IP Library › Granted Patent US 9,433,687

Granted Patent B2

US 9,433,687 · App. 14/073,273 · Granted Sep 6, 2016

Anti-Notch3 antibodies and antibody-drug conjugates

Inventors: Kenneth G. Geles (Nyack, NY); Yijie Gao (Chestnut Hill, MA); Puja Sapra (River Edge, NJ); Lioudmila Gennadievna Tchistiakova (Stoneham, MA); Bin-Bing Stephen Zhou (Rohnert Park, CA)

Assignee: Pfizer Inc.

A61K47/48438 A61K39/395 A61K47/48561 A61K47/48569 A61K47/48584 A61K47/48592 A61K47/48638 A61K47/48715 C07K16/28 C07K16/32 A61K39/3955 A61K2039/505 C07K16/2866 C07K16/30 C07K2316/96 C07K2317/24 C07K2317/51 C07K2317/515 C07K2317/56 C07K2317/565 C07K2317/732 C07K2317/75 C07K2317/76 C07K2317/92

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Quick Facts

Patent No.: US 9,433,687
App. No.: 14/073,273
Granted: Sep 6, 2016
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention provides for anti-Notch3 antibodies, anti-Notch3 antibody-drug conjugates and methods for preparing and using the same.

Claims (142)

1. An isolated antibody, or antigen-binding fragment thereof, that binds to Notch3 comprising:

a VH CDR1, a VH CDR2, and a VH CDR3 of a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 13; and

a VL CDR1, a VL CDR2, and a VL CDR3 of a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 25.

2. The isolated antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antibody or antigen-binding fragment:

(a) internalizes into a cell,

(b) does not inhibit Notch3 signaling, or

3. The isolated antibody, or antigen-binding fragment thereof, of claim 1 , wherein the antibody or antigen-binding fragment:

(a) binds to the Lin 12/Notch repeat (LNR)-C and heterodimerization (HD)-1 domains of the Notch3 Negative Regulatory Region (NRR),

(b) does not maintain the Notch3 NRR in an auto-inhibitory conformation, or

4. The isolated antibody, or antigen-binding fragment thereof, of claim 1 , comprising:

a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 15 or 16; a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 19 or 20; a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 23; a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 27; a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 29; and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 31.

5. The isolated antibody, or antigen-binding fragment thereof, of claim 1 , comprising a heavy chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 13 or a light chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 25.

6. The isolated antibody, or antigen-binding fragment thereof, of claim 5 , comprising a heavy chain variable region amino acid sequence of SEQ ID NO: 13.

7. The isolated antibody, or antigen-binding fragment thereof, of claim 6 , comprising a heavy chain amino acid sequence of SEQ ID NO: 33.

8. The isolated antibody, or antigen-binding fragment thereof, of claim 5 , comprising a light chain variable region amino acid sequence of SEQ ID NO: 25.

9. The isolated antibody, or antigen-binding fragment thereof, of claim 8 , comprising a light chain amino acid sequence of SEQ ID NO: 35.

10. An antibody-drug conjugate comprising a cytotoxic agent conjugated to the antibody, or antigen-binding fragment thereof, of claim 1 .

11. A pharmaceutical composition comprising the antibody-drug conjugate of claim 10 and a pharmaceutically acceptable carrier.

12. A composition comprising the antibody of claim 1 .

13. An isolated antibody, or antigen-binding fragment thereof, that binds to Notch3 comprising:

a VH CDR1, a VH CDR2, and a VH CDR3 of a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 37; and

a VL CDR1, a VL CDR2, and a VL CDR3 of a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 49.

14. An isolated antibody, or antigen-binding fragment thereof, of claim 13 , comprising:

a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 39 or 40; a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 43 or 44; a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 47; a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 51; a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 53; and a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 55.

15. The isolated antibody, or antigen-binding fragment thereof, of claim 13 , comprising a heavy chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 37 or a light chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 49.

