IP Library › Granted Patent US 9,200,072
Granted Patent B2
US 9,200,072 · App. 13/744,766 · Granted Dec 1, 2015

Anti-LRP5 antibodies and methods of use

Inventors: Yan Wu (Foster City, CA); Weilan Ye (Foster City, CA); Jeremy Bryant Burton (Burlingame, CA); Cecilia Chiu (San Carlos, CA)
Assignee: GENENTECH INC.
C07K16/28A61K39/395A61K2039/505C07K2317/92
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Quick Facts
Patent No.
US 9,200,072
App. No.
13/744,766
Granted
Dec 1, 2015
Kind
B2
Abstract

The invention provides anti-LRP5 antibodies and methods of making and using the same.

Claims (35)

1. An isolated antibody that binds to Low-density lipoprotein receptor-related protein 5 (LRP5), wherein the antibody potentiates Norrin activity and/or Norrin/Fzd4 (Frizzled4) signaling, wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMX 1 , wherein X 1 is H or S (SEQ ID NO: 28), (b) HVR-H2 comprising the amino acid sequence GX 1 ISX 2 X 3 GX 4 STYYADSVKG, wherein X 1 is A or G, X 2 is A or S, X 3 is P or S, X 4 is S or W (SEQ ID NO: 26), or SRISSNGGSTYYADSVKG (SEQ ID NO: 27), (c) HVR-H3 comprising the amino acid sequence YYRYAPYRSLGMDV (SEQ ID NO: 23) or WIPQSYPFX 1 SYKSGFDY, wherein X 1 is A or R (SEQ ID NO: 24), (d) HVR-L1 comprising the amino acid sequence RASQGISSYLA (SEQ ID NO: 29) or RASQX 1 X 2 X 3 X 4 YLA, wherein X 1 is A, G, S or V, X 2 is I or M, X 3 is F, G, S or Y, and X 4 is G, S or Y (SEQ ID NO: 30); (e) HVR-L2 comprising the amino acid sequence AASSLQS (SEQ ID NO: 31) or DASX 1 X 2 ES, wherein X 1 is S or T and X 2 is L or R (SEQ ID NO: 32); and (f) HVR-L3 comprising the amino acid sequence QQYYX 1 YPFT, wherein X 1 is L or S (SEQ ID NO: 33).

2. The antibody of claim 1 , which is a monoclonal antibody.

3. The antibody of claim 1 , which is a human, humanized, or chimeric antibody.

4. The antibody of claim 1 , which is an antibody fragment that binds LRP5.

5. The antibody of claim 1 , further comprising one or more heavy chain variable domain framework sequences selected from the group consisting of SEQ ID NO: 34-37.

6. The antibody of claim 1 , which is a full length IgG1 antibody.

7. An immunoconjugate comprising the antibody of claim 1 and a cytotoxic agent.

8. A pharmaceutical formulation comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.

9. An antibody comprising a VH sequence of one of SEQ ID NOs: 1 to 11 and a VL sequence of one of SEQ ID NOs: 12 to 22.

10. The antibody of claim 9 , wherein the antibody comprises the VH sequence of SEQ ID NO: 7 and the VL sequence of SEQ ID NO: 18.

11. The antibody of claim 9 , wherein the antibody comprises the VH sequence of SEQ ID NO: 1 and the VL sequence of SEQ ID NO: 12.

12. An isolated antibody that binds to LRP5 comprising (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMH (SEQ ID NO: 43), (b) HVR-H2 comprising the amino acid sequence SRISSNGGSTYYADSVKG (SEQ ID NO: 27), (c) HVR-H3 comprising the amino acid sequence WIPQSYPFASYKSGFDY (SEQ ID NO: 44), (d) HVR-L 1 comprising the amino acid sequence RASQVMGYYLA (SEQ ID NO: 45); (e) HVR-L2 comprising the amino acid sequence DASSLES (SEQ ID NO: 46); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

