Human anti-OPGL neutralizing antibodies as selective OPGL pathway inhibitors

1. A method of treating an osteopenic disorder, 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.

2. A method of treating an osteopenic disorder, 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.

3. A method of treating an osteopenic disorder, 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.

4. A method of treating an osteopenic disorder, 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.

5. A method of treating an osteopenic disorder, 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.

6. A method of treating an osteopenic disorder, 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.

7. A method of treating an osteopenic disorder, 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.

8. The method of any of claim 1 , 3 , 5 , or 7 , wherein the human antibody or antigen-binding fragment specifically binds the D-E loop region of human OPGL.

9. A method of treating an osteopenic disorder, 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.

10. The method of any of claim 1 , 4 , 6 , or 9 , 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.

11. The method of claim 10 , 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.

12. A method of treating an osteopenic disorder, 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.

13. A method of treating an osteopenic disorder, 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 compring 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.

14. A method of treating an osteopenic disorder, 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.

15. A method of treating an osteopenic disorder, 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.

16. A method of treating an osteopenic disorder, 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.

17. The method of any of claim 12 , 13 or 16 , wherein the antibody or antigen-binding fragment thereof specifically binds the D-E loop region of human osteoprotegerin ligand (OPGL).

18. A method of treating an osteopenic disorder, 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.

19. The method of any of claim 14 , 15 or 18 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.

20. The method claim 19 , 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.

21. The method of any of claim 12 - 16 or 18 , wherein the antibody or antigen-binding fragment thereof is a single-chain antibody.

22. The method of claim 21 wherein antibody or antigen-binding fragment is a single-chain Fv antibody.

23. The method of any of claim 12 - 16 or 18 , wherein the antigen-binding fragment thereof is a Fab antibody fragment.

24. The method of any of claim 12 - 16 or 18 , wherein the antigen-binding fragment thereof is a Fab' antibody fragment.

25. The method of any of claim 12 - 16 or 18 , wherein the antigen-binding fragment thereof is a (Fab') 2 antibody fragment.

26. The method of any of claim 12 - 16 or 18 , wherein the antibody or antigen-binding fragment thereof inhibits binding of OPGL to an osteoclast differentiation and activation receptor (ODAR).

27. The method of any of claim 12 - 16 or 18 , 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.

28. A method of treating an osteopenic disorder, 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.

29. A method of treating an osteopenic disorder, 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.

30. A method of treating an osteopenic disorder, 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.

31. A method of treating an osteopenic disorder, 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.

32. The method of any one of claims 1 - 7 , 9 , 12 - 16 , 18 , or 28 - 31 wherein the osteopenic disorder is selected from osteoporosis, osteopenia, Paget's disease, lytic bone metastasis, periodontitis, rheumatoid arthritis, and bone loss due to immobilization.