Immunobinders directed against tnf

Abstract

Isolated binding proteins, e.g., antibodies or antigen binding portions thereof, which bind to tumor necrosis factor-alpha (TNF-α), e.g., human TNF-α, and related antibody-based compositions and molecules are disclosed. Also disclosed are pharmaceutical compositions comprising the antibodies, as well as therapeutic and diagnostic methods for using the antibodies.

1 - 18 . (canceled) 
     
     
         19 . A method for treating a mammal comprising administering to the mammal an effective amount of a pharmaceutical composition comprising a binding protein that binds human TNFα, the binding protein comprising at least one heavy chain variable region (VH region) and at least one light chain variable region (VL region),
 wherein the VH region comprises the amino acid sequences of the three complementarity determining regions (CDRs) from SEQ ID NO: 1077 or the amino acid sequence of SEQ ID NO: 1077, 
 wherein the VL region comprises the amino acid sequence of the three CDRs from SEQ ID NO: 1078 or the amino acid sequence of SEQ ID NO: 1078. 
 
     
     
         20 . (canceled) 
     
     
         21 . A method for reducing human TNF-α activity in a human subject suffering from a disorder in which TNF-α activity is detrimental, the method comprising administering to the human subject a binding protein of  claim 19  such that human TNF-α activity in the human subject is reduced and/or treatment is achieved. 
     
     
         22 . A method for treating a patient suffering from a disorder in which TNF-α is detrimental comprising administering to the patient the binding protein of  claim 19  either before, concurrent, or after the administration to the patient of a second agent, wherein the second agent is selected from the group consisting of an antibody, or fragment thereof, capable of binding human IL-12; PGE2; LPA; NGF; CGRP; SubP; RAGE; histamine; a histamine receptor blocker; bradykinin; IL-1alpha; IL-1beta; VEGF; PLGF; methotrexate; a corticosteroid, a glucocorticoid receptor modulator; cyclosporin, rapamycin, FK506, and a non-steroidal anti-inflammatory agent. 
     
     
         23 . The method of  claim 21 , wherein the disorder is an autoimmune and/or inflammatory disorder. 
     
     
         24 . The method of  claim 23 , wherein the disorder is selected from the group consisting of Crohn's disease, psoriasis, plaque psoriasis, arthritis, rheumatoid arthritis, psoratic arthritis, osteoarthritis, or juvenile idiopathic arthritis, multiple sclerosis, and ankylo sing spondylitis. 
     
     
         25 . The method of  claim 23 , wherein the disorder is selected from the group consisting of a respiratory disorder; asthma; allergic and nonallergic asthma; asthma due to infection; asthma due to infection with respiratory syncytial virus (RSV); chronic obstructive pulmonary disease (COPD); a condition involving airway inflammation; eosinophilia; fibrosis and excess mucus production; cystic fibrosis; pulmonary fibrosis; an atopic disorder; atopic dermatitis; urticaria; eczema; allergic rhinitis; allergic enterogastritis; an inflammatory and/or autoimmune condition of the skin; an inflammatory and/or autoimmune condition of gastrointestinal organs; inflammatory bowel diseases (IBD); ulcerative colitis; Crohn's disease; an inflammatory and/or autoimmune condition of the liver; liver cirrhosis; liver fibrosis; liver fibrosis caused by hepatitis B and/or C virus; scleroderma; tumors or cancers; hepatocellular carcinoma; glioblastoma; lymphoma; Hodgkin's lymphoma; a viral infection; a bacterial infection; a parasitic infection; HTLV-1 infection; suppression of expression of protective type 1 immune responses, and suppression of expression of a protective type 1 immune response during vaccination. 
     
     
         26 - 29 . (canceled) 
     
     
         30 . The method of  claim 22 , wherein the disorder is an autoimmune and/or inflammatory disorder. 
     
     
         31 . The method of  claim 30 , wherein the disorder is selected from the group consisting of Crohn's disease, psoriasis, plaque psoriasis, arthritis, rheumatoid arthritis, psoratic arthritis, osteoarthritis, or juvenile idiopathic arthritis, multiple sclerosis, and ankylo sing spondylitis. 
     
