Novel MAdCAM antibodies

Abstract

The invention provides new, improved anti-MAdCAM antibodies. Uses of these antibodies in medicine are also included, in particular for the treatment of inflammatory conditions such as inflammatory bowel disease.

1 . A monoclonal antibody that specifically binds MAdCAM, or antigen-binding portion thereof, selected from the group consisting of: 
 (a) an antibody comprising the variable region of the heavy chain of 6.22.2-mod_V (SEQ ID NO: 2);    (b) an antibody comprising the variable region of the light chain of 6.34.2-mod_SSQ, 6.34.2-mod_QT, or 6.34.2-mod_SSQ,QT (SEQ ID NOs: 8, 10, 12);    (c) an antibody comprising the variable region of the light chain of 6.67.1-mod_Y, 6.67.1-mod_TAP, or 6.67.1-mod_Y,TΔP (SEQ ID NOs: 16, 18, 20);    (d) an antibody comprising the variable region of the heavy chain of 6.77.1-mod_AS (SEQ ID NO: 22);    (e) an antibody comprising the variable region of the heavy chain of 7.16.6_L (SEQ ID NO: 28); or    (f) an antibody comprising the variable region of the light chain of 7.16.6_V, 7.16.6_S, or 7.16.6_VS (SEQ ID NOs: 30, 32, 34);    (g) an antibody comprising the variable region of the light chain of 7.16.6_V, 7.16.6_S, or 7.16.6_VS (SEQ ID NOs: 30, 32, 34) and the variable region of the heavy chain of 7.16.6_L (SEQ ID NO: 28);    (h) an antibody comprising the variable region of the heavy chain of 9.8.2_ΔRGAYH,D (SEQ ID NO: 36); and    (i) an antibody comprising the variable region of the light chain of 9.8.2-mod (SEQ ID NO: 38).    
     
     
         2 . The antibody or portion thereof of  claim 1 , selected from the group consisting of: 
 (a) an antibody comprising the variable regions encoded by the nucleic acid sequences set forth in SEQ ID NO: 1 and SEQ ID NO: 3;    (b) an antibody comprising the variable regions encoded by the nucleic acid sequences set forth in SEQ ID NO: 5 and SEQ ID NOs: 7, 9 or 11;    (c) an antibody comprising the variable regions encoded by the nucleic acid sequences set forth in SEQ ID NO: 13 and SEQ ID NOs: 15, 17, or 19;    (d) an antibody comprising the variable regions encoded by the nucleic acid sequences set forth in SEQ ID NO: 21 and SEQ ID NO: 23;    (e) an antibody comprising the variable regions encoded by the nucleic acid sequences set forth in SEQ ID NOs: 25 or 27 and SEQ ID NOs: 29, 31, or 33; and    (f) an antibody comprising the variable regions encoded by the nucleic acid sequences set forth in SEQ ID NO: 35 and SEQ ID NO: 37.    
     
     
         3 . The antibody or portion thereof of  claim 1 , wherein the antibody is selected from the group consisting of: 
 (a) an antibody comprising the variable regions of 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 variable regions of the amino acid sequences set forth in SEQ ID NO: 6 and SEQ ID NOs: 8, 10, or 12, without the signal sequences;    (c) an antibody comprising the variable regions of the amino acid sequences set forth in SEQ ID NO: 14 and SEQ ID NOs: 16, 18, or 20, without the signal sequences;    (d) an antibody comprising the variable regions of the amino acid sequences set forth in SEQ ID NO: 22 and SEQ ID NO: 24, without the signal sequences;    (e) an antibody comprising the variable regions of the amino acid sequences set forth in SEQ ID NOs: 26 or 28 and SEQ ID NOs: 30, 32 or 34, without the signal sequences; and    (f) an antibody comprising the variable regions of the amino acid sequences set forth in SEQ ID NO: 36 and SEQ ID NO: 38, without the signal sequences.    
     
     
         4 . The antibody or portion thereof of  claim 1 , selected from the group consisting of: 
 (a) an antibody encoded by the nucleic acid sequences set forth in SEQ ID NO: 1 and SEQ ID NO: 3;    (b) an antibody encoded by the nucleic acid sequences set forth in SEQ ID NO: 5 and SEQ ID NOs: 7, 9 or 11;    (c) an antibody encoded by the nucleic acid sequences set forth in SEQ ID NO: 13 and SEQ ID NOs: 15, 17, or 19;    (d) an antibody encoded by the nucleic acid sequences set forth in SEQ ID NO: 21 and SEQ ID NO: 23;    (e) an antibody encoded by the nucleic acid sequences set forth in SEQ ID NOs: 25 or 27 and SEQ ID NOs: 29, 31, or 33; and    (f) an antibody encoded by the nucleic acid sequences set forth in SEQ ID NO: 35 and SEQ ID NO: 37.    
     
     
         5 . The monoclonal antibody or portion thereof of any of  claims 1  to  4 , wherein the heavy chain C-terminal lysine is cleaved.  
     
