Antibodies to MAdCAM

Abstract

The present disclosure relates to antibodies including human antibodies and antigen-binding portions thereof that specifically bind to MAdCAM, preferably human MAdCAM and that function to inhibit MAdCAM. The disclosure also relates to human anti-MAdCAM antibodies and antigen-binding portions thereof. The disclosure also relates to antibodies that are chimeric, bispecific, derivatized, single chain antibodies or portions of fusion proteins. The disclosure also relates to isolated heavy and light chain immunoglobulins derived from human anti-MAdCAM antibodies and nucleic acid molecules encoding such immunoglobulins. The present disclosure also relates to methods of making human anti-MAdCAM antibodies, compositions comprising these antibodies and methods of using the antibodies and compositions for diagnosis and treatment. The disclosure also provides gene therapy methods using nucleic acid molecules encoding the heavy and/or light immunoglobulin molecules that comprise the human anti-MAdCAM antibodies. The disclosure also relates to transgenic animals or plants comprising nucleic acid molecules of the disclosure.

1 . A human monoclonal antibody or an antigen-binding portion thereof that specifically binds to Mucosal Adressin Cell Adhesion Molecule (MAdCAM). 
     
     
         2 . The human monoclonal antibody or antigen-binding portion according to  claim 1 , wherein said antibody or portion possesses at least one of the following properties:
 (a) binds to human cells;   (b) has a selectivity for MAdCAM over VCAM or fibronectin of at least 100 fold;   (c) binds to human MAdCAM with a K d  of 3×10 −10  M or less; or   (d) inhibits the binding of α 4 β 7  expressing cells to human MAdCAM.   (e) inhibits the recruitment of lymphocytes to gastrointestinal lymphoid tissue.   
     
     
         3 . The human monoclonal antibody or antigen-binding portion according to  claim 2 , wherein said antibody or portion binds human MAdCAM with a K d  of 3×10 −10  M or less and inhibits α 4 β 7  binding to human MAdCAM. 
     
     
         4 . The human monoclonal antibody of  claim 1 , wherein the heavy chain comprises an amino acid sequence at least 80%, 85%, or 90% identical to SEQ ID NO: 148. 
     
     
         5 . The human monoclonal antibody of  claim 4 , wherein the heavy chain comprises an amino acid sequence identical to SEQ ID NO: 148. 
     
     
         6 . The human monoclonal antibody of  claim 4 , wherein the heavy chain comprises between 1 and 25 amino acid substitutions as compared to SEQ ID NO: 148. 
     
     
         7 . (canceled) 
     
     
         8 . The human monoclonal antibody of  claim 1 , wherein the light chain comprises an amino acid sequence at least 80%, 85%, or 90% identical to SEQ ID NO: 150. 
     
     
         9 . The human monoclonal antibody of  claim 8 , wherein the light chain comprises an amino acid sequence identical to SEQ ID NO: 150. 
     
     
         10 . The human monoclonal antibody of  claim 8 , wherein the light chain comprises between 1 and 25 amino acid substitutions as compared to SEQ ID NO: 150. 
     
     
         11 . (canceled) 
     
     
         12 . The human monoclonal antibody of  claim 1 , wherein the heavy chain comprises an amino acid sequence at least 80%, 85%, or 90% identical to SEQ ID NO: 148, and the light chain comprises an amino acid sequence at least 80%, 85%, or 90% identical to SEQ ID NO: 150. 
     
     
         13 . (canceled) 
     
     
         14 . A nucleic acid sequence encoding the amino acid sequence of  claim 4 . 
     
     
         15 . A cell producing the human monoclonal antibody  claim 1 . 
     
     
         16 - 30 . (canceled) 
     
     
         31 . A pharmaceutical composition comprising an effective amount of the monoclonal antibody or antigen-binding portion thereof according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         32 . A method of treating inflammatory disease in a subject in need thereof, comprising the step of administering to said subject the monoclonal antibody or antigen-binding portion thereof according to  claim 1  wherein said antibody or antigen-binding portion inhibits binding of MAdCAM to α 4 β 7 . 
     
     
         33 - 37 . (canceled) 
     
     
         38 . A cell line that produces an antibody selected from the group consisting of: 1.7.2, 1.8.2, 6.14.2, 6.22.2, 6.34.2, 6.67.1, 6.73.2, 6.77.1, 7.16.6, 7.20.5, 7.26.4, 9.8.2, and X481.2 or an antibody comprising the amino acid sequences of one of said antibodies. 
     
     
         39 - 44 . (canceled) 
     
     
         45 . A non-human transgenic animal or transgenic plant comprising (a) nucleic acid molecule encoding the heavy chain or an antigen-binding portion thereof; (b) a nucleic acid molecule encoding the light chain or an antigen-binding portion thereof; or (c) both (a) and (b) of an antibody according to  claim 1 , wherein the non-human transgenic animal or transgenic plant expresses said heavy chain or light chain or both. 
     
     
         46 . (canceled) 
     
     
         47 . A method of treating a subject in need thereof with a human antibody or antigen-binding portion thereof that specifically binds to MAdCAM and inhibits binding to α 4 β 7  comprising the steps of:
 (a) administering an effective amount of an isolated nucleic acid molecule encoding the heavy chain or an antigen-binding portion thereof, an isolated nucleic acid molecule encoding the light chain or an antigen-binding portion thereof, or nucleic acid molecules encoding the light chain and the heavy chain or antigen-binding portions thereof; and 
 (b) expressing the nucleic acid molecule. 
 
     
     
         48 - 49 . (canceled) 
     
     
         50 . A method of inhibiting α 4 β 7  binding to cells expressing human MAdCAM comprising contacting the cells with the monoclonal antibody according to  claim 1  or an antigen-binding portion thereof. 
     
     
         51 - 66 . (canceled) 
     
     
         67 . The monoclonal antibody, or antigen-binding portion thereof, of  claim 1  comprising the variable region of the light chain of SEQ ID NO: 150 and the variable region heavy chain of SEQ ID NO: 148. 
     
     
         68 . The monoclonal antibody, or antigen-binding fragment thereof, of  claim 1  comprising a heavy chain variable region encoded by nucleotide SEQ ID NO: 149, and a light chain variable region encoded by nucleotide SEQ ID NO: 35.