IP Library › Granted Patent US 9,598,485

Granted Patent B2

US 9,598,485 · App. 14/773,332 · Granted Mar 21, 2017

Anti-tau antibodies and methods of use

Inventors: Gai Ayalon (Moraga, CA); Danielle Marie Di Cara (San Francisco, CA); Isidro Hotzel (Brisbane, CA); Andrea Pfeifer (St-Legier, CH); Andreas Muhs (Cugy, CH); Maria Pihlgren (Mont-sur-Lausan, CH); Oskar Adolfsson (Bercher, CH)

Assignees: AC IMMUNE S.A.; GENENTECH, INC.

C07K16/18 A61K47/48538 C07K16/44 C07K2317/24 C07K2317/33 C07K2317/34 C07K2317/55 C07K2317/565 C07K2317/92

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Quick Facts

Patent No.: US 9,598,485
App. No.: 14/773,332
Granted: Mar 21, 2017
Kind: B2

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Abstract

The present invention relates to anti-Tau antibodies, such as antibodies that bind to a phosphorylated epitope on human Tau protein with high specificity and/or affinity, and methods of using the same.

Claims (85)

1. An isolated antibody that binds to a phosphorylated epitope of Tau protein, wherein the antibody comprises HVR-L1, HVR-L2 and HVR-L3, wherein:

(a) HVR-L1 comprises the amino acid sequence X 1 SSQX 2 LX 3 X 4 X 5 X 6 GX 7 TYX 8 H (SEQ ID NO:89), wherein X 1 =R or T; X 2 =S, R or V; X 3 =V, I or R; X 4 =H or R; X 5 =S, R, G or K; X 6 =H, N, R, K or G; X 7 =K or R; and X 8 =L or V;

(b) HVR-L2 comprises the amino acid sequence KVX 9 X 10 RFX 11 (SEQ ID NO:90), wherein X 9 =S, K or R; X 10 =N, K or H; and X 11 =S, F, G, K, R, Y or L; and

(c) HVR-L3 comprises the amino acid sequence SQTX 12 X 13 FPX 14 T (SEQ ID NO:91), wherein X 12 =A or R; X 13 =H, R, Q or Y; X 14 =Y or R;

and wherein the antibody does not comprise an HVR-L1, HVR-L2 and HVR-L3 wherein the HVR-L1 amino acid sequence is RSSQSLVHSHGKTYLH (SEQ ID NO:15) or RSSQRLVHSHGKTYLH (SEQ ID NO:92); the HVR-L2 amino acid sequence is KVSNRFS (SEQ ID NO:16); and the HVR-L3 amino acid sequence is SQTAHFPYT (SEQ ID NO:30).

2. The antibody of claim 1 , wherein the phosphorylated epitope includes a phosphorylated amino acid residue selected from the group consisting of serine at position 409 of human tau (SEQ ID NO:59); serine at position 404 of human tau (SEQ ID NO:59); and serine at position 404 and 409 of human tau (SEQ ID NO:59).

3. The antibody of claim 1 , wherein the antibody comprises HVR-H1, HVR-H2 and HVR-H3, wherein HVR-H1 comprises the amino acid sequence GYTFTDYYMN (SEQ ID NO:33); HVR-H2 comprises the amino acid sequence DINPNRGGTTYNQKFKG (SEQ ID NO:34); and HVR-H3 comprises the amino acid sequence YYAVGY (SEQ ID NO:35).

4. The antibody of claim 1 , wherein the antibody comprises an HVR-L1, HVR-L2 and HVR-L3, wherein (a) HVR-L1 comprises the amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, and SEQ ID NO:14; (b) HVR-L2 comprises the amino acid sequence selected from the group consisting of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO: 26; and (c) HVR-L3 comprises the amino acid sequence selected from the group consisting of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, and SEQ ID NO:32.

5. The antibody of claim 4 , comprising:

(a)(i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:1; (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:16; and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO:27; or

(b)(i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:2; (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:17; and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO:27; or

(c)(i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:8; (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:21; and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO:29; or

(d)(i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:14; (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:25; and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO:31; or

(e)(i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:9; (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:17; and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO:31.

6. The antibody of claim 4 , comprising a light chain variable domain (VL) sequence selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:44, SEQ ID NO:54, and SEQ ID NO:55, or a VL having at least 95% sequence identity to the amino acid sequence selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:44, SEQ ID NO:54, and SEQ ID NO:55.

7. The antibody of claim 6 , further comprising a heavy chain variable domain (VH) sequence of SEQ ID NO:58, or a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:58.