16. The isolated antibody, or antigen-binding fragment thereof, of claim 15 , comprising a heavy chain variable region amino acid sequence of SEQ ID NO: 37.

17. The isolated antibody, or antigen-binding fragment thereof, of claim 16 , comprising a heavy chain amino acid sequence of SEQ ID NO: 57.

18. The isolated antibody, or antigen-binding fragment thereof, of claim 15 , comprising a light chain variable region amino acid sequence of SEQ ID NO: 49.

19. The isolated antibody, or antigen-binding fragment thereof, of claim 18 , comprising a light chain amino acid sequence of SEQ ID NO: 59.

20. An antibody-drug conjugate comprising a cytotoxic agent conjugated to the antibody, or antigen-binding fragment thereof, of claim 13 .

21. A pharmaceutical composition comprising the antibody-drug conjugate of claim 20 and a pharmaceutically acceptable carrier.

22. A composition comprising the antibody of claim 13 .

23. An antibody-drug conjugate of the formula:

Ab-(L-D) p,

wherein:

(a) Ab is an antibody, or antigen-binding fragment thereof, that binds to Notch3;

(b) L-D is a linker-drug moiety, wherein L is a linker selected from the group consisting of maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (vc), maleimidocaproyl (mc), maleimido-heptanoyl (me) and maleimido-Peg6C2 (MalPeg6C2) and D is a drug selected from the group consisting of:

(i) 0101 having the formula:

(ii) 6780 having the formula:

(iii) 0131 having the formula:

(iv) 3377 having the formula:

and

(v) 8261 having the formula:

and

24. A pharmaceutical composition comprising the antibody-drug conjugate of claim 23 and a pharmaceutically acceptable carrier.

25. The antibody-drug conjugate of claim 23 , wherein Ab comprises:

a VH CDR1, a VH CDR2, and a VH CDR3 of a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 13; and a VL CDR1, a VL CDR2, and a VL CDR3 of a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 25; or

a VH CDR1, a VH CDR2, and a VH CDR3 of a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 37; and a VL CDR1, a VL CDR2, and a VL CDR3 of a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 49.

26. The antibody-drug conjugate of claim 23 , wherein Ab comprises:

27. The antibody-drug conjugate of claim 26 , wherein Ab comprises:

a heavy chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 13 or a light chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 25; or

a heavy chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 37 or a light chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 49.

28. The antibody-drug conjugate of claim 27 , wherein Ab comprises a heavy chain variable region amino acid sequence of SEQ ID NO: 13; or a heavy chain variable region amino acid sequence of SEQ ID NO: 37.

29. The antibody-drug conjugate of claim 28 , wherein Ab comprises a heavy chain amino acid sequence of SEQ ID NO: 33; or a heavy chain amino acid sequence of SEQ ID NO: 57.

30. The antibody-drug conjugate of claim 27 , wherein Ab comprises a light chain variable region amino acid sequence of SEQ ID NO: 25 or a light chain variable region amino acid sequence of SEQ ID NO: 49.

31. The antibody-drug conjugate of claim 30 , wherein Ab comprises a light chain amino acid sequence of SEQ ID NO: 35; or a light chain amino acid sequence of SEQ ID NO: 59.

32. An antibody-drug conjugate of the formula:

Ab-(L-D) p,

wherein:

(a) Ab is an antibody, or antigen-binding fragment thereof, that binds to Notch3,

(b) L-D is a linker-drug moiety, wherein L is a linker and D is a drug, wherein L-D is selected from the group consisting of:

vc0101 having the formula:

and vc6780 having the formula:

and

33. A pharmaceutical composition comprising the antibody-drug conjugate of claim 32 and a pharmaceutically acceptable carrier.

34. The antibody-drug conjugate of claim 32 , wherein Ab comprises:

35. The antibody-drug conjugate of claim 32 , wherein Ab comprises:

36. The antibody-drug conjugate of claim 35 , wherein Ab comprises:

37. The antibody-drug conjugate of claim 36 , wherein Ab