     
         6 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the antibody or antigen-binding portion thereof selected from the group consisting of: 
 (a) an antibody comprising the variable region of the heavy chain of 6.22.2-mod_V (SEQ ID NO: 2);    (b) an antibody comprising the variable region of the light chain of 6.34.2-mod_SSQ, 6.34.2-mod_QT, or 6.34.2-mod_SSQ,QT (SEQ ID NOs: 8, 10, 12);    (c) an antibody comprising the variable region of the light chain of 6.67.1-mod_Y, 6.67.1-mod_TΔP, or 6.67.1-mod_Y,TΔP (SEQ ID NOs: 16, 18, 20);    (d) an antibody comprising the variable region of the heavy chain of 6.77.1-mod_ΔS (SEQ ID NO: 22);    (e) an antibody comprising the variable region of the heavy chain of 7.16.6_L (SEQ ID NO: 28); or    (f) an antibody comprising the variable region of the light chain of 7.16.6_V, 7.16.6_S, or 7.16.6_VS (SEQ ID NOs: 30, 32, 34);    (g) an antibody comprising the variable region of the light chain of 7.16.6_V, 7.16.6_S, or 7.16.6_VS (SEQ ID NOs: 30, 32, 34) and the variable region of the heavy chain of 7.16.6_L (SEQ ID NO: 28);    (h) an antibody comprising the variable region of the heavy chain of 9.8.2_ΔRGAYH,D (SEQ ID NO: 36); and    (i) an antibody comprising the variable region of the light chain of 9.8.2-mod (SEQ ID NO: 38). of  claim 1 .    
     
     
         7 . The pharmaceutical composition of  claim 6  comprising an antibody or portion thereof selected from the group consisting of: 
 (a) an antibody comprising the variable regions encoded by the nucleic acid sequences set forth in SEQ ID NO: 1 and SEQ ID NO: 3;    (b) an antibody comprising the variable regions encoded by the nucleic acid sequences set forth in SEQ ID NO: 5 and SEQ ID NOs: 7, 9 or 11;    (c) an antibody comprising the variable regions encoded by the nucleic acid sequences set forth in SEQ ID NO: 13 and SEQ ID NOs: 15, 17, or 19;    (d) an antibody comprising the variable regions encoded by the nucleic acid sequences set forth in SEQ ID NO: 21 and SEQ ID NO: 23;    (e) an antibody comprising the variable regions encoded by the nucleic acid sequences set forth in SEQ ID NOs: 25 or 27 and SEQ ID NOs: 29, 31, or 33; and    (f) an antibody comprising the variable regions encoded by the nucleic acid sequences set forth in SEQ ID NO: 35 and SEQ ID NO: 37.    
     
     
         8 . The pharmaceutical composition of  claim 6  comprising an antibody or portion thereof selected from the group consisting of: 
 (a) an antibody comprising the variable regions of 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 variable regions of the amino acid sequences set forth in SEQ ID NO: 6 and SEQ ID NOs: 8, 10, or 12, without the signal sequences;    (c) an antibody comprising the variable regions of the amino acid sequences set forth in SEQ ID NO: 14 and SEQ ID NOs: 16, 18, or 20, without the signal sequences;    (d) an antibody comprising the variable regions of the amino acid sequences set forth in SEQ ID NO: 22 and SEQ ID NO: 24, without the signal sequences;    (e) an antibody comprising the variable regions of the amino acid sequences set forth in SEQ ID NOs: 26 or 28 and SEQ ID NOs: 30, 32 or 34, without the signal sequences; and    (f) an antibody comprising the variable regions of the amino acid sequences set forth in SEQ ID NO: 36 and SEQ ID NO: 38, without the signal sequences.    
     
     
         9 . The pharmaceutical composition of  claim 6  comprising an antibody or portion thereof selected from the group consisting of: 
 (a) an antibody encoded by the nucleic acid sequences set forth in SEQ ID NO: 1 and SEQ ID NO: 3;    (b) an antibody encoded by the nucleic acid sequences set forth in SEQ ID NO: 5 and SEQ ID NOs: 7, 9 or 11;    (c) an antibody encoded by the nucleic acid sequences set forth in SEQ ID NO: 13 and SEQ ID NOs: 15, 17, or 19;    (d) an antibody encoded by the nucleic acid sequences set forth in SEQ ID NO: 21 and SEQ ID NO: 23;    (e) an antibody encoded by the nucleic acid sequences set forth in SEQ ID NOs: 25 or 27 and SEQ ID NOs: 29, 31, or 33; and    (f) an antibody encoded by the nucleic acid sequences set forth in SEQ ID NO: 35 and SEQ ID NO: 37.    
     
     
         10 . The pharmaceutical composition any of  claims 6  to  9 , wherein the heavy chain C-terminal lysine of the antibody of portion thereof is cleaved.  
     
