Neutralizing anti-tl1a monoclonal antibodies

Abstract

Described herein are methods and pharmaceutical compositions for the treatment of inflammatory bowel disease (IBD), Crohn's Disease (CD), ulcerative colitis (UC) and medically refractive-ulcerative colitis (MR-UC). In particular, disclosed are anti-TL1A antibodies useful for the treatment of IBD.

What is claimed is: 
     
         1 . An antibody or antigen-binding fragment that specifically binds to a TL1A polypeptide, comprising: a heavy chain comprising complementarity determining regions (CDRs) of SEQ ID NOs: 6-8 and a light chain comprising complementarity determining regions (CDRs) of SEQ ID NOs: 14-16. 
     
     
         2 . An antibody or antigen-binding fragment that specifically binds to a TL1A polypeptide, comprising: a heavy chain comprising complementarity determining regions (CDRs) of SEQ ID NOs: 22-24 and a light chain comprising complementarity determining regions (CDRs) of SEQ ID NOs: 30-32. 
     
     
         3 . The antibody or antigen-binding fragment of  claim 1  or  claim 2 , provided that the antibody or antigen-binding fragment is: a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a humanized antibody, a Fab, a Fab′, a F(ab′)2, a Fv, a disulfide linked Fv, a scFv, a single domain antibody, a diabody, a multispecific antibody, a dual specific antibody, an anti-idiotypic antibody, a bispecific antibody, or a combination thereof. 
     
     
         4 . A pharmaceutical composition comprising: a therapeutically effective amount of the antibody or antigen-binding fragment of  claim 1  or  claim 2 , and a pharmaceutically acceptable carrier. 
     
     
         5 . A method of treating inflammatory bowel disease in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of the antibody or an antigen-binding fragment of  claim 1  or  claim 2 . 
     
     
         6 . The method of  claim 5 , provided that the inflammatory bowel disease comprises Crohn's Disease, ulcerative colitis, medically refractive-ulcerative colitis, or a combination thereof. 
     
     
         7 . The method of  claim 5 , provided that prior to administering the antibody or antigen-binding fragment to the subject, the subject over-expresses TL1A. 
     
     
         8 . The method of  claim 5 , provided that the subject comprises a risk variant associated with the inflammatory bowel disease. 
     
     
         9 . A polypeptide comprising: one or more complementarity determining regions selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 30, SEQ ID NO: 31, and SEQ ID NO: 32. 
     
     
         10 . An antibody or antigen binding fragment that binds to the same region of human TL1A as a reference antibody comprising the heavy chain complementarity determining regions (CDRs) of SEQ ID NOs: 6-8 and the light chain complementarity determining regions (CDRs) of SEQ ID NOs: 14-16. 
     
     
         11 . The antibody or antigen binding fragment of  claim 10 , provided that the reference antibody comprises a heavy chain variable domain of SEQ ID NO: 5 and a light chain variable domain of SEQ ID NO: 13. 
     
     
         12 . An antibody or antigen binding fragment that binds to the same region of human TL1A as a reference antibody comprising the heavy chain complementarity determining regions (CDRs) of SEQ ID NOs: 22-24 and the light chain complementarity determining regions (CDRs) of SEQ ID NOs: 30-32. 
     
     
         13 . The antibody or antigen binding fragment of  claim 12 , provided that the reference antibody comprises a heavy chain variable domain of SEQ ID NO: 21 and a light chain variable domain of SEQ ID NO: 29. 
     
     
         14 . The antibody or antigen-binding fragment of any of  claims 10 - 13 , provided that the antibody or antigen-binding fragment is: a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a humanized antibody, a Fab, a Fab′, a F(ab′)2, a Fv, a disulfide linked Fv, a scFv, a single domain antibody, a diabody, a multispecific antibody, a dual specific antibody, an anti-idiotypic antibody, a bispecific antibody, or a combination thereof. 
     
