Methods of treating multiple myeloma and myeloma-induced bone resorption using integrin antagonists

Abstract

Antagonists of α4 integrin/α4 integrin ligand adhesion, which inhibit the biological effects of such adhesion are described and methods for their use are detailed. Such antagonists are useful in suppressing bone destruction associated with multiple myeloma. The homing of multiple myeloma cells to bone marrow and their α4 integrin-dependent release of bone-resorbing factors, resulting in bone destruction in patients with multiple myeloma, is inhibited.

1 - 50 . (canceled) 
     
     
         51 . A method for inhibiting osteoclastogensis, the method comprising administering to an individual a therapeutically effective amount of a composition comprising an antagonist of an interaction between an α4 subunit-bearing integrin and a ligand for an α4 subunit bearing integrin, wherein the antagonist is an antagonist of VLA-4. 
     
     
         52 . A method for inhibiting osteoclastogensis, the method comprising administering to an individual a therapeutically effective amount of a composition comprising an antagonist of an interaction between an α4 subunit-bearing integrin and a ligand for an α4 subunit bearing integrin and a compound. 
     
     
         53 . The method according to  claim 52 , wherein the compound is a chemotherapeutic agent. 
     
     
         54 . The method according to  claim 51 , wherein the antagonist is an anti-VLA4 antibody, or antigen-binding fragment thereof. 
     
     
         55 . The method according to  claim 52 , wherein the antagonist is an anti-VLA4 antibody, or antigen-binding fragment thereof. 
     
     
         56 . The method according to  claim 52 , wherein the compound is selected from the group consisting of melphalan, a bisphosphonate, thalidomide, erythropoietin, an antagonist of IL-6 and an antagonist of IL-15. 
     
     
         57 . The method according to  claim 55 , wherein the compound is melphalan. 
     
     
         58 . The method according to  claim 54 , wherein the antibody or antigen-binding fragment thereof, is a monoclonal antibody or antigen-binding fragment thereof. 
     
     
         59 . The method according to  claim 55 , wherein the antibody or antigen-binding fragment thereof, is a monoclonal antibody or antigen-binding fragment thereof. 
     
     
         60 . The method according to  claim 54 , wherein the anti-VLA-4 antibody or antigen-binding fragment thereof is selected from the group consisting of a human antibody, a chimeric antibody, a humanized antibody and an antigen-binding Fab, Fab′, F(ab′) 2  or F(v) fragment of a human, chimeric or humanized antibody. 
     
     
         61 . The method according to  claim 55 , wherein the anti-VLA-4 antibody or antigen-binding fragment thereof is selected from the group consisting of a human antibody, a chimeric antibody, a humanized antibody and an antigen-binding Fab, Fab′, F(ab′) 2 , or F(v) fragment of a human, chimeric or humanized antibody. 
     
     
         62 . The method of  claim 52 , wherein the antagonist is administered at a dosage that is lower when administered in combination with the compound than when not administered in combination with the compound. 
     
     
         63 . The method of  claim 52 , wherein the compound is administered at a dosage that is lower when administered in combination with the antagonist than when not administered in combination with the antagonist. 
     
     
         64 . The method of  claim 52 , wherein the antagonist is administered at a dosage that is lower when administered in combination with the compound than when not administered in combination with the compound; and wherein the compound is administered at a dosage that is lower when administered in combination with the antagonist than when not administered in combination with the antagonist. 
     
     
         65 . The method of  claim 54 , wherein the anti-VLA4 antibody or antigen-binding fragment thereof, binds the α chain of VLA-4. 
     
     
         66 . The method of  claim 55 , wherein the anti-VLA4 antibody or antigen-binding fragment thereof, binds the α chain of VLA-4. 
     
     
         67 . The method of  claim 54 , wherein the anti-VLA4 antibody or antigen-binding fragment thereof, is a B epitope specific anti-VLA-4 antibody or antigen-binding fragment thereof. 
     
     
         68 . The method of  claim 55 , wherein the anti-VLA4 antibody or antigen-binding fragment thereof, is a B epitope specific anti-VLA-4 antibody or antigen-binding fragment thereof. 
     
     
         69 . The method of  claim 54 , wherein the anti-VLA4 antibody or antigen-binding fragment thereof, is a humanized anti-VLA-4 antibody or antigen-binding fragment thereof. 
     
     
         70 . The method of  claim 55 , wherein the anti-VLA4 antibody or antigen-binding fragment thereof, is a humanized anti-VLA-4 antibody or antigen-binding fragment thereof.