     
         11 . 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 selected from the group consisting of: 
 (a) an antibody comprising the variable region of the heavy chain of 6.22.2-mod_V (SEQ ID NO: 2);    (b) an antibody comprising the variable region of the light chain of 6.34.2-mod_SSQ, 6.34.2-mod_QT, or 6.34.2-mod_SSQ,QT (SEQ ID NOs: 8, 10, 12);    (c) an antibody comprising the variable region of the light chain of 6.67.1-mod_Y, 6.67.1-mod_TΔP, or 6.67.1-mod_Y,TΔP (SEQ ID NOs: 16, 18, 20);    (d) an antibody comprising the variable region of the heavy chain of 6.77.1-mod_ΔS (SEQ ID NO: 22);    (e) an antibody comprising the variable region of the heavy chain of 7.16.6_L (SEQ ID NO: 28); or    (f) an antibody comprising the variable region of the light chain of 7.16.6_V, 7.16.6_S, or 7.16.6_VS (SEQ ID NOs: 30, 32, 34);    (g) an antibody comprising the variable region of the light chain of 7.16.6_V, 7.16.6_S, or 7.16.6_VS (SEQ ID NOs: 30, 32, 34) and the variable region of the heavy chain of 7.16.6_L (SEQ ID NO: 28);    (h) an antibody comprising the variable region of the heavy chain of 9.8.2_ΔRGAYH,D (SEQ ID NO: 36); and    (i) an antibody comprising the variable region of the light chain of 9.8.2-mod (SEQ ID NO: 38).    
     
     
         12 . The method of  claim 11 , wherein said inflammatory disease involves MAdCAM-mediated adhesion of leukocytes.  
     
     
         13 . The method of  claim 11 , wherein the disease is selected from inflammatory bowel disease, liver fibrosis, graft versus host disease, uveitis, encephalitis, insulin-dependent diabetes,  
     
     
         14 . The method of  claim 13 , wherein inflammatory bowel disease is Crohn's disease or ulcerative colitis.  
     
     
         15 . The method of  claim 11 , comprising administering an antibody or portion thereof selected from the group consisting of: 
 (a) an antibody comprising the variable regions encoded by the nucleic acid sequences set forth in SEQ ID NO: 1 and SEQ ID NO: 3;    (b) an antibody comprising the variable regions encoded by the nucleic acid sequences set forth in SEQ ID NO: 5 and SEQ ID NOs: 7, 9 or 11;    (c) an antibody comprising the variable regions encoded by the nucleic acid sequences set forth in SEQ ID NO: 13 and SEQ ID NOs: 15, 17, or 19;    (d) an antibody comprising the variable regions encoded by the nucleic acid sequences set forth in SEQ ID NO: 21 and SEQ ID NO: 23;    (e) an antibody comprising the variable regions encoded by the nucleic acid sequences set forth in SEQ ID NOs: 25 or 27 and SEQ ID NOs: 29, 31, or 33; and    (f) an antibody comprising the variable regions encoded by the nucleic acid sequences set forth in SEQ ID NO: 35 and SEQ ID NO: 37.    
     
     
         16 . The method of  claim 11 , comprising administering an antibody or portion thereof selected from the group consisting of: 
 (a) an antibody comprising the variable regions of 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 variable regions of the amino acid sequences set forth in SEQ ID NO: 6 and SEQ ID NOs: 8, 10, or 12, without the signal sequences;    (c) an antibody comprising the variable regions of the amino acid sequences set forth in SEQ ID NO: 14 and SEQ ID NOs: 16, 18, or 20, without the signal sequences;    (d) an antibody comprising the variable regions of the amino acid sequences set forth in SEQ ID NO: 22 and SEQ ID NO: 24, without the signal sequences;    (e) an antibody comprising the variable regions of the amino acid sequences set forth in SEQ ID NOs: 26 or 28 and SEQ ID NOs: 30, 32 or 34, without the signal sequences; and    (f) an antibody comprising the variable regions of the amino acid sequences set forth in SEQ ID NO: 36 and SEQ ID NO: 38, without the signal sequences.    
     
     
         17 . The method of  claim 11 , comprising administering an antibody or portion thereof of selected from the group consisting of: 
 (a) an antibody encoded by the nucleic acid sequences set forth in SEQ ID NO: 1 and SEQ ID NO: 3;    (b) an antibody encoded by the nucleic acid sequences set forth in SEQ ID NO: 5 and SEQ ID NOs: 7, 9 or 11;    (c) an antibody encoded by the nucleic acid sequences set forth in SEQ ID NO: 13 and SEQ ID NOs: 15, 17, or 19;    (d) an antibody encoded by the nucleic acid sequences set forth in SEQ ID NO: 21 and SEQ ID NO: 23;    (e) an antibody encoded by the nucleic acid sequences set forth in SEQ ID NOs: 25 or 27 and SEQ ID NOs: 29, 31, or 33; and    (f) an antibody encoded by the nucleic acid sequences set forth in SEQ ID NO: 35 and SEQ ID NO: 37.    
     
     
         18 . The method of any of claims  11 - 17 , comprising administering the antibody or portion thereof wherein the heavy chain C-terminal lysine of the antibody of portion thereof is cleaved.