IP Library › Granted Patent US 7,718,776
Granted Patent B2
US 7,718,776 · App. 10/408,901 · Granted May 18, 2010

Human anti-OPGL neutralizing antibodies as selective OPGL pathway inhibitors

Assignees: Amgen Inc.; Medarex, Inc.
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Quick Facts
Patent No.
US 7,718,776
App. No.
10/408,901
Granted
May 18, 2010
Kind
B2
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.

Claims (64)

1. An isolated antibody or an antigen-binding fragment thereof that specifically binds human osteoprotegerin ligand (OPGL), comprising 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. An isolated antibody or an antigen-binding fragment thereof, that specifically binds human osteoprotegerin ligand (OPGL), comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises any of SEQ ID NO: 10 or SEQ ID NO: 18.

3. An isolated antibody or an antigen-binding fragment thereof, that specifically binds human osteoprotegerin ligand (OPGL), comprising 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. An isolated antibody or an antigen-binding fragment thereof, that specifically binds human osteoprotegerin ligand (OPGL), comprising a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises any of SEQ ID NO: 12 or SEQ ID NO: 20.

5. An isolated antibody or an antigen-binding fragment thereof, that specifically binds human osteoprotegerin ligand (OPGL), comprising 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. An isolated antibody or an antigen-binding fragment thereof, that specifically binds human osteoprotegerin ligand (OPGL), comprising a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 34 or SEQ ID NO: 42.

7. An isolated antibody or an antigen-binding fragment thereof, that specifically binds human osteoprotegerin ligand (OPGL), comprising 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 antibody of any of claims 1 , 3 , 5 , or 7 , wherein the antibody specifically binds the D-E loop region of human osteoprotegerin ligand (OPGL).

9. An isolated antibody or an antigen-binding fragment thereof, that specifically binds human osteoprotegerin ligand (OPGL), comprising a heavy chain and a light chain, wherein the light chain comprises SEQ ID NO: 36 or SEQ ID NO: 44.

10. The antibody of any of claims 2 , 4 , 6 , or 9 , wherein the antibody specifically binds to:

a. a region of human osteoprotegerin ligand (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 antibody of claim 10 , 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.

12. An isolated antibody or an antigen-binding fragment thereof, that specifically binds human osteoprotegerin ligand (OPGL), wherein the antibody comprises 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.

13. An isolated antibody or an antigen-binding fragment thereof, that specifically binds human osteoprotegerin ligand (OPGL), wherein the antibody comprises 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.

14. An isolated antibody or an antigen-binding fragment thereof, that specifically binds human osteoprotegerin ligand (OPGL), wherein the antibody comprises 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.

15. An isolated antibody or an antigen-binding fragment thereof, that specifically binds human osteoprotegerin ligand (OPGL), wherein the antibody comprises 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.

16. An isolated antibody or an antigen-binding fragment thereof, that specifically binds human osteoprotegerin ligand (OPGL), wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 30 and the light chain comprises 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.

17. An isolated antibody or an antigen-binding fragment thereof, that specifically binds human osteoprotegerin ligand (OPGL), wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 38 and the light chain comprises 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.

18. An isolated antibody or an antigen-binding fragment thereof, that specifically binds human osteoprotegerin ligand (OPGL), wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 46 and the light chain comprises 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.

19. An isolated antibody or an antigen-binding fragment thereof, that specifically binds human osteoprotegerin ligand (OPGL), wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 50 and the light chain comprises 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.

20. An isolated antibody or an antigen-binding fragment thereof, that specifically binds human osteoprotegerin ligand (OPGL), wherein the antibody comprises 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.

21. An isolated antibody or an antigen-binding fragment thereof, that specifically binds human osteoprotegerin ligand (OPGL), wherein the antibody comprises 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.

22. An isolated antibody or an antigen-binding fragment thereof, that specifically binds human osteoprotegerin ligand (OPGL), wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 34 and the light chain comprises 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.

23. An isolated antibody or an antigen-binding fragment thereof, that specifically binds human osteoprotegerin ligand (OPGL), wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 42 and the light chain comprises 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.

24. An isolated antibody or antigen-binding fragment thereof comprising:

(i) CDR1, CDR2, and CDR3 of SEQ ID NO: 6, and CDR1, CDR2, and CDR3 of SEQ ID NO: 8;

(ii) CDR1, CDR2, and CDR3 of SEQ ID NO: 14, and CDR1, CDR2, and CDR3 of SEQ ID NO: 16;

(iii) CDR1, CDR2, and CDR3 of SEQ ID NO: 22, and CDR1, CDR2, and CDR3 of SEQ ID NO: 24; or

(iv) CDR1, CDR2, and CDR3 of SEQ ID NO: 26, and CDR1, CDR2, and CDR3 of SEQ ID NO: 28;

wherein the antibody or antigen-binding fragment thereof specifically binds to human osteoprotegerin ligand (OPGL).

25. The antibody or antigen-binding fragment thereof of claim 24 , wherein the antibody or antigen-binding fragment thereof specifically binds the D-E loop region of human osteoprotegerin ligand (OPGL).

