Antibodies to MAdCAM

Abstract

The present invention 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 invention also relates to human anti-MAdCAM antibodies and antigen-binding portions thereof. The invention also relates to antibodies that are chimeric, bispecific, derivatized, single chain antibodies or portions of fusion proteins. The invention also relates to isolated heavy and light chain immunoglobulins derived from human anti-MAdCAM antibodies and nucleic acid molecules encoding such immunoglobulins. The present invention 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 invention 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 invention also relates to transgenic animals or plants comprising nucleic acid molecules of the invention.

1 . (canceled) 
     
     
         2 . A human monoclonal antibody or antigen-binding portion thereof that specifically binds to Mucosal Adressin  Cell  Adhesion Molecule (MAdCAM), 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 . (canceled) 
     
     
         4 . A hybridoma cell line that produces the human monoclonal antibody according to claim  claim 2 , wherein the hybridoma is selected from the group consisting of 1.7.2 (ECACC Accession No. 03090901), 1.8.2 (ECACC Accession No. 03090902), 6.14.2 (ECACC Accession No. 03090903), 6.22.2 (ECACC Accession No. 03090904), 6.34.2 (ECACC Accession No. 03090905), 6.67.1 (ECACC Accession No. 03090906), 6.73.2 (ECACC Accession No. 03090907), 6.77.1 (ECACC Accession No. 03090908), 7.16.6 (ECACC Accession No. 03090909), 7.20.5 (ECACC Accession No. 03090910), 7.26.4 (ECACC Accession No. 03090911), and 9.8.2 (ECACC Accession No. 03090912). 
     
     
         5 . The human monoclonal antibody produced by the hybridoma cell line according to  claim 4  or an antigen-binding portion of said monoclonal antibody. 
     
     
         6 . (canceled) 
     
     
         7 . The human monoclonal antibody or antigen-binding portion thereof according to  claim 1 , wherein said antibody or antigen-binding portion inhibits binding of human MAdCAM to α 4 β 7 , and wherein the antibody or portion thereof has at least one of the following properties:
 (a) cross-competes with a reference antibody for binding to MAdCAM; 
 (b) competes with a reference antibody for binding to MAdCAM; 
 (c) binds to the same epitope of MAdCAM as a reference antibody; 
 (d) binds to MAdCAM with substantially the same K d  as a reference antibody; 
 (e) binds to MAdCAM with substantially the same off rate as a reference antibody; 
 
       wherein the reference antibody is selected from the group consisting of: monoclonal antibody 1.7.2, monoclonal antibody 1.8.2, monoclonal antibody 6.14.2, monoclonal antibody 6.22.2, monoclonal antibody 6.34.2, monoclonal antibody 6.67.1, monoclonal antibody 6.73.2, monoclonal antibody 6.77.1, monoclonal antibody 7.16.6, monoclonal antibody 7.20.5, monoclonal antibody 7.26.4, monoclonal antibody 9.8.2, monoclonal antibody 6.22.2-mod, monoclonal antibody 6.34.2-mod, monoclonal antibody 6.67.1-mod, monoclonal antibody 6.77.1-mod and monoclonal antibody 7.26.4-mod. 
     
     
         8 . The monoclonal antibody of  claim 5 , wherein the antibody is selected from the group consisting of:
 (a) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 2 and SEQ ID NO: 4, without the signal sequences;   (b) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 6 and SEQ ID NO: 8, without the signal sequences;   (c) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 10 and SEQ ID NO: 12, without the signal sequences;   (d) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 14 and SEQ ID NO: 16, without the signal sequences;   (e) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 18 and SEQ ID NO: 20, without the signal sequences;   (f) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 22 and SEQ ID NO: 24, without the signal sequences;   (g) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 26 and SEQ ID NO: 28, without the signal sequences;   (h) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 30 and SEQ ID NO: 32, without the signal sequences;   (i) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 34 and SEQ ID NO: 36, without the signal sequences;   (j) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 38 and SEQ ID NO: 40, without the signal sequences;   (k) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 42 and SEQ ID NO: 44, without the signal sequences;   (l) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 46 and SEQ ID NO: 48, without the signal sequences;   (m) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 52 and SEQ ID NO: 54, without the signal sequences;   (n) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 56 and SEQ ID NO: 58, without the signal sequences;   (o) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 60 and SEQ ID NO: 62, without the signal sequences;   (p) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 64 and SEQ ID NO: 66, without the signal sequences; and   (q) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 42 and SEQ ID NO: 68, without the signal sequences.   
     
     
         9 . A monoclonal antibody or an antigen-binding portion thereof, wherein the heavy chain of said antibody or portion thereof comprises the heavy chain CDR1, CDR2 and CDR3 or wherein the light chain comprises the light chain CDR1, CDR2 and CDR3 of a monoclonal 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, 6.22.2-mod, 6.34.2-mod, 6.67.1-mod, 6.77.1-mod and 7.26.4-mod. 
     
