Human antibody against aggrecanase-type adamts species for therapeutics of aggrecanase-related diseases

Abstract

The present invention provides an antibody that specifically binds to human aggrecanase, and inhibits enzymatic activity of the human aggrecanase. In one embodiment, aggrecanase is ADAMTS4. In one embodiment, the antibody recognizes a particular epitope in human ADAMTS4, and inhibits not only aggrecanase activity of human ADAMTS4 but also aggrecanase activity of human ADAMTS5. In addition, the present invention also provides use of said antibody in the prophylaxis or treatment of the progression of arthritis.

1 . An antibody which specifically binds to a human aggrecanase and inhibits aggrecanase activity of said aggrecanase. 
     
     
         2 . The antibody according to  claim 1 , wherein the human aggrecanase is human ADAMTS4. 
     
     
         3 . The antibody according to  claim 2 , which further inhibits aggrecanase activity of human ADAMTS5. 
     
     
         4 . The antibody according to  claim 2 , which binds to human ADAMTS4 at an epitope comprising the amino acid sequence depicted in SEQ ID NO: 9. 
     
     
         5 . The antibody according to  claim 2 , which comprises a light chain variable region and a heavy chain variable region, wherein
 (1) the light chain variable region comprises CDR1 comprising the amino acid sequence depicted in SEQ ID NO: 1, CDR2 comprising the amino acid sequence depicted in SEQ ID NO: 2 and CDR3 comprising the amino acid sequence depicted in SEQ ID NO: 3, and   the heavy chain variable region comprises CDR1 comprising the amino acid sequence depicted in SEQ ID NO: 4, CDR2 comprising the amino acid sequence depicted in SEQ ID NO: 5 and CDR3 comprising the amino acid sequence depicted in SEQ ID NO: 6; or   (2) the light chain variable region comprises CDR1 comprising the amino acid sequence depicted in SEQ ID NO: 1, CDR2 comprising the amino acid sequence depicted in SEQ ID NO: 2 and CDR3 comprising the amino acid sequence depicted in SEQ ID NO: 3, and   the heavy chain variable region comprises CDR1 comprising the amino acid sequence depicted in SEQ ID NO: 4, CDR2 comprising the amino acid sequence depicted in SEQ ID NO: 5 and CDR3 comprising the amino acid sequence depicted in SEQ ID NO: 6,   except that 1 to 3 amino acids are substituted, deleted, inserted, or added in at least one amino acid sequence selected from the group consisting of SEQ ID NO: 1 to 3, and/or   1 to 3 amino acids are substituted, deleted, inserted, or added in at least one amino acid sequence selected from the group consisting of SEQ ID NO: 4 to 6.   
     
     
         6 . The antibody according to  claim 5 , wherein the light chain variable region comprises the amino acid sequence depicted in SEQ ID NO: 7 and the heavy chain variable region comprises the amino acid sequence depicted in SEQ ID NO: 8. 
     
     
         7 . The antibody according to  claim 1 , which is a human antibody. 
     
     
         8 . A pharmaceutical composition which comprises the antibody according to  claim 1 . 
     
     
         9 . A polynucleotide which encodes the antibody according to  claim 1 . 
     
     
         10 . A vector which comprises the polynucleotide according to  claim 9 . 
     
     
         11 . A transformant which comprises the vector according to  claim 10 . 
     
     
         12 .- 14 . (canceled) 
     
     
         15 . A method of preventing or treating arthritis in a mammal, which comprises administering an effective amount of an antibody which specifically binds to a human aggrecanase and inhibits aggrecanase activity of said aggrecanase to the mammal. 
     
     
         16 . The method according to  claim 15 , wherein the human aggrecanase is human ADAMTS4. 
     
     
         17 .- 23 . (canceled) 
     
     
         24 . The method according to  claim 16 , wherein the antibody further inhibits aggrecanase activity of human ADAMTS5. 
     
     
         25 . The method according to  claim 16 , wherein the antibody binds to human ADAMTS4 at an epitope comprising the amino acid sequence depicted in SEQ ID NO: 9. 
     
     
         26 . The method according to  claim 16 , wherein the antibody comprises a light chain variable region and a heavy chain variable region, wherein
 (1) the light chain variable region comprises CDR1 comprising the amino acid sequence depicted in SEQ ID NO: 1, CDR2 comprising the amino acid sequence depicted in SEQ ID NO: 2 and CDR3 comprising the amino acid sequence depicted in SEQ ID NO: 3, and   the heavy chain variable region comprises CDR1 comprising the amino acid sequence depicted in SEQ ID NO: 4, CDR2 comprising the amino acid sequence depicted in SEQ ID NO: 5 and CDR3 comprising the amino acid sequence depicted in SEQ ID NO: 6; or   (2) the light chain variable region comprises CDR1 comprising the amino acid sequence depicted in SEQ ID NO: 1, CDR2 comprising the amino acid sequence depicted in SEQ ID NO: 2 and CDR3 comprising the amino acid sequence depicted in SEQ ID NO: 3, and   the heavy chain variable region comprises CDR1 comprising the amino acid sequence depicted in SEQ ID NO: 4, CDR2 comprising the amino acid sequence depicted in SEQ ID NO: 5 and CDR3 comprising the amino acid sequence depicted in SEQ ID NO: 6,   except that 1 to 3 amino acids are substituted, deleted, inserted, or added in at least one amino acid sequence selected from the group consisting of SEQ ID NO: 1 to 3, and/or   1 to 3 amino acids are substituted, deleted, inserted, or added in at least one amino acid sequence selected from the group consisting of SEQ ID NO: 4 to 6.   
     
     
         27 . The method according to  claim 26 , wherein the light chain variable region comprises the amino acid sequence depicted in SEQ ID NO: 7 and the heavy chain variable region comprises the amino acid sequence depicted in SEQ ID NO: 8. 
     
     
         28 . The method according to  claim 15 , wherein the antibody is a human antibody.