Glucagon receptor antagonists

Abstract

The present invention relates to glucagon receptor polypeptide antagonists which inhibit the binding of the hormone glucagon to its receptor. More particularly, the present invention relates to high affinity glucagon receptor antibodies or Fab fragments thereof that inhibit binding of glucagon to its receptor and their use in the treatment or prevention of type 2 diabetes (NIDDM) and related disorders in mammalian species.

1 - 15 . (canceled) 
     
     
         16 . A humanized monoclonal antibody that inhibits binding of glucagon to a glucagon receptor, wherein the antibody comprises a light chain and a heavy chain, wherein
 (i) the light chain comprises   
       
         
           
                 
                 
                 
               
                     
                   a CDRL1: S X S S S V S Y X 1  H, 
                   SEQ ID NO: 53 
                 
                     
                     
                 
                     
                   a CDRL2: T T S X 2  L A H, 
                   SEQ ID NO: 54 
                 
                     
                     
                 
                     
                   a CDRL3: X 3  X 4  R S T X 5  P P T; 
                   SEQ ID NO: 55 
                 
                     
                   and 
                     
                 
             
                
                
                
                
                
                
               
            
           
         
         (ii) the heavy chain comprises 
       
       
         
           
                 
                 
               
                     
                   SEQ ID NO: 56 
                 
                     
                   a CDRH1: G D D I T S G Y X 6  X 7 , 
                 
                     
                     
                 
                     
                   SEQ ID NO: 57 
                 
                     
                   a CDRH2: Y I S Y S G S T X 8  Y X 9  P S L K S, 
                 
                     
                     
                 
                     
                   SEQ ID NO: 58 
                 
                     
                   a CDRH3: P P X 10  Y Y G F G P Y A X 11  D Y, 
                 
             
                
                
                
                
                
                
                
                
               
            
           
         
         wherein: 
         X is Y or A; X 1  is M or I; X 2  is N or Y; X 3  is Q or L; X 4  is Q or W; X 5  is L or I; X 6  is W or H; X 7  is N, D or E; X 8  is Y, Q, S or V; X 9  is N, S or I; X 10  is G or A; X 11  is M or L. 
       
     
     
         17 . The humanized monoclonal antibody according to  claim 16 , wherein X is Y or A; X 1  is I; X 2  is Y; X 3  is Q or L; X 4  is Q or W; X 5  is L or I; X 6  is W or H; X 7  is D or E; X 8  is Y, Q, S or V; X 9  is S; X 10  is G or A; X 11  is L. 
     
     
         18 . The humanized monoclonal antibody according to  claim 17 , wherein X is A; X 1  is I; X 2  is Y; X 3  is Q; X 4  is Q; X 5  is L; X 6  is H; X 7  is D or E; X 8  is Y, Q or S; X 9  is S; X 10  is G or A; X 11  is L. 
     
     
         19 . A pharmaceutical composition comprising an effective amount of the humanized monoclonal antibody according to  claim 18  and a pharmaceutically acceptable excipient. 
     
     
         20 . A method of treating type 1 diabetes in a human, wherein the method comprises administrating an effective amount of the humanized monoclonal antibody according to  claim 18  to a human patient in need thereof. 
     
     
         21 . A method of treating type 2 diabetes in a human, wherein the method comprises administrating an effective amount of the humanized monoclonal antibody according to  claim 18  to a human patient in need thereof. 
     
     
         22 . A method for achieving weight loss in a human, wherein the method comprises administrating an effective amount of the humanized monoclonal antibody according to  claim 18  to a human patient in need thereof.