     
         10 - 11 . (canceled) 
     
     
         12 . The human monoclonal antibody or antigen-binding portion according to  claim 2 , wherein the heavy chain variable region, the light chain variable region or both are at least 90% identical in amino acid sequence to the corresponding region or regions of a monoclonal antibody selected from the group consisting of: monoclonal antibody 1.7.2, monoclonal antibody 1.8.2, monoclonal antibody 6.14.2, monoclonal antibody 6.22.2, monoclonal antibody 6.34.2, monoclonal antibody 6.67.1, monoclonal antibody 6.73.2, monoclonal antibody 6.77.1, monoclonal antibody 7.16.6, monoclonal antibody 7.20.5, monoclonal antibody 7.26.4 monoclonal antibody 9.8.2, monoclonal antibody 6.22.2-mod, monoclonal antibody 6.34.2-mod, monoclonal antibody 6.67.1-mod, monoclonal antibody 6.77.1-mod and monoclonal antibody 7.26.4-mod. 
     
     
         13 . A monoclonal antibody or an antigen-binding portion thereof that specifically binds MAdCAM according to  claim 2 , wherein:
 (a) the heavy chain comprises the heavy chain CDR1, CDR2 and CDR3 amino acid sequences of a reference 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, 6.22.2-mod, 6.34.2-mod, 6.67.1-mod, 6.77.1-mod and 7.26.4-mod   (b) the light chain comprises the light chain CDR1, CDR2 and CDR3 amino acid sequences of a reference 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, 6.22.2-mod, 6.34.2-mod, 6.67.1-mod, 6.77.1-mod and 7.26.4-mod   (c) the antibody comprises a heavy chain of (a) and a light chain of (b); and   (d) the antibody of (c) wherein the heavy chain and light chain CDR amino acid sequences are selected from the same reference antibody.   
     
     
         14 .- 17 . (canceled) 
     
     
         18 . A pharmaceutical composition comprising an effective amount of the monoclonal antibody or antigen-binding portion thereof according to  claim 2  and a pharmaceutically acceptable carrier. 
     
     
         19 . 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 2  wherein said antibody or antigen-binding portion inhibits binding of MAdCAM to α 4 β 7 . 
     
     
         20 .- 24 . (canceled) 
     
     
         25 . The cell line according to  claim 2  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 and 9.8.2, or an antibody comprising the amino acid sequences of one of said antibodies. 
     
     
         26 . (canceled) 
     
     
         27 . An isolated nucleic acid molecule comprising a nucleotide sequence that encodes the heavy chain or an antigen-binding portion thereof or the light chain or an antigen-binding portion thereof of an antibody according to  claim 2 . 
     
     
         28 .- 33 . (canceled) 
     
     
         34 . 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. 
 
     
     
         35 . A method for producing a human monoclonal antibody that specifically binds MAdCAM, comprising the steps of:
 (a) immunizing a non-human transgenic animal that is capable of producing human antibodies with MAdCAM, with an immunogenic portion of MAdCAM or a with cell or tissue expressing MAdCAM; and   (b) allowing the transgenic animal to mount an immune response to MAdCAM.   
     
     
         36 .- 41 . (canceled) 
     
     
         42 . A monoclonal antibody or an antigen-binding portion thereof of  claim 5  that specifically binds MAdCAM, and wherein said antibody or portion thereof comprises one or more of an FR1, FR2, FR3 or FR4 amino acid sequence of a human monoclonal 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, 6.22.2-mod, 6.34.2-mod, 6.67.1-mod, 6.77.1-mod and 7.26.4-mod. 
     
     
         43 . The human monoclonal antibody or antigen-binding portion according to  claim 2 , wherein the antibody comprises:
 (a) a heavy chain amino acid sequence that is at least 90% identical to the heavy chain amino acid sequence of a monoclonal 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, 6.22.2-mod, 6.34.2-mod, 6.67.1-mod, 6.77.1-mod and 7.26.4-mod;   (b) a light chain amino acid sequence that is at least 90% identical to the light chain amino acid sequence of a monoclonal 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, 6.22.2-mod, 6.34.2-mod, 6.67.1-mod, 6.77.1-mod and 7.26.4-mod;   (c) both (a) and (b); or   (d) either (a), (b) or (c), with or without the signal sequence.   
     
     
         44 . A method for diagnosing a disorder characterized by circulating soluble human MAdCAM comprising the steps of: (1) contacting a biological sample with the monoclonal antibody according to  claim 2  or antigen-binding portion and (2) detecting binding. 
     
     
         45 . A method for detecting inflammation in a subject comprising the steps of: (1) administering to said subject the monoclonal antibody or antigen-binding portion according to  claim 2  wherein said antibody or portion thereof is detectably labeled and (2) detecting binding. 
     
     
         46 .- 48 . (canceled) 
     
     
         49 . A vaccine comprising an effective amount of the human antibody thereof according to  claim 2  or antigen-binding portion and a pharmaceutically acceptable carrier. 
     
     
         50 . (canceled) 
     
     
         51 . A method of detecting the effect of administration of an inhibitory anti-MAdCAM antibody or antigen-binding portion thereof to a subject comprising the steps of:
 (a) administering to a subject a human monoclonal antibody that specifically binds to MAdCAM; and   (b) determining whether there is an increase in the levels of circulating α 4 β 7 -expressing leukocytes.   
     
     
         52 .- 53 . (canceled)