METHODS OF ADMINISTERING ANTI-TNFalpha ANTIBODIES

Abstract

Methods of treating disorders in which TFNα activity is detrimental via biweekly, subcutaneous administration of human antibodies, preferably recombinant human antibodies, that specifically bind to human tumor necrosis factor α (hTNFα) are disclosed. The antibody may be administered with or without methotrexate. These antibodies have high affinity for hTNFα (e.g., K d =10 −8 M or less), a slow off rate for hTNFα dissociation (e.g., K off =10 −3 sec −1 or less) and neutralize hTNFα activity in vitro and in vivo. An antibody of the invention can be a full-length antibody or an antigen-binding portion thereof. Kits containing a pharmaceutical composition and instructions for dosing, and preloaded syringes containing pharmaceutical compositions are also encompassed by the invention.

1 . A method for treating an intestinal disorder in a human subject, comprising subcutaneously administering a total body dose of 20-80 mg of an isolated human anti-TNFα antibody, or an antigen-binding fragment thereof, to the human subject, on a biweekly dosing regimen such that the intestinal disorder is treated. 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein said human antibody, or an antigen-binding portion thereof, dissociates from human TNFα with a K d  of 1×10 −8  M or less and a K off  rate constant of 1×10 −3  s −1  or less, both determined by surface plasmon resonance, and neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC 50  of 1×10 −7  M or less. 
     
     
         5 . The method of  claim 4 , wherein said human antibody, or antigen-binding portion thereof, dissociates from human TNFα with a K off  rate constant of 5×10 −4  s −1  or less. 
     
     
         6 . The method of  claim 4 , wherein said human antibody, or antigen-binding portion thereof, dissociates from human TNFα with a K off  rate constant of 1×10 −4  s −1  or less. 
     
     
         7 . The method of  claim 4 , wherein said human antibody, or antigen-binding portion thereof, neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC 50  of 1×10 −8  M or less. 
     
     
         8 . The method of  claim 4 , wherein said human antibody, or antigen-binding portion thereof, neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC 50  of 1×10 −9  M or less. 
     
     
         9 . The method of  claim 4 , wherein said human antibody, or antigen-binding portion thereof, neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC 50  of 1×10 −10  M or less. 
     
     
         10 . (canceled) 
     
     
         11 . A method for inhibiting human TNFα activity in a human subject suffering from an intestinal disorder, comprising subcutaneously administering a total body dose of 20-80 mg of an isolated human anti-TNFα antibody, or an antigen-binding fragment thereof, to the human subject on a biweekly dosing regimen, wherein said human antibody, or antigen-binding portion thereof, has the following characteristics:
 dissociates from human TNFα with a K off  rate constant of 1×10 −3  s −1  or less, as determined by surface plasmon resonance, dissociates from human TNFα with a K d  of 1×10 −8  M or less as determined by surface plasmon resonance, and neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC 50  of 1×10 −7  M or less. 
 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 11 , wherein said human antibody, or an antigen-binding portion thereof, dissociates from human TNFα with a K off  rate constant of 5×10 −4  s −1  or less. 
     
     
         14 . A method for inhibiting human TNFα activity in a human subject suffering from an intestinal disorder, comprising subcutaneously administering a total body dose of 20-80 mg of a human anti-TNFα antibody, or an antigen-binding fragment thereof, to the human subject on a biweekly dosing regimen, wherein said human antibody, or an antigen-binding portion thereof, has a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 7, and has a heavy chain variable region (HCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 6, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 8. 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . A method for inhibiting human TNFα activity in a human subject suffering from an intestinal disorder, comprising subcutaneously administering a total body dose of 20-80 mg of a human anti-TNFα antibody, or an antigen-binding fragment thereof, to the human subject on a biweekly dosing regimen, wherein said human antibody, or an antigen binding portion thereof, has a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 2. 
     
     
         18 . The method of  claim 17 , wherein said human antibody has an IgG1 heavy chain constant region. 
     
     
         19 . The method of  claim 17 , wherein said human antibody has an IgG4 heavy chain constant region. 
     
     
         20 . The method of  claim 17 , wherein said human antibody is a Fab fragment. 
     
     
         21 . The method of  claim 17 , wherein said human antibody is a single chain Fv fragment. 
     
     
         22 . (canceled) 
     
     
         23 . A method for inhibiting human TNFα activity in a human subject suffering from an intestinal disorder, comprising subcutaneously administering a total body dose of 20-80 mg of a human anti-TNFα antibody, or an antigen-binding fragment thereof, to the human subject on a biweekly dosing regimen, said composition containing a human anti-TNFα antibody wherein said human antibody is the antibody D2E7 or an antigen-binding portion thereof. 
     
     
         24 .- 58 . (canceled) 
     
     
         59 . The method of  claim 1 , wherein the antibody is administered to the human subject together with the cytokine interleukin-6 (IL-6) or is administered to a human subject with a serum or plasma concentration of IL-6 above 500 pg/ml. 
     
     
         60 .- 72 . (canceled) 
     
     
         73 . The method of  claim 1 , wherein the intestinal disorder is an idiopathic inflammatory bowel disease. 
     
     
         74 . The method of  claim 11 , wherein the intestinal disorder is an idiopathic inflammatory bowel disease. 
     
     
         75 . The method of  claim 14 , wherein the intestinal disorder is an idiopathic inflammatory bowel disease. 
     
     
         76 . The method of  claim 17 , wherein the intestinal disorder is an idiopathic inflammatory bowel disease. 
     
     
         77 . The method of  claim 23 , wherein the intestinal disorder is an idiopathic inflammatory bowel disease. 
     
     
         78 . The method of  claim 73 , wherein the idiopathic inflammatory bowel disease is either Crohn's disease or ulcerative colitis. 
     
     
         79 . The method of  claim 74 , wherein the idiopathic inflammatory bowel disease is either Crohn's disease or ulcerative colitis. 
     
     
         80 . The method of  claim 75 , wherein the idiopathic inflammatory bowel disease is either Crohn's disease or ulcerative colitis. 
     
     
         81 . The method of  claim 76 , wherein the idiopathic inflammatory bowel disease is either Crohn's disease or ulcerative colitis. 
     
     
         82 . The method of  claim 77 , wherein the idiopathic inflammatory bowel disease is either Crohn's disease or ulcerative colitis.