26. An isolated antibody or antigen-binding fragment thereof comprising:

(i) CDR1, CDR2, and CDR3 of SEQ ID NO: 10, and CDR1, CDR2, and CDR3 of SEQ ID NO: 12; or

(ii) CDR1, CDR2, and CDR3 of SEQ ID NO: 18, and CDR1, CDR2, and CDR3 of SEQ ID NO: 20;

wherein the antibody or antigen-binding fragment thereof specifically binds to human osteoprotegerin ligand (OPGL).

27. The antibody or antigen-binding fragment thereof of claim 26 , wherein the antibody or antigen-binding fragment thereof specifically binds to:

c. a region of human osteoprotegerin ligand (OPGL) that is outside the D-E loop region; or

d. 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, wherein binding is consecutive or simultaneous.

28. The antibody or antigen-binding fragment thereof of claim 27 , 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.

29. The antibody of any of claims 12 , 13 , 14 , 15 , 16 , 17 , 18 , or 19 , wherein the antibody specifically binds the D-E loop region of human osteoprotegerin ligand (OPGL).

30. The antibody of any of claims 20 , 21 , 22 , or 23 , wherein the antibody specifically binds to:

a. a region of human osteoprotegerin ligand (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.

31. The antibody of claim 30 , wherein binding to both a region of OPGL that is outside the D-E loop region and all or a portion of the D-E loop region is consecutive or simultaneous.

32. The antibody or antigen-binding fragment thereof of any of claims 12 , 13 , 14 , 15 , 20 , 21 , 24 , or 26 , which is a single-chain antibody.

33. The antibody or antigen-binding fragment thereof of claim 32 , which is a single-chain Fv antibody.

34. The antigen-binding fragment of any of claims 12 , 13 , 14 , 15 , 20 , 21 , 24 , or 26 , which is a Fab antibody fragment.

35. The antigen-binding fragment of any of claims 12 , 13 , 14 , 15 , 20 , 21 , 24 , 26 , which is Fab′ antibody fragment.

36. The antigen-binding fragment of any of claims 12 , 13 , 14 , 15 , 20 , 21 , 24 , 26 , which is a (Fab′) 2 antibody fragment.

37. The antibody or antigen-binding fragment thereof of any of claims 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , or 26 wherein the antibody or antigen-binding fragment thereof inhibits binding of OPGL to an osteoclast differentiation and activation receptor (ODAR).

38. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the antibody or antigen-binding fragment thereof of claim 37 .

39. An isolated antibody comprising a heavy chain variable region comprising SEQ ID NO: 6, and a light chain variable region comprising SEQ ID NO: 8.

40. An isolated antibody comprising a heavy chain variable region comprising SEQ ID NO: 14, and a light chain variable region comprising SEQ ID NO: 16.

41. An isolated antibody comprising a heavy chain variable region comprising SEQ ID NO: 22, and a light chain variable region comprising SEQ ID NO: 24.

42. An isolated antibody comprising a heavy chain variable region comprising SEQ ID NO: 26, and a light chain variable region comprising SEQ ID NO: 28.

43. An isolated antibody comprising a heavy chain variable region comprising SEQ ID NO: 10, and a light chain variable region comprising SEQ ID NO: 12.

44. An isolated antibody comprising a heavy chain variable region comprising SEQ ID NO: 18, and a light chain variable region comprising SEQ ID NO: 20.

45. An isolated antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 30, and the light chain comprises SEQ ID NO: 32.

46. An isolated antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 34, and the light chain comprises SEQ ID NO: 36.

47. An isolated antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 38, and the light chain comprises SEQ ID NO: 40.

48. An isolated antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 42, and the light chain comprises SEQ ID NO: 44.

49. An isolated antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 46, and the light chain comprises SEQ ID NO: 48.

50. An isolated antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 50, and the light chain comprises SEQ ID NO: 52.

Assignments (5)
MERGER Recorded Jun 2, 2015
From: MEDAREX, L.L.C.
To: E. R. SQUIBB & SONS, L.L.C.
Reel/Frame 035767/0494 →
MERGER Recorded Aug 15, 2013
From: MEDAREX, INC.
To: MEDAREX, L.L.C.
Reel/Frame 031016/0678 →
CORRECTIVE ASSIGNMENT TO CORRECT THE NATURE OF CONVEYANCE PREVIOUSLY RECORDED ON REEL 020426 FRAME 0703. ASSIGNOR(S) HEREBY CONFIRMS THE NATURE OF CONVEYANCE IS ASSIGNMENT OF EQUAL, UNDIVIDED INTEREST. Recorded Mar 11, 2008
From: AMGEN INC.
To: MEDAREX, INC.
Reel/Frame 020634/0257 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 16, 2008
From: AMGEN INC.
To: MEDAREX, INC.
Reel/Frame 020426/0703 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 3, 2003
From: BOYLE, WILLIAM J.; MEDLOCK, EUGENE; SULLIVAN, JOHN K.; ELLIOTT, ROBIN L.; MARTIN, FRANK; HUANG, HAICHUN
To: AMGEN INC.
Reel/Frame 014549/0060 →
Continuity (2)
Provisional Application 6037040700 · Apr 5, 2002
Related Publication 20040023313A1 · Feb 5, 2004