Human Anti-OPGL Neutralizing Antibodies As Selective OPGL Pathway Inhibitors

Abstract

Monoclonal antibodies and hybridomas producing them that interact with osteoprotegerin ligand (OPGL) are provided. Methods of treating osteopenic disorders by administering a pharmaceutically effective amount of antibodies to OPGL are also provided. Methods of detecting the amount of OPGL in a sample using antibodies to OPGL are further provided.

1 - 4 . (canceled) 
     
     
         5 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human osteoprotegerin ligand (OPGL) and comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises any of SEQ ID NO: 6, SEQ ID NO: 14, SEQ ID NO: 22, or SEQ ID NO: 26. 
     
     
         6 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL and comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises either SEQ ID NO: 10 or SEQ ID NO: 18. 
     
     
         7 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL and comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises any of SEQ ID NO: 8, SEQ ID NO: 16, SEQ ID NO: 24, or SEQ ID NO: 28. 
     
     
         8 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL and comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises either SEQ ID NO: 12 or SEQ ID NO: 20. 
     
     
         9 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL and comprises a heavy chain and a light chain, wherein the heavy chain comprises any of SEQ ID NO: 30, SEQ ID NO: 38, SEQ ID NO: 46, or SEQ ID NO: 50. 
     
     
         10 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL and comprises a heavy chain and a light chain, wherein the heavy chain comprises either SEQ ID NO: 34 or SEQ ID NO: 42. 
     
     
         11 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL and comprises a heavy chain and a light chain, wherein the light chain comprises any of SEQ ID NO: 32, SEQ ID NO: 40, SEQ ID NO: 48, or SEQ ID NO: 52. 
     
     
         12 . The method of any of  claim 5 ,  7 ,  9 , or  11 , wherein the human antibody or antigen-binding fragment specifically binds the D-E loop region of human OPGL. 
     
     
         13 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL and comprises a heavy chain and a light chain, wherein the light chain comprises either of SEQ ID NO: 36 or SEQ ID NO: 44. 
     
     
         14 . The method of any of  claim 6 ,  8 ,  10 , or  13 , wherein the human antibody or antigen-binding fragment specifically binds to:
 (a) a region of human OPGL that is outside the D-E loop region; or   (b) both a region of human OPGL that is outside the D-E loop region and all or a portion of the D-E loop region.   
     
     
         15 . The method of  claim 14 , wherein the antibody or antigen-binding fragment binding to both a region of human OPGL that is outside the D-E loop region and all or a portion of the D-E loop region, is consecutive or simultaneous. 
     
     
         16 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof, that specifically binds human OPGL, wherein the antibody or antigen-binding fragment thereof comprises:
 (a) a heavy chain variable region comprising SEQ ID NO: 6 and a light chain variable region comprising SEQ ID NO: 8, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 6 and CDR1, CDR2, and CDR3 of SEQ ID NO: 8;   (b) a heavy chain variable region comprising SEQ ID NO: 14 and a light chain variable region comprising SEQ ID NO: 16, or wherein antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 14 and CDR1, CDR2, and CDR3 of SEQ ID NO: 16;   (c) a heavy chain variable region comprising SEQ ID NO: 22 and a light chain variable region comprising SEQ ID NO: 24, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 22 and CDR1, CDR2, and CDR3 of SEQ ID NO: 24; or   (d) a heavy chain variable region comprising SEQ ID NO: 26 and a light chain variable region comprising SEQ ID NO: 28, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 26 and CDR1, CDR2, and CDR3 of SEQ ID NO: 28.   
     
     
         17 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a in need thereof patient a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof, that specifically binds human OPGL, wherein the antibody or antigen-binding fragment thereof comprises:
 (a) a heavy chain comprising SEQ ID NO: 30 and a light chain comprising SEQ ID NO: 32, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 6 and CDR1, CDR2, and CDR3 of SEQ ID NO: 8;   (b) a heavy chain comprising SEQ ID NO: 38 and a light chain comprising SEQ ID NO: 40, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 14 and CDR1, CDR2, and CDR3 of SEQ ID NO: 16;   (c) a heavy chain comprising SEQ ID NO: 46 and a light chain comprising SEQ ID NO: 48, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 22 and CDR1, CDR2, and CDR3 of SEQ ID NO: 24; or   (d) a heavy chain comprising SEQ ID NO: 50 and a light chain comprising SEQ ID NO: 52, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 26 and CDR1, CDR2, and CDR3 of SEQ ID NO: 28.   
     
     
         18 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof, that specifically binds human OPGL, wherein the antibody or antigen-binding fragment thereof comprises:
 (a) a heavy chain variable region comprising SEQ ID NO: 10 and a light chain variable region comprising SEQ ID NO: 12, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 10 and CDR1, CDR2, and CDR3 of SEQ ID NO: 12; or   (b) a heavy chain variable region comprising SEQ ID NO: 18 and a light chain variable region comprising SEQ ID NO: 20, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 18 and CDR1, CDR2, and CDR3 of SEQ ID NO: 20.   
     
     
         19 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof, that specifically binds human OPGL, wherein the antibody or antigen-binding fragment thereof comprises:
 (a) a heavy chain comprising SEQ ID NO: 34 and a light chain comprising SEQ ID NO: 36, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 10 and CDR1, CDR2, and CDR3 of SEQ ID NO: 12; or   (b) a heavy chain comprising SEQ ID NO: 42 and a light chain comprising SEQ ID NO: 44, or wherein the antigen-binding fragment thereof comprises CDR1, CDR2, and CDR3 of SEQ ID NO: 18 and CDR1, CDR2, and CDR3 of SEQ ID NO: 20.   
     
