Humanized anti-human alpha 9-integrin antibody

Abstract

The present invention provides a humanized anti-human α9 integrin antibody having improved activity and/or property as compared to donor mouse anti-human α9 integrin antibody, namely, a humanized anti-human α9 integrin antibody comprising a heavy-chain variable region consisting of the amino acid sequence shown by SEQ ID NO: 1 or the amino acid sequence shown by SEQ ID NO: 1 wherein one or several amino acids are substituted, deleted, inserted and/or added and a light-chain variable region consisting of the amino acid sequence shown by SEQ ID NO: 61 or the amino acid sequence shown by SEQ ID NO: 61 wherein one or several amino acids are substituted, deleted, inserted and/or added, as well as a means for preventing or treating various diseases involving human α9 integrin in their pathogenesis, which uses the antibody.

1 . A humanized anti-human α9 integrin antibody comprising a heavy-chain variable region consisting of the amino acid sequence shown by SEQ ID NO: 1 or the amino acid sequence shown by SEQ ID NO: 1 wherein one or several amino acids are substituted, deleted, inserted and/or added and a light-chain variable region consisting of the amino acid sequence shown by SEQ ID NO: 61 or the amino acid sequence shown by SEQ ID NO: 61 wherein one or several amino acids are substituted, deleted, inserted and/or added. 
     
     
         2 . The humanized anti-human α9 integrin antibody according to  claim 1 , wherein the heavy chain variable region consists of the amino acid sequence shown by SEQ ID NO: 1 or SEQ ID NO: 31 having at least one substitution selected from the group consisting of
 1) substitution of the 34th methionine residue by leucine or isoleucine in SEQ ID NO: 1 or SEQ ID NO: 31; 
 2) substitution of the 65th lysine residue and the 66th aspartic acid residue by glutamine and glycine, respectively, in SEQ ID NO: 1 or SEQ ID NO: 31; 
 3) substitution of the 104th aspartic acid residue and the 105th phenylalanine residue by alanine and leucine, alanine and tryptophan, tryptophan and glutamic acid, or serine and tryptophan, respectively, in SEQ ID NO: 1 or SEQ ID NO: 31, and 
 the light chain variable region consists of the amino acid sequence shown by SEQ ID NO: 61 or the amino acid sequence shown by SEQ ID NO: 61, having 
 4) substitution of the 24th lysine residue by glutamine or arginine in SEQ ID NO: 61. 
 
     
     
         3 . The humanized anti-human α9 integrin antibody according to  claim 2 , wherein the heavy chain variable region consists of the amino acid sequence shown by SEQ ID NO: 1 or SEQ ID NO: 31, having
 2) substitution of the 65th lysine residue and the 66th aspartic acid residue by glutamine and glycine, respectively, in SEQ ID NO: 1 or SEQ ID NO: 31, and 
 the light chain variable region consists of the amino acid sequence shown by SEQ ID NO: 61, having 
 4) substitution of the 24th lysine residue by glutamine or arginine in SEQ ID NO: 61. 
 
     
     
         4 . The humanized anti-human α9 integrin antibody according to  claim 1 , wherein the heavy-chain constant region of the antibody is human Igγ1. 
     
     
         5 . The humanized anti-human α9 integrin antibody according to  claim 1 , wherein the light-chain constant region of the antibody is human Igκ. 
     
     
         6 . The humanized anti-human α9 integrin antibody according to  claim 1 , wherein the heavy-chain constant region of the antibody is human Igγ1 and the light-chain constant region of the antibody is human Igκ. 
     
     
         7 . A polynucleotide comprising a sequence that encodes the heavy-chain variable region of the humanized anti-human α9 integrin antibody according to  claim 1 . 
     
     
         8 . A polynucleotide comprising a sequence that encodes the light-chain variable region of the humanized anti-human α9 integrin antibody according to  claim 1 . 
     
     
         9 . An expression vector comprising the polynucleotide comprising a sequence that encodes the heavy-chain variable region of the humanized anti-human α9 integrin antibody according to  claim 1  and/or the polynucleotide comprising a sequence that encodes the light-chain variable region of the humanized anti-human α9 integrin antibody according to  claim 1 . 
     
     
         10 . A host cell incorporating the expression vector according to  claim 9 . 
     
     
         11 . A method of producing a humanized anti-human α9 integrin antibody, comprising culturing the host cell according to  claim 10  to allow the cell to express the humanized anti-human α9 integrin antibody. 
     
     
         12 . A therapeutic drug for rheumatoid arthritis, comprising the humanized anti-human α9 integrin antibody according to  claim 1 . 
     
     
         13 . A method of preventing or treating rheumatoid arthritis, comprising administering a therapeutically effective amount of the humanized anti-human α9 integrin antibody according to  claim 1 . 
     
     
         14 . A pharmaceutical for preventing or treating rheumatoid arthritis comprising the humanized anti-human α9 integrin antibody according to  claim 1 .