     
         15 . A pharmaceutical composition comprising: a therapeutically effective amount of the antibody or antigen-binding fragment of any of  claims 10 - 14 , and a pharmaceutically acceptable carrier. 
     
     
         16 . A method of treating inflammatory bowel disease in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of the antibody or an antigen-binding fragment of any of  claims 10 - 14 . 
     
     
         17 . The method of  claim 16 , provided that the inflammatory bowel disease comprises Crohn's Disease, ulcerative colitis, medically refractive-ulcerative colitis, or a combination thereof. 
     
     
         18 . The method of  claim 16  or  claim 17 , provided that prior to administering the antibody or antigen-binding fragment to the subject, the subject over-expresses TL1A. 
     
     
         19 . The method of  claim 16  or  claim 17 , provided that the subject comprises a risk variant associated with the inflammatory bowel disease. 
     
     
         20 . A composition comprising a peptide having SEQ ID NO: 7. 
     
     
         21 . The composition of  claim 20 , further comprising one or more peptides selected from SEQ ID NOs: 6, 8, and 14-16. 
     
     
         22 . A composition comprising a peptide having SEQ ID NO: 23. 
     
     
         23 . The composition of  claim 22 , further comprising one or more peptides selected from SEQ ID NOs: 22, 24 and 30-32. 
     
     
         24 . A method of treating a subject having an inflammatory bowel disease, the method comprising administering to the subject an effective amount of the composition of any of  claims 20 - 23 . 
     
     
         25 . A method of treating an inflammatory bowel disease in a subject in need thereof, the method comprising administering to the subject an effective amount of an anti-TL1A antibody, provided that the subject comprises one or more risk variants at the TNFSF15 locus, and provided that the anti-TL1A antibody comprises a heavy chain comprising complementarity determining regions (CDRs) of SEQ ID NOs: 6-8 and a light chain comprising complementarity determining regions (CDRs) of SEQ ID NOs: 14-16. 
     
     
         26 . A method of treating an inflammatory bowel disease in a subject in need thereof, the method comprising administering to the subject an effective amount of an anti-TL1A antibody, provided that the subject comprises one or more risk variants at the TNFSF15 locus, and provided that the anti-TL1A antibody comprises a heavy chain comprising complementarity determining regions (CDRs) of SEQ ID NOs: 22-24 and a light chain comprising complementarity determining regions (CDRs) of SEQ ID NOs: 30-32. 
     
     
         27 . A method of treating an inflammatory bowel disease in a subject in need thereof, the method comprising administering to the subject an effective amount of an anti-TL1A antibody, provided that the subject over-express TL1A, and provided that the anti-TL1A antibody comprises a heavy chain comprising complementarity determining regions (CDRs) of SEQ ID NOs: 6-8 and a light chain comprising complementarity determining regions (CDRs) of SEQ ID NOs: 14-16. 
     
     
         28 . A method of treating an inflammatory bowel disease in a subject in need thereof, the method comprising administering to the subject an effective amount of an anti-TL1A antibody, provided that the subject over-express TL1A, and provided that the anti-TL1A antibody comprises a heavy chain comprising complementarity determining regions (CDRs) of SEQ ID NOs: 22-24 and a light chain comprising complementarity determining regions (CDRs) of SEQ ID NOs: 30-32. 
     
     
         29 . The method of any of  claims 25 - 28 , provided that the anti-TL1A antibody is: a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a humanized antibody, a Fab, a Fab′, a F(ab′)2, a Fv, a disulfide linked Fv, a scFv, a single domain antibody, a diabody, a multispecific antibody, a dual specific antibody, an anti-idiotypic antibody, a bispecific antibody, or a combination thereof. 
     
     
         30 . The method of any of  claims 25 - 29 , provided that the inflammatory bowel disease comprises Crohn's Disease, ulcerative colitis, medically refractive-ulcerative colitis, or a combination thereof.