     
         20 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof, that specifically binds human OPGL, wherein the antibody or antigen-binding fragment thereof comprises:
 (a) CDR1, CDR2, and CDR3 of SEQ ID NO: 6, and CDR1, CDR2, and CDR3 of SEQ ID NO: 8;   (b) CDR1, CDR2, and CDR3 of SEQ ID NO: 14, and CDR1, CDR2, and CDR3 of SEQ ID NO: 16;   (c) CDR1, CDR2, and CDR3 of SEQ ID NO: 22, and CDR1, CDR2, and CDR3 of SEQ ID NO: 24; or   (d) CDR1, CDR2, and CDR3 of SEQ ID NO: 26, and CDR1, CDR2, and CDR3 of SEQ ID NO: 28.   
     
     
         21 . The method of any of  claim 16 ,  17  or  20 , wherein the antibody or antigen-binding fragment thereof specifically binds the D-E loop region of human osteoprotegerin ligand (OPGL). 
     
     
         22 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL, wherein the antibody or antigen-binding fragment thereof comprises:
 (a) CDR1, CDR2, and CDR3 of SEQ ID NO: 10, and CDR1, CDR2, and CDR3 of SEQ ID NO: 12; or   (b) CDR1, CDR2, and CDR3 of SEQ ID NO: 18, and CDR1, CDR2, and CDR3 of SEQ ID NO: 20.   
     
     
         23 . The method of any of  claim 18 ,  19  or  22  wherein the antibody or antigen-binding fragment thereof, specifically binds to:
 (a) a region of human OPGL that is outside the D-E loop region; or 
 (b) both a region of human OPGL that is outside the D-E loop region and all or a portion of the D-E loop region. 
 
     
     
         24 . The method  claim 23 , wherein binding to both a region of human OPGL that is outside the D-E loop region and all or a portion of the D-E loop region is consecutive or simultaneous. 
     
     
         25 . The method of any of  claim 16 - 20  or  22 , wherein the antibody or antigen-binding fragment thereof is a single-chain antibody. 
     
     
         26 . The method of  claim 25  wherein antibody or antigen-binding fragment is a single-chain Fv antibody. 
     
     
         27 . The method of any of  claim 16 - 20  or  22 , wherein the antigen-binding fragment thereof is a Fab antibody fragment. 
     
     
         28 . The method of any of  claim 16 - 20  or  22 , wherein the antigen-binding fragment thereof is a Fab′ antibody fragment. 
     
     
         29 . The method of any of  claim 16 - 20  or  22 , wherein the antigen-binding fragment thereof is a (Fab′) 2  antibody fragment. 
     
     
         30 . The method of any of  claim 16 - 20  or  22 , wherein the antibody or antigen-binding fragment thereof inhibits binding of OPGL to an osteoclast differentiation and activation receptor (ODAR). 
     
     
         31 . The method of any of  claim 16 - 20  or  22 , wherein the antibody or antigen-binding fragment thereof is administered as a pharmaceutical composition comprising a therapeutically effective amount of the antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier. 
     
     
         32 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL, and comprises:
 (a) a heavy chain variable region comprising SEQ ID NO: 6, and a light chain variable region comprising SEQ ID NO: 8;   (b) a heavy chain variable region comprising SEQ ID NO: 14, and a light chain variable region comprising SEQ ID NO: 16;   (c) a heavy chain variable region comprising SEQ ID NO: 22, and a light chain variable region comprising SEQ ID NO: 24; or   (d) a heavy chain variable region comprising SEQ ID NO: 26, and a light chain variable region comprising SEQ ID NO: 28.   
     
     
         33 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human OPGL and comprises:
 (a) a heavy chain variable region comprising SEQ ID NO: 10, and a light chain variable region comprising SEQ ID NO: 12; or   (b) a heavy chain variable region comprising SEQ ID NO: 18, and a light chain variable region comprising SEQ ID NO: 20.   
     
     
         34 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody or antigen-binding fragment thereof that specifically binds human osteoprotegerin ligand OPGL and comprises:
 (a) a heavy chain comprising SEQ ID NO: 30, and a light chain comprising SEQ ID NO: 32;   (b) a heavy chain comprising SEQ ID NO: 34, and a light chain comprising SEQ ID NO: 36; or   (c) a heavy chain comprising SEQ ID NO: 38, and a light chain comprising SEQ ID NO: 40.   
     
     
         35 . A method of inhibiting bone resorption induced by cancer that has metastasized to bone, comprising administering to a patient in need thereof a pharmaceutically effective amount of an isolated human antibody that specifically binds human OPGL and comprises:
 (a) a heavy chain comprising SEQ ID NO: 42, and a light chain comprising SEQ ID NO: 44;   (b) a heavy chain comprising SEQ ID NO: 46, and a light chain comprising SEQ ID NO: 48; or   (c) a heavy chain comprising SEQ ID NO: 50, and a light chain comprising SEQ ID NO: 52.   
     
     
         36 . The method of any one of  claim 5 - 11 ,  13 ,  16 - 20 ,  22 , or  32 - 35  wherein the cancer is selected from breast cancer, prostate cancer and multiple myeloma.