     
         32 . The method of  claim 30 , wherein the disorder is selected from the group consisting of a respiratory disorder; asthma; allergic and nonallergic asthma; asthma due to infection; asthma due to infection with respiratory syncytial virus (RSV); chronic obstructive pulmonary disease (COPD); a condition involving airway inflammation; eosinophilia; fibrosis and excess mucus production; cystic fibrosis; pulmonary fibrosis; an atopic disorder; atopic dermatitis; urticaria; eczema; allergic rhinitis; allergic enterogastritis; an inflammatory and/or autoimmune condition of the skin; an inflammatory and/or autoimmune condition of gastrointestinal organs; inflammatory bowel diseases (IBD); ulcerative colitis; Crohn's disease; an inflammatory and/or autoimmune condition of the liver; liver cirrhosis; liver fibrosis; liver fibrosis caused by hepatitis B and/or C virus; scleroderma; tumors or cancers; hepatocellular carcinoma; glioblastoma; lymphoma; Hodgkin's lymphoma; a viral infection; a bacterial infection; a parasitic infection; HTLV-1 infection; suppression of expression of protective type 1 immune responses, and suppression of expression of a protective type 1 immune response during vaccination. 
     
     
         33 . A method for treating a mammal comprising administering to the mammal an effective amount of a pharmaceutical composition comprising a binding protein that binds human TNFα, the binding protein comprising at least one heavy chain variable region (VH region), wherein the VH region comprises the amino acid sequences of the three complementarity determining regions (CDRs) from SEQ ID NO: 1077 or the amino acid sequence of SEQ ID NO: 1077. 
     
     
         34 . A method for reducing human TNF-α activity in a human subject suffering from a disorder in which TNF-α activity is detrimental, the method comprising administering to the human subject the binding protein of  claim 33  such that human TNF-α activity in the human subject is reduced and/or treatment is achieved. 
     
     
         35 . A method for treating a patient suffering from a disorder in which TNF-α is detrimental comprising administering to the patient the binding protein of  claim 33  either before, concurrent, or after the administration to the patient of a second agent, wherein the second agent is selected from the group consisting of an antibody, or fragment thereof, capable of binding human IL-12; PGE2; LPA; NGF; CGRP; SubP; RAGE; histamine; a histamine receptor blocker; bradykinin; IL-1alpha; IL-1beta; VEGF; PLGF; methotrexate; a corticosteroid, a glucocorticoid receptor modulator; cyclosporin, rapamycin, FK506, and a non-steroidal anti-inflammatory agent. 
     
     
         36 . The method of  claim 34 , wherein the disorder is an autoimmune and/or inflammatory disorder. 
     
     
         37 . The method of  claim 36 , wherein the disorder is selected from the group consisting of Crohn's disease, psoriasis, plaque psoriasis, arthritis, rheumatoid arthritis, psoratic arthritis, osteoarthritis, or juvenile idiopathic arthritis, multiple sclerosis, and ankylo sing spondylitis. 
     
     
         38 . The method of  claim 36 , wherein the disorder is selected from the group consisting of a respiratory disorder; asthma; allergic and nonallergic asthma; asthma due to infection; asthma due to infection with respiratory syncytial virus (RSV); chronic obstructive pulmonary disease (COPD); a condition involving airway inflammation; eosinophilia; fibrosis and excess mucus production; cystic fibrosis; pulmonary fibrosis; an atopic disorder; atopic dermatitis; urticaria; eczema; allergic rhinitis; allergic enterogastritis; an inflammatory and/or autoimmune condition of the skin; an inflammatory and/or autoimmune condition of gastrointestinal organs; inflammatory bowel diseases (IBD); ulcerative colitis; Crohn's disease; an inflammatory and/or autoimmune condition of the liver; liver cirrhosis; liver fibrosis; liver fibrosis caused by hepatitis B and/or C virus; scleroderma; tumors or cancers; hepatocellular carcinoma; glioblastoma; lymphoma; Hodgkin's lymphoma; a viral infection; a bacterial infection; a parasitic infection; HTLV-1 infection; suppression of expression of protective type 1 immune responses, and suppression of expression of a protective type 1 immune response during vaccination. 
     