13. An isolated antibody that binds to LRP5 comprising (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMS (SEQ ID NO: 48), (b) HVR-H2 comprising the amino acid sequence GAISSSGSSTYYADSVKG (SEQ ID NO: 49), (c) HVR-H3 comprising the amino acid sequence YYRYAPYRSLGMDV (SEQ ID NO: 23), (d) HVR-L1 comprising the amino acid sequence RASQGISSYLA (SEQ ID NO: 29); (e) HVR-L2 comprising the amino acid sequence AASSLQS (SEQ ID NO: 31); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

14. An isolated antibody that binds to LRP 5 comprising (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMS (SEQ ID NO: 48), (b) HVR-H2 comprising the amino acid sequence GAISAPGSSTYYADSVKG (SEQ ID NO: 50), (c) HVR-H3 comprising the amino acid sequence YYRYAPYRSLGMDV (SEQ ID NO: 23), (d) HVR-L1 comprising the amino acid sequence RASQGISSYLA (SEQ ID NO: 29); (e) HVR-L2 comprising the amino acid sequence AASSLQS (SEQ ID NO: 31); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

15. An isolated antibody that binds to LRP5 comprising (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMS (SEQ ID NO: 48), (b) HVR-H2 comprising the amino acid sequence GAISSPGWSTYYADSVKG (SEQ ID NO: 51), (c) HVR-H3 comprising the amino acid sequence YYRYAPYRSLGMDV (SEQ ID NO: 23), (d) HVR-L1 comprising the amino acid sequence RASQGISSYLA (SEQ ID NO: 29); (e) HVR-L2 comprising the amino acid sequence AASSLQS (SEQ ID NO: 31); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

16. An isolated antibody that binds to LRP5 comprising (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMS (SEQ ID NO: 48), (b) HVR-H2 comprising the amino acid sequence GGISSPGSSTYYADSVKG (SEQ ID NO: 52), (c) HVR-H3 L1 comprising the amino acid sequence RASQVIYGYLA (SEQ ID NO: 56); (e) HVR-L2 comprising the amino acid sequence DASTRES (SEQ ID NO: 57); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

17. An isolated antibody that binds to LRP5 comprising (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMH (SEQ ID NO: 43), (b) HVR-H2 comprising the amino acid sequence SRISSNGGSTYYADSVKG (SEQ ID NO: 27), (c) HVR-H3 comprising the amino acid sequence WIPQSYPFASYKSGFDY (SEQ ID NO: 44), (d) HVR-L1 comprising the amino acid sequence RASQGISSYLA (SEQ ID NO: 29); (e) HVR-L2 comprising the amino acid sequence DASSLES (SEQ ID NO: 46); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

18. An isolated antibody that binds to LRP5 comprising (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMH (SEQ ID NO: 43), (b) HVR-H2 comprising the amino acid sequence SRISSNGGSTYYADSVKG (SEQ ID NO: 27), (c) HVR-H3 comprising the amino acid sequence WIPQSYPFRSYKSGFDY (SEQ ID NO: 54), (d) HVR-L1 comprising the amino acid sequence RASQGISSYLA (SEQ ID NO: 29); (e) HVR-L2 comprising the amino acid sequence DASSLES (SEQ ID NO: 46); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

19. An isolated antibody that binds to LRP5 comprising (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMH (SEQ ID NO: 43), (b) HVR-H2 comprising the amino acid sequence SRISSNGGSTYYADSVKG (SEQ ID NO: 27), (c) HVR-H3 comprising the amino acid sequence WIPQSYPFASYKSGFDY (SEQ ID NO: 44), (d) HVR-L1 comprising the amino acid sequence RASQSIYYYLA (SEQ ID NO: 55); (e) HVR-L2 comprising the amino acid sequence DASSLES (SEQ ID NO: 46); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

