Cadherin-11 antagonists and methods for the treatment of inflammatory joint disorders

Abstract

The present invention relates to Cadherin-11 antagonists and compositions comprising Cadherin-11 antagonists. The invention also relates to methods for treating inflammatory joint disorders, such as rheumatoid arthritis, in a mammalian subject by administering a therapeutically effective amount of a Cadherin-11 antagonist.

1 . A Cadherin-11 antagonist that specifically binds an EC1 domain of a mammalian Cadherin-11 protein, wherein the Cadherin-11 antagonist inhibits aggregation of cells that express said mammalian Cadherin-11 protein. 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . An isolated antibody that specifically binds an EC1 domain of a mammalian Cadherin-11 protein, wherein the antibody inhibits aggregation of cells that express said mammalian Cadherin-11 protein. 
     
     
         5 - 18 . (canceled) 
     
     
         19 . A method of treating an inflammatory joint disorder in a mammalian subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Cadherin-11 antagonist that specifically binds an EC1 domain of a mammalian Cadherin-11 protein, wherein the Cadherin-11 antagonist inhibits aggregation of cells that express said mammalian Cadherin-11 protein in one or more joints of said subject. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 19 , wherein the inflammatory joint disorder is selected from the group consisting of rheumatoid arthritis, osteoarthritis, psoriatic arthritis, Reiter's syndrome and ankylosing spondylitis. 
     
     
         22 . The method of  claim 19 , wherein the inflammatory joint disorder is rheumatoid arthritis. 
     
     
         23 . The method of  claim 19 , wherein the Cadherin-11 antagonist is an isolated antibody. 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 19 , wherein the mammalian subject is a human. 
     
     
         26 - 28 . (canceled) 
     
     
         29 . The method of  claim 19 , wherein the Cadherin-11 antagonist inhibits migration, adhesion, invasion into cartilage, or intercellular signaling of cells that express said mammalian Cadherin-11 protein in one or more joints of said subject. 
     
     
         30 . The method of  claim 19 , wherein the Cadherin-11 antagonist inhibits induction of expression or activity of an enzyme selected from the group consisting of a collagenase, a serine protease, and a matrix metalloproteinase in cells that express said mammalian Cadherin-11 protein in one or more joints of said subject. 
     
     
         31 . The method of  claim 19 , wherein the Cadherin-11 antagonist inhibits induction of expression or activity of a cytokine or growth factor selected from the group consisting of a IL-6, IL-8, RANKL and TRANCE in cells that express said mammalian Cadherin-11 protein in one or more joints of said subject. 
     
     
         32 . The method of  claim 19 , wherein the Cadherin-11 antagonist is administered in combination with a disease-modifying anti-rheumatic drug. 
     
     
         33 - 36 . (canceled) 
     
     
         37 . A pharmaceutical composition comprising the Cadherin-11 antagonist of  claim 1 , and a pharmaceutically-acceptable carrier. 
     
     
         38 . (canceled) 
     
     
         39 . The pharmaceutical composition of  claim 37 , wherein the Cadherin-11 antagonist is an isolated antibody. 
     
     
         40 - 52 . (canceled) 
     
     
         53 . An isolated nucleic acid encoding the antibody of  claim 4 . 
     
     
         54 . (canceled) 
     
     
         55 . An isolated cell expressing the antibody of  claim 4 . 
     
     
         56 . The cell of  claim 55 , wherein said cell is a cell of hybridoma H1M1 (ATCC accession number PTA-9699). 
     
     
         57 . The cell of  claim 55 , wherein said cell is a cell of hybridoma H14 (ATCC accession number PTA-9701). 
     
     
         58 . The antibody of  claim 4 , wherein said antibody is produced by hybridoma H1M1 (ATCC accession number PTA-9699). 
     
     
         59 . The antibody of  claim 4 , wherein said antibody is produced by hybridoma H14 (ATCC accession number PTA-9701). 
     
     
         60 . (canceled) 
     
     
         61 . (canceled) 
     
     
         62 . The isolated antibody of  claim 4 , comprising an antibody variable heavy chain region comprising SEQ ID NO:51. 
     
     
         63 . (canceled) 
     
     
         64 . The isolated antibody of  claim 62 , wherein the antibody further comprises an antibody variable light chain region comprising SEQ ID NO:56. 
     
     
         65 . The isolated antibody of  claim 62 , wherein the antibody is a humanized antibody. 
     
     
         66 . The isolated antibody of  claim 4 , comprising an antibody variable light chain region comprising SEQ ID NO:56. 
     
     
         67 . (canceled) 
     
     
         68 . The isolated antibody of  claim 66 , wherein the antibody is a humanized antibody. 
     
     
         69 . The isolated antibody of  claim 4 , comprising a first antibody variable region having:
 a) a CDR1 consisting of SEQ ID NO:52;   b) a CDR2 consisting of SEQ ID NO:53; and   c) a CDR3 consisting of SEQ ID NO:54.   
     
     
         70 . The isolated antibody of  claim 69 , further comprising a second antibody variable region having:
 a) a CDR1 consisting of SEQ ID NO:57;   b) a CDR2 consisting of SEQ ID NO:58; and   c) a CDR3 consisting of SEQ ID NO:59;   
     
     
         71 . The isolated antibody of  claim 69 , wherein the antibody is a humanized antibody. 
     
     
         72 . The isolated antibody of  claim 4 , comprising an antibody variable region comprising:
 a) a CDR1 consisting of SEQ ID NO:57;   b) a CDR2 consisting of SEQ ID NO:58; and   c) a CDR3 consisting of SEQ ID NO:59.   
     
     
         73 . The isolated antibody of  claim 72 , wherein the antibody is a humanized antibody.