IP Library › Granted Patent US 9,518,121
Granted Patent B2
US 9,518,121 · App. 14/619,930 · Granted Dec 13, 2016

Anti-Jagged1 antibodies and methods of use

Inventors: Yvonne Chinn (Foster City, CA); Julie Q. Hang (San Jose, CA); Christian W. Siebel (Berkeley, CA); Yan Wu (Foster City, CA)
Assignee: Genentech, Inc.
C07K16/2896A61K39/3955A61K47/48561C07K16/28A61K2039/505A61K2039/507C07K2317/21C07K2317/33C07K2317/56C07K2317/565C07K2317/73C07K2317/76C07K2317/92
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Quick Facts
Patent No.
US 9,518,121
App. No.
14/619,930
Granted
Dec 13, 2016
Kind
B2
Abstract

The invention provides anti-Jagged1 antibodies and methods of using the same.

Claims (62)

1. An isolated antibody that binds to human Jagged 1, wherein the antibody comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 35 or 78; an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 28 or 36; an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 55 or 59, wherein X is any amino acid other than S; an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 38; an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39; and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16 or 40.

2. The isolated antibody of claim 1 , wherein the antibody comprises:

a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 78; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 55; or

b) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 78; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 59; or

c) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 78; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 28; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 59.

3. The isolated antibody of claim 1 , wherein the antibody comprises:

a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 38; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 40; or

b) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 38; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16.

4. The isolated antibody of claim 1 , wherein the antibody comprises:

a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 78; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 55; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 38; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 40; or

b) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 78; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 59; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 38; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16; or

c) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 78; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 28; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 59; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 38; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16.

5. The isolated antibody of claim 1 , wherein the antibody comprises a VH sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 54, 58, or 62.

6. The isolated antibody of claim 1 , wherein the antibody comprises a VL sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 10, 26, or 34.

7. The isolated antibody of claim 1 , wherein the antibody comprises:

a) a VH sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 54 and a VL sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 34; or

b) a VH sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 58 and a VL sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 10; or

c) a VH sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 62 and a VL sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 26.

8. An isolated antibody that binds human Jagged1, comprising:

a) a VH sequence of SEQ ID NO: 54, wherein X is any amino acid other than S, and a VL sequence of SEQ ID NO: 34; or

b) a VH sequence of SEQ ID NO: 58, wherein X is any amino acid other than S, and a VL sequence of SEQ ID NO: 10; or

c) a VH sequence of SEQ ID NO: 62, wherein X is any amino acid other than S, and a VL sequence of SEQ ID NO: 26.

9. The isolated antibody of claim 8 , wherein the antibody comprises a VH sequence of SEQ ID NO: 54 and a VL sequence of SEQ ID NO: 34.

10. The isolated antibody of claim 9 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 56 and the light chain comprises the amino acid sequence of SEQ ID NO: 53.

11. The isolated antibody of claim 9 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 57 and the light chain comprises the amino acid sequence of SEQ ID NO: 53.

12. The isolated antibody of claim 1 , wherein X is any amino acid other than S or H.

13. The isolated antibody of claim 1 , wherein X is selected from A, D, E, G, I, K, L, N, Q, R T, and V.

14. The isolated antibody of claim 1 , wherein X is T.

15. An isolated antibody that binds human Jagged1, comprising:

a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 78; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 37; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 38; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 40; or

b) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 78; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 64; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 38; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16; or

c) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 78; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 28; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 64; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 38; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16.

16. The isolated antibody of claim 15 , wherein the antibody comprises:

a) a VH sequence of SEQ ID NO: 33 and a VL sequence of SEQ ID NO: 34; or

b) a VH sequence of SEQ ID NO: 65 and a VL sequence of SEQ ID NO: 10; or

c) a VH sequence of SEQ ID NO: 66 and a VL sequence of SEQ ID NO: 26.

17. An isolated antibody that binds human Jagged 1 , wherein the antibody comprises a VH sequence of SEQ ID NO: 33 and a VL sequence of SEQ ID NO: 34.

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

19. The isolated antibody of claim 18 , wherein the antibody substantially lacks effector function.

20. The isolated antibody of claim 18 , wherein the heavy chain comprises a N297G or N297A mutation.

21. An isolated antibody that binds human Jagged 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 51 and the light chain comprises the amino acid sequence of SEQ ID NO: 53.

22. An isolated antibody that binds human Jagged 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 52 and the light chain comprises the amino acid sequence of SEQ ID NO: 53.

23. The isolated antibody of claim 16 , wherein the antibody comprises:

a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 69 and a light chain comprising the amino acid sequence of SEQ ID NO: 75; or

b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 70 and a light chain comprising the amino acid sequence of SEQ ID NO: 76; or

c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 79 and a light chain comprising the amino acid sequence of SEQ ID NO: 75; or

d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 80 and a light chain comprising the amino acid sequence of SEQ ID NO: 76.

24. The isolated antibody of claim 1 , wherein the antibody is an antagonist of Jagged1-mediated signaling.

25. The isolated antibody of claim 1 , wherein the antibody does not bind human Jagged2.

26. The isolated antibody of claim 1 , wherein the antibody does not bind human DLL4.

27. The isolated antibody of claim 1 , wherein the antibody does not bind human DLL1.

28. The isolated antibody of claim 1 , wherein the antibody does not bind murine Jagged2, murine DLL4, and/or murine DLL1.

29. The isolated antibody of claim 1 , wherein the antibody reduces tumor growth in a mouse xenograft model without causing weight loss.

30. The isolated antibody of claim 29 , wherein the mouse xenograft model is a liver cancer xenograft model.

31. The isolated antibody of claim 30 , wherein tumor growth is reduced by at least 50, at least 60, at least 70, at least 80, or at least 90 AUC/day TGI %.

32. An immunoconjugate comprising an antibody, wherein the antibody comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 35 or 78; an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 28 or 36; an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 55 or 59, wherein X is any amino acid other than S; an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 38; an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39; and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16 or 40, and a cytotoxic agent.

33. A pharmaceutical formulation comprising an antibody, wherein the antibody comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 35 or 78; an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 28 or 36; an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 55 or 59, wherein X is any amino acid other than S; an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 38; an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39; and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16 or 40, and a pharmaceutically acceptable carrier.

34. A pharmaceutical formulation comprising the immunoconjugate of claim 32 and a pharmaceutically acceptable carrier.

35. The isolated antibody of claim 1 conjugated to a label.

36. An isolated antibody that binds human Jagged 1 , comprising: HVR-H1 comprising the amino acid sequence of SEQ ID NO: 78; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 37; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 38; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 40.

37. An isolated antibody that binds human Jagged 1 , comprising: HVR-H1 comprising the amino acid sequence of SEQ ID NO: 78; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 64; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 38; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16.

38. An isolated antibody that binds human Jagged 1 , comprising: HVR-H1 comprising the amino acid sequence of SEQ ID NO: 78; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 28; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 64; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 38; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 39; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 22, 2016
From: GENENTECH, INC.
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 040748/0839 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 27, 2015
From: CHINN, YVONNE; HANG, JULIE Q.; SIEBEL, CHRISTIAN W.; WU, YAN
To: GENENTECH, INC.
Reel/Frame 036184/0643 →
Continuity (2)
Provisional Application 61939110 · Feb 12, 2014
Related Publication 20150252117A1 · Sep 10, 2015