20. An isolated antibody that binds to LRP5 comprising (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMH (SEQ ID NO: 43), (b) HVR-H2 comprising the amino acid sequence SRISSNGGSTYYADSVKG (SEQ ID NO: 27), (c) HVR-H3 comprising the amino acid sequence WIPQSYPFASYKSGFDY (SEQ ID NO: 44), (d) HVR-6 comprising the amino acid sequence RASQGISSYLA (SEQ ID NO: 29); (e) HVR-L2 comprising the amino acid sequence AASSLQS (SEQ ID NO: 31); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

21. An isolated antibody that binds to LRP5 comprising (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMH (SEQ ID NO: 43), (b) HVR-H2 comprising the amino acid sequence SRISSNGGSTYYADSVKG (SEQ ID NO: 27), (c) HVR-H3 comprising the amino acid sequence WIPQSYPFASYKSGFDY (SEQ ID NO: 44), (d) HVR-L1 comprising the amino acid sequence RASQGIFYYLA (SEQ ID NO: 58); (e) HVR-L2 comprising the amino acid sequence DASTLES (SEQ ID NO: 59); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

22. An isolated antibody that binds to LRP5 comprising (a) HVR-H1 comprising the amino acid sequence GFTFSSYAMH (SEQ ID NO: 43), (b) HVR-H2 comprising the amino acid sequence SRISSNGGSTYYADSVKG (SEQ ID NO: 27), (c) HVR-H3 comprising the amino acid sequence WIPQSYPFASYKSGFDY (SEQ ID NO: 44), (d) HVR-L1 comprising the amino acid sequence RASQAIYSYLA (SEQ ID NO: 60); (e) HVR-L2 comprising the amino acid sequence DASSLES (SEQ ID NO: 46); and (f) HVR-L3 comprising the amino acid sequence QQYYSYPFT (SEQ ID NO: 47).

23. The antibody of claim 9 , wherein the antibody comprises the VH sequence of SEQ ID NO: 2 and the VL sequence of SEQ ID NO: 13.

24. The antibody of claim 9 , wherein the antibody comprises the VH sequence of SEQ ID NO: 3 and the VL sequence of SEQ ID NO: 14.

25. The antibody of claim 9 , wherein the antibody comprises the VH sequence of SEQ ID NO: 4 and the VL sequence of SEQ ID NO: 15.

26. The antibody of claim 9 , wherein the antibody comprises the VH sequence of SEQ ID NO: 5 and the VL sequence of SEQ ID NO: 16.

27. The antibody of claim 9 , wherein the antibody comprises the VH sequence of SEQ ID NO: 6 and the VL sequence of SEQ ID NO: 17.

28. The antibody of claim 9 , wherein the antibody comprises the VH sequence of SEQ ID NO: 8 and the VL sequence of SEQ ID NO: 19.

29. The antibody of claim 9 , wherein the antibody comprises the VH sequence of SEQ ID NO: 9 and the VL sequence of SEQ ID NO: 20.

30. The antibody of claim 9 , wherein the antibody comprises the VH sequence of SEQ ID NO: 10 and the VL sequence of SEQ ID NO: 21.

31. The antibody of claim 9 , wherein the antibody comprises the VH sequence of SEQ ID NO: 11 and the VL sequence of SEQ ID NO: 22.

32. An immunoconjugate comprising the antibody of any one of claims 12 , 13 , or 14 - 22 and a cytotoxic agent.

33. A pharmaceutical formulation comprising the antibody of any one of claims 12 , 13 , or 14 - 22 and a pharmaceutically acceptable carrier.

34. An immunoconjugate comprising the antibody of any one of claims 10 , 11 , or 23 - 31 and a cytotoxic agent.

35. A pharmaceutical formulation comprising the antibody of any one of claims 10 , 11 , or 23 - 31 and a pharmaceutically acceptable carrier.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 1, 2013
From: GENENTECH, INC.
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 030926/0839 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 27, 2013
From: WU, YAN; YE, WEILAN; BURTON, JEREMY BRYANT; CHIU, CECILIA
To: GENENTECH, INC.
Reel/Frame 030699/0427 →
Continuity (2)
Provisional Application 61588100 · Jan 18, 2012
Related Publication 20130183320A1 · Jul 18, 2013