     
         39 . The method of  claim 35 , wherein the disorder is an autoimmune and/or inflammatory disorder. 
     
     
         40 . The method of  claim 39 , wherein the disorder is selected from the group consisting of Crohn's disease, psoriasis, plaque psoriasis, arthritis, rheumatoid arthritis, psoratic arthritis, osteoarthritis, or juvenile idiopathic arthritis, multiple sclerosis, and ankylo sing spondylitis. 
     
     
         41 . The method of  claim 39 , wherein the disorder is selected from the group consisting of a respiratory disorder; asthma; allergic and nonallergic asthma; asthma due to infection; asthma due to infection with respiratory syncytial virus (RSV); chronic obstructive pulmonary disease (COPD); a condition involving airway inflammation; eosinophilia; fibrosis and excess mucus production; cystic fibrosis; pulmonary fibrosis; an atopic disorder; atopic dermatitis; urticaria; eczema; allergic rhinitis; allergic enterogastritis; an inflammatory and/or autoimmune condition of the skin; an inflammatory and/or autoimmune condition of gastrointestinal organs; inflammatory bowel diseases (IBD); ulcerative colitis; Crohn's disease; an inflammatory and/or autoimmune condition of the liver; liver cirrhosis; liver fibrosis; liver fibrosis caused by hepatitis B and/or C virus; scleroderma; tumors or cancers; hepatocellular carcinoma; glioblastoma; lymphoma; Hodgkin's lymphoma; a viral infection; a bacterial infection; a parasitic infection; HTLV-1 infection; suppression of expression of protective type 1 immune responses, and suppression of expression of a protective type 1 immune response during vaccination. 
     
     
         42 . A method for treating a mammal comprising administering to the mammal an effective amount of a pharmaceutical composition comprising a binding protein that binds human TNFα, the binding protein comprising at least one light chain variable region (VL region), wherein the VL region comprises the amino acid sequences of the three complementarity determining regions (CDRs) from SEQ ID NO: 1078 or the amino acid sequence of SEQ ID NO: 1078. 
     
     
         43 . A method for reducing human TNF-α activity in a human subject suffering from a disorder in which TNF-α activity is detrimental, the method comprising administering to the human subject the binding protein of  claim 40  such that human TNF-α activity in the human subject is reduced and/or treatment is achieved. 
     
     
         44 . A method for treating a patient suffering from a disorder in which TNF-α is detrimental comprising administering to the patient the binding protein of  claim 40  either before, concurrent, or after the administration to the patient of a second agent, wherein the second agent is selected from the group consisting of an antibody, or fragment thereof, capable of binding human IL-12; PGE2; LPA; NGF; CGRP; SubP; RAGE; histamine; a histamine receptor blocker; bradykinin; IL-1alpha; IL-1beta; VEGF; PLGF; methotrexate; a corticosteroid, a glucocorticoid receptor modulator; cyclosporin, rapamycin, FK506, and a non-steroidal anti-inflammatory agent. 
     
     
         45 . The method of  claim 43 , wherein the disorder is an autoimmune and/or inflammatory disorder. 
     
     
         46 . The method of  claim 45 , wherein the disorder is selected from the group consisting of Crohn's disease, psoriasis, plaque psoriasis, arthritis, rheumatoid arthritis, psoratic arthritis, osteoarthritis, or juvenile idiopathic arthritis, multiple sclerosis, and ankylo sing spondylitis. 
     
     
         47 . The method of  claim 45 , wherein the disorder is selected from the group consisting of a respiratory disorder; asthma; allergic and nonallergic asthma; asthma due to infection; asthma due to infection with respiratory syncytial virus (RSV); chronic obstructive pulmonary disease (COPD); a condition involving airway inflammation; eosinophilia; fibrosis and excess mucus production; cystic fibrosis; pulmonary fibrosis; an atopic disorder; atopic dermatitis; urticaria; eczema; allergic rhinitis; allergic enterogastritis; an inflammatory and/or autoimmune condition of the skin; an inflammatory and/or autoimmune condition of gastrointestinal organs; inflammatory bowel diseases (IBD); ulcerative colitis; Crohn's disease; an inflammatory and/or autoimmune condition of the liver; liver cirrhosis; liver fibrosis; liver fibrosis caused by hepatitis B and/or C virus; scleroderma; tumors or cancers; hepatocellular carcinoma; glioblastoma; lymphoma; Hodgkin's lymphoma; a viral infection; a bacterial infection; a parasitic infection; HTLV-1 infection; suppression of expression of protective type 1 immune responses, and suppression of expression of a protective type 1 immune response during vaccination. 
     
