Humanized Antibodies Targeting the EC1 Domain of Cadherin-11 and Related Compositions and Methods

Abstract

The present invention relates to humanized antibodies that specifically bind an EC1 domain of a mammalian Cadherin-11 protein and compositions (e.g., pharmaceutical compositions) comprising such antibodies. The invention also relates to methods for treating Cadherin-11-mediated disorders in a mammalian subject by administering a therapeutically effective amount of a humanized antibody of the invention. Cadherin-11-mediated disorders suitable for treatment by the methods of the invention include inflammatory disorders (e.g., inflammatory joint disorders, such as rheumatoid arthritis), fibrosis and cancer.

What is claimed is: 
     
         1 . A method of treating a Cadherin-11-mediated disorder in a mammalian subject in need thereof, comprising administering to the subject a therapeutically effective amount of a humanized antibody that specifically binds an EC1 domain of a mammalian Cadherin-11 protein, wherein the antibody comprises an antibody heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:65, SEQ ID NO:67 and SEQ ID NO:69. 
     
     
         2 . The method of  claim 1 , wherein erosion of cartilage is inhibited in one or more joints of said subject following administration of the antibody. 
     
     
         3 . The method of  claim 1 , wherein the antibody comprises an antibody light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO:71, SEQ ID NO:73, and SEQ ID NO:75. 
     
     
         4 . The method of  claim 1 , wherein the antibody is a whole antibody. 
     
     
         5 . The method of  claim 1 , wherein the antibody is an antigen-binding antibody fragment. 
     
     
         6 . The method of  claim 1 , wherein the Cadherin-11-mediated disorder is selected from the group consisting of an inflammatory disorder, a fibrosis, and a cancer. 
     
     
         7 . The method of  claim 1 , wherein the Cadherin-11-mediated disorder is an inflammatory joint disorder selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, Reiter's syndrome, ankylosing spondylitis, juvenile chronic arthritis, chronic Lyme disease and joint arthritis associated with systemic lupus erythrematosus. 
     
     
         8 . The method of  claim 1 , wherein the Cadherin-11-mediated disorder is a fibrosis. 
     
     
         9 . The method of  claim 1 , wherein the Cadherin-11-mediated disorder is a cancer. 
     
     
         10 . The method of  claim 1 , wherein the mammalian subject is a human. 
     
     
         11 . The method of  claim 1 , wherein the antibody is administered systemically. 
     
     
         12 . The method of  claim 1 , wherein the antibody is administered intravenously. 
     
     
         13 . The method of  claim 1 , wherein the antibody is administered by direct injection into a joint. 
     
     
         14 . The method of  claim 1 , wherein the antibody is administered in combination with at least one agent selected from the group consisting of a disease-modifying anti-rheumatic drug and an anti-inflammatory agent. 
     
     
         15 . The method of  claim 1 , wherein the antibody heavy chain variable region comprises SEQ ID NO:69 and the antibody light chain variable region comprises SEQ ID NO:71. 
     
     
         16 . A method of treating fibrosis in a mammalian subject in need thereof, comprising administering to the subject a therapeutically effective amount of an isolated antibody that specifically binds an EC1 domain of a mammalian Cadherin-11 protein, wherein the antibody comprises an antibody heavy chain 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;   and an antibody light chain variable region having:   d) a CDR1 consisting of SEQ ID NO: 57;   e) a CDR2 consisting of SEQ ID NO: 58; and   f) a CDR3 consisting of SEQ ID NO: 59.   
     
     
         17 . The method of  claim 16 , wherein the antibody binds an epitope that is present in SEQ ID NO: 3. 
     
     
         18 . The method of  claim 16 , wherein the antibody is selected from the group consisting of a monoclonal antibody, a polyclonal antibody, a humanized antibody, a chimeric antibody, a single chain antibody, and an antigen-binding antibody fragment. 
     
     
         19 . The method of  claim 16 , wherein the antibody is a whole antibody. 
     
     
         20 . The method of  claim 16 , wherein the antibody comprises an antibody heavy chain variable region consisting of SEQ ID NO: 51 and an antibody light chain variable region consisting of SEQ ID NO: 56. 
     
     
         21 . The method of  claim 16 , wherein the antibody is a humanized antibody. 
     
     
         22 . The method of  claim 21 , wherein the humanized antibody comprises an antibody heavy chain variable region comprising SEQ ID NO:69 and an antibody light chain variable region comprising SEQ ID NO:71. 
     
     
         23 . The method of  claim 16 , wherein the mammalian subject is a human. 
     
     
         24 . The method of  claim 16 , wherein the fibrosis is pulmonary fibrosis. 
     
     
         25 . The method of  claim 16 , wherein the fibrosis is dermal fibrosis.