO: 28). 
     
     
         90 . The method of  claim 74 , wherein the antibody or fragment thereof comprises a light chain variable framework region that is the product of human gene IGKV3-11*01 (SEQ ID NO: 24) and wherein the light chain variable framework region comprises at least one amino acid modification, wherein the amino acid modification comprises an amino acid substitution or deletion from the corresponding framework region of the light chain variable region of the corresponding murine antibody of SEQ ID NO: 8 and/or wherein the antibody or fragment thereof comprises a light chain sequence comprising the amino acid sequence of SEQ ID NO: 39 and wherein the light chain variable framework region comprises at least one amino acid modification, wherein the amino acid modification comprises an amino acid substitution or deletion from the corresponding light chain variable framework region of the corresponding murine antibody of SEQ ID NO: 8. 
     
     
         91 . The method of  claim 90 , wherein the amino acid substitution is at an amino acid position selected from the group consisting of 1, 33, 34, 46, 47, 54, 56, and 71, wherein the amino acid position of each group member is indicated according to the Kabat numbering. 
     
     
         92 . The method of  claim 90 , wherein the amino acid substitution is selected from the group consisting of 1Q, 33M, 34H, 46P, 47W, 54L, 56S, and 71Y, wherein the amino acid position of each group member is indicated according to the Kabat numbering. 
     
     
         93 . The method of  claim 90 , wherein the amino acid deletion is at amino acid position 31, wherein the amino acid position is indicated according to the Kabat numbering. 
     
     
         94 . The method of  claim 74 , wherein the antibody or fragment thereof comprises:
 (a) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 37 or SEQ ID NO: 38; and   (b) a light chain sequence comprising the amino acid sequence of SEQ ID NO: 47.   
     
     
         95 . The method of  claim 74 , wherein the antibody or fragment thereof comprises:
 (a) a heavy chain variable region sequence comprising the amino acid sequence of SEQ ID NO: 58 or SEQ ID NO: 59; and   (b) a light chain variable region sequence comprising the amino acid sequence of SEQ ID NO: 60.   
     
     
         96 . The method of  claim 74 , wherein the antibody or fragment thereof comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 3; and/or comprises a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 5 and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 6, wherein at least one of the heavy chain CDRs and/or at least one of the light chain CDRs comprises no more than three amino acid modifications, wherein the amino acid modification is an amino acid substitution, insertion and/or deletion. 
     
     
         97 . The method of  claim 74 , further comprising heavy and/or light constant regions. 
     
     
         98 . The method of  claim 97 , wherein the human heavy constant region is selected from the group of human immunoglobulins consisting of IGHG1, non fucosylated IGHG1 and IGHG4. 
     
     
         99 . The method of  claim 74 , wherein the antibody is a monovalent antibody, a full length antibody, or an antibody fragment selected from the group consisting of Fab, Fab′, Fab′-SH, Fd, Fv, dAb, F(ab′)2, scFv, bispecific single chain Fv dimers, diabodies, triabodies and scFv genetically fused to the same or a different antibody. 
     
     
         100 . The method of  claim 74 , wherein the antibody comprises a variant Fc region which comprises at least one amino acid modification relative to the Fc region of a parent antibody, whereas the antibody comprising the variant Fc region exhibits altered effector function compared to the parent antibody. 
     
     
         101 . The method of  claim 74 , wherein the antibody or fragment thereof binds to human OX40 with an affinity (KD) of 110 nM or less, the antibody or fragment thereof retains at least 75% of the OX40 binding affinity (KD) of the corresponding chimeric antibody, the antibody or fragment thereof has equivalent or higher OX40 binding affinity (KD) when compared to the corresponding chimeric antibody and/or the antibody has a FAB fragment thermostability temperature greater than 75° C. 
     
     
         102 . A method for treating an OX40-mediated disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an antagonistic antibody or fragment thereof that binds to human OX40, wherein the antibody or fragment thereof that binds to human OX40 binds to the same epitope as the antibody of  claim 74  comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 3; and/or comprising a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 5 and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 6. 
     