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

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

10. The antibody of claim 9 , which is a human or humanized antibody.

11. The antibody of claim 1 , which is a full length IgG1 antibody or a full-length IgG4 antibody.

12. The antibody of claim 1 , which is a full length IgG1 N297G antibody.

13. The antibody of claim 1 , wherein the Tau protein is a human Tau protein.

14. The antibody of claim 1 , which does not bind to the same epitope of the Tau protein which is not phosphorylated, or which binds to the same epitope of the Tau protein which is not phosphorylated with substantially reduced affinity.

15. The antibody of claim 1 , wherein the Tau protein comprises the amino acid sequence of SEQ ID NO:59.

16. The antibody of claim 13 , wherein the epitope on the human Tau protein comprises amino acid residues 404-411.

17. The antibody of claim 1 , which binds to the phosphorylated epitope with a Kd of between about 1 nM and 45 nM.

18. The antibody of claim 1 , which binds to the phosphorylated epitope with a Kd of ≦1 nM.

19. The antibody of claim 1 , which has a dissociation rate constant of ≦5×10 −3 s −1 .

20. The antibody of claim 1 , which has an association rate constant of ≧3×10 5 M −1 s −1 or ≧7×10 5 M −1 s −1 .

21. The antibody of claim 1 , wherein the Tau protein is an aggregated microtubule-associated and/or hyperphosphorylated Tau protein.

22. An isolated nucleic acid encoding the antibody of claim 1 .

23. A host cell comprising the nucleic acid of claim 22 .

24. A method of producing an antibody comprising culturing the host cell of claim 23 so that the antibody is produced.

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

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

27. A method of treating an individual having a disease or disorder selected from: a tauopathy, Alzheimer's disease (AD), frontotemporal dementia (FTD), and a Tau protein associated impairment in or loss of cognitive functions, comprising administering to the individual an effective amount of the antibody of claim 1 .

28. A method of reducing the levels of total Tau protein, phosphorylated Tau protein or hyperphosphorylated Tau protein in the brain of an individual, comprising administering to the individual an effective amount of the antibody of claim 1 to reduce the levels of total Tau protein, phosphorylated Tau protein or hyperphosphorylated Tau protein in the brain of the individual.

29. The method of claim 27 , wherein the phosphorylated epitope includes a phosphorylated amino acid residue selected from the group consisting of serine at position 409 of human tau (SEQ ID NO:59); serine at position 404 of human tau (SEQ ID NO:59); and serine at position 404 and 409 of human tau (SEQ ID NO:59).

30. The method of claim 27 , wherein the antibody comprises at least one sequence selected from the group consisting of HVR-H1, HVR-H2 and HVR-H3, wherein HVR-H1 comprises the amino acid sequence GYTFTDYYMN (SEQ ID NO:33); HVR-H2 comprises the amino acid sequence DINPNRGGTTYNQKFKG (SEQ ID NO:34); and HVR-H3 comprises the amino acid sequence YYAVGY (SEQ ID NO:35).

31. The method of claim 27 , wherein the antibody comprises an HVR-L1, HVR-L2 and HVR-L3, wherein (a) HVR-L1 comprises the amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, and SEQ ID NO:14; (b) HVR-L2 comprises the amino acid sequence selected from the group consisting of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO: 26; and (c) HVR-L3 comprises the amino acid sequence selected from the group consisting of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, and SEQ ID NO:32.

32. The method of claim 31 , wherein the antibody comprises:

(e)(i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:9; (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:17; and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO:31.

33. The method of claim 31 , wherein the antibody comprises a light chain variable domain (VL) sequence selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:44, SEQ ID NO:54, and SEQ ID NO:55, or a VL having at least 95% sequence identity to the amino acid sequence selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:44, SEQ ID NO:54, and SEQ ID NO:55.

34. The method of claim 33 , wherein the antibody further comprises a heavy chain variable domain (VH) sequence of SEQ ID NO:58, or a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:58.

35. The method of claim 27 , wherein the antibody is a monoclonal antibody.

36. The method of claim 35 , wherein the antibody is a human, humanized, or chimeric antibody.

37. The method of claim 35 , wherein the antibody is a full length IgG1 antibody or a full-length IgG4 antibody.

38. The method of claim 35 , wherein the antibody is a full length IgG1 N297G antibody.

39. The method of claim 27 , wherein the antibody binds to human Tau protein.

40. The method of claim 39 , wherein the antibody does not bind to the same epitope of the Tau protein which is not phosphorylated, or which binds to the same epitope of the Tau protein which is not phosphorylated with substantially reduced affinity.