     
         48 . The method of  claim 44 , wherein the disorder is an autoimmune and/or inflammatory disorder. 
     
     
         49 . The method of  claim 48 , wherein the disorder is selected from the group consisting of Crohn's disease, psoriasis, plaque psoriasis, arthritis, rheumatoid arthritis, psoratic arthritis, osteoarthritis, or juvenile idiopathic arthritis, multiple sclerosis, and ankylo sing spondylitis. 
     
     
         50 . The method of  claim 48 , wherein the disorder is selected from the group consisting of a respiratory disorder; asthma; allergic and nonallergic asthma; asthma due to infection; asthma due to infection with respiratory syncytial virus (RSV); chronic obstructive pulmonary disease (COPD); a condition involving airway inflammation; eosinophilia; fibrosis and excess mucus production; cystic fibrosis; pulmonary fibrosis; an atopic disorder; atopic dermatitis; urticaria; eczema; allergic rhinitis; allergic enterogastritis; an inflammatory and/or autoimmune condition of the skin; an inflammatory and/or autoimmune condition of gastrointestinal organs; inflammatory bowel diseases (IBD); ulcerative colitis; Crohn's disease; an inflammatory and/or autoimmune condition of the liver; liver cirrhosis; liver fibrosis; liver fibrosis caused by hepatitis B and/or C virus; scleroderma; tumors or cancers; hepatocellular carcinoma; glioblastoma; lymphoma; Hodgkin's lymphoma; a viral infection; a bacterial infection; a parasitic infection; HTLV-1 infection; suppression of expression of protective type 1 immune responses, and suppression of expression of a protective type 1 immune response during vaccination. 
     
     
         51 . The method of  claim 19 , wherein the binding protein:
 (a) modulates a biological function of the TNF-α;   (b) neutralizes the TNF-α;   (c) diminishes the ability of the TNF-α to bind to its receptor;   (d) diminishes the ability of pro-human TNF-α, mature-human TNF-α, or truncated-human TNF-α to bind to its receptor; and/or   (e) reduces one or more of TNF-dependent cytokine production, TNF-dependent cell killing, TNF-dependent inflammation, TNF-dependent bone erosion, and TNF-dependent cartilage damage.   
     
     
         52 . The method of  claim 19 , wherein the binding protein comprises:
 (a) a heavy chain constant region comprising an amino acid sequence of SEQ ID NO:2 or SEQ ID NO: 3; and   (b) a light chain constant region comprising an amino acid sequence of SEQ ID NO:4 or SEQ ID NO: 5.   
     
     
         53 . The method of  claim 19 , the at least one heavy chain variable region (VH region) comprising: (a) three CDRs from any one of SEQ ID NOs: 74-83 and 778-956; or (b) any one of SEQ ID NOs: 74-83 and 778-956. 
     
     
         54 . The method of  claim 19 , the at least one light chain variable region (VL region) comprising: (a) three CDRs from any one of SEQ ID NOs: 84-93 and 957-1052; or (b) any one of SEQ ID NOs: 84-93 and 957-1052. 
     
     
         55 . The method of  claim 19 , the at least one heavy chain variable region (VH region) comprising: (a) three CDRs from any one of SEQ ID NOs: 74-83, 778-956; or (b) the sequence of any one of SEQ ID NOs: 74-83 and 778-956; and the at least one light chain variable region (VL region) comprising: (c) three CDRs from any one of SEQ ID NOs: 84-93 and 957-1052; or
 (d) the sequence of any one of SEQ ID NOs: 84-93 and 957-1052.   
     
     
         56 . The method of  claim 55 , wherein the VH region comprises the sequence of SEQ ID NO: 74 and the VL region comprises the sequence of SEQ ID NO: 84.