     
         103 . The method of  claim 74 , the method comprising administering to the subject an immunoconjugate comprising a therapeutically effective amount of an antagonistic antibody or fragment thereof that binds to human OX40 comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 3; and/or comprising a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 5 and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 6 linked to a therapeutic agent and/or a pharmaceutically acceptable carrier. 
     
     
         104 . The method of  claim 103 , wherein the composition further comprises another pharmaceutically active agent. 
     
     
         105 . The method of  claim 103 , wherein the immunoconjugate further comprises a pharmaceutically acceptable carrier and another pharmaceutically active agent. 
     
     
         106 . The method of  claim 74 , wherein the OX40 mediated disorder is selected from the group consisting of infections (viral, bacterial, fungal and parasitic), endotoxic shock associated with infection, arthritis, rheumatoid arthritis, COPD, pelvic inflammatory disease, Alzheimer's Disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, Peyronie's Disease, coeliac disease, gallbladder disease, Pilonidal disease, peritonitis, psoriasis, vasculitis, surgical adhesions, stroke, Type I Diabetes, lyme disease, arthritis, meningoencephalitis, autoimmune uveitis, immune mediated inflammatory disorders of the central and peripheral nervous system such as multiple sclerosis, lupus (such as systemic lupus erythematosus) and Guillain-Barr syndrome, Atopic dermatitis, autoimmune hepatitis, fibrosing alveolitis, Grave's disease, IgA nephropathy, idiopathic thrombocytopenic purpura, Meniere's disease, pemphigus, primary biliary cirrhosis, sarcoidosis, scleroderma, Wegener's granulomatosis, other autoimmune disorders, pancreatitis, trauma (surgery), cardiovascular disease including ischaemic diseases such as myocardial infarction as well as atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, osteoarthritis, periodontitis, hypochlorhydia and neuromyelitis optica. 
     
     
         107 . The method of  claim 74 , wherein the OX40 mediated disorder is selected from the group consisting of infections (viral, bacterial, fungal and parasitic), endotoxic shock associated with infection, arthritis, rheumatoid arthritis, bronchitis, influenza, respiratory syncytial virus, pneumonia, COPD, idiopathic pulmonary fibrosis (IPF), cryptogenic fibrosing alveolitis (CFA), idiopathic fibrosing interstitial pneumonia, emphysema, pelvic inflammatory disease, Alzheimer's Disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, Peyronie's Disease, coehac disease, gallbladder disease, Pilonidal disease, peritonitis, psoriasis, vasculitis, surgical adhesions, stroke, Type I Diabetes, lyme disease, arthritis, meningoencephalitis, autoimmune uveitis, immune mediated inflammatory disorders of the central and peripheral nervous system such as multiple sclerosis, lupus (such as systemic lupus erythematosus) and Guillain-Barr syndrome, Atopic dermatitis, autoimmune hepatitis, fibrosing alveolitis, Grave's disease, IgA nephropathy, idiopathic thrombocytopenic purpura, Meniere's disease, pemphigus, primary biliary cirrhosis, sarcoidosis, scleroderma, Wegener's granulomatosis, other autoimmune disorders, pancreatitis, trauma (surgery), cardiovascular disease including ischaemic diseases such as myocardial infarction as well as atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, osteoarthritis, periodontitis, hypochlorhydia and neuromyelitis optica. 
     
     
         108 . The method of  claim 74 , wherein the subject has a low expression level of OX40, and/or wherein the antibody has enhanced cytotoxicity as compared to the antibody having human heavy chain constant region IGHG1. 
     
     
         109 . An article of manufacture comprising the antibody or fragment thereof of the method of  claim 74  for the treatment of an OX40 mediated disorder, wherein the OX40 mediated disorder is selected from the group consisting of: multiple sclerosis, rheumatoid arthritis, colitis, psoriasis, COPD, IPF, atherosclerosis and diabetes. 
     
     
         110 . A kit comprising the antibody or fragment thereof of the method of  claim 74  for the treatment of an OX40 mediated disorder, wherein the OX40 mediated disorder is selected from the group consisting of: multiple sclerosis, rheumatoid arthritis, colitis, psoriasis, COPD, IPF, atherosclerosis and diabetes.