41. The method of claim 39 , wherein the Tau protein comprises the amino acid sequence of SEQ ID NO:59.

42. The method of claim 39 , wherein the epitope on the human Tau protein comprises amino acid residues 404-411.

43. The method of claim 27 , wherein the antibody binds to the phosphorylated epitope with a Kd of between about 1 nM and 45 nM.

44. The method of claim 27 , wherein the antibody binds to the phosphorylated epitope with a Kd of ≦1 nM.

45. The method of claim 27 , wherein the antibody has a dissociation rate constant of ≦5×10 −3 s −1 .

46. The method of claim 27 , wherein the antibody has an association rate constant of ≧3×10 5 M −1 s −1 or ≧7×10 5 M −1 s −1 .

47. The method of claim 27 , wherein the antibody binds to a Tau protein that is an aggregated microtubule-associated and/or hyperphosphorylated Tau protein.

48. The method of claim 28 , wherein the phosphorylated epitope includes a phosphorylated amino acid residue selected from the group consisting of serine at position 409 of human tau (SEQ ID NO:59); serine at position 404 of human tau (SEQ ID NO:59); and serine at position 404 and 409 of human tau (SEQ ID NO:59).

49. The method of claim 28 , wherein the antibody comprises at least one sequence selected from the group consisting of HVR-H1, HVR-H2 and HVR-H3, wherein HVR-H1 comprises the amino acid sequence GYTFTDYYMN (SEQ ID NO:33); HVR-H2 comprises the amino acid sequence DINPNRGGTTYNQKFKG (SEQ ID NO:34); and HVR-H3 comprises the amino acid sequence YYAVGY (SEQ ID NO:35).

50. The method of claim 28 , wherein the antibody comprises an HVR-L1, HVR-L2 and HVR-L3, wherein (a) HVR-L1 comprises the amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, and SEQ ID NO:14; (b) HVR-L2 comprises the amino acid sequence selected from the group consisting of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO: 26; and (c) HVR-L3 comprises the amino acid sequence selected from the group consisting of SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, and SEQ ID NO:32.

51. The method of claim 50 , wherein the antibody comprises:

(e)(i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:9; (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:17; and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO:31.

52. The method of claim 50 , wherein the antibody comprises a light chain variable domain (VL) sequence selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:44, SEQ ID NO:54, and SEQ ID NO:55, or a VL having at least 95% sequence identity to the amino acid sequence selected from the group consisting of SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:44, SEQ ID NO:54, and SEQ ID NO:55.

53. The method of claim 52 , wherein the antibody further comprises a heavy chain variable domain (VH) sequence of SEQ ID NO:58, or a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:58.

54. The method of claim 28 , wherein the antibody is a monoclonal antibody.

55. The method of claim 54 , wherein the antibody is a human, humanized, or chimeric antibody.

56. The method of claim 54 , wherein the antibody is a full length IgG1 antibody or a full-length IgG4 antibody.

57. The method of claim 54 , wherein the antibody is a full length IgG1 N297G antibody.

58. The method of claim 28 , wherein the antibody binds to human Tau protein.

59. The method of claim 58 , wherein the antibody does not bind to the same epitope of the Tau protein which is not phosphorylated, or which binds to the same epitope of the Tau protein which is not phosphorylated with substantially reduced affinity.

60. The method of claim 58 , wherein the Tau protein comprises the amino acid sequence of SEQ ID NO:59.

61. The method of claim 58 , wherein the epitope on the human Tau protein comprises amino acid residues 404-411.

62. The method of claim 28 , wherein the antibody binds to the phosphorylated epitope with a Kd of between about 1 nM and 45 nM.

63. The method of claim 28 , wherein the antibody binds to the phosphorylated epitope with a Kd of ≦1 nM.

64. The method of claim 28 , wherein the antibody has a dissociation rate constant of ≦5×10 −3 s −1 .

65. The method of claim 28 , wherein the antibody has an association rate constant of ≧3×10 5 M −1 s −1 or ≧7×10 5 M −1 s −1 .

66. The method of claim 28 , wherein the antibody binds to a Tau protein that is an aggregated microtubule-associated and/or hyperphosphorylated Tau protein.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 18, 2016

From: AYALON, GAI; DI CARA, DANIELLE MARIE; HOTZEL, ISIDRO

To: GENENTECH, INC.

Reel/Frame 037764/0531 →

Continuity (2)

Provisional Application 61800949 · Mar 15, 2013

Related Publication 20160024193A1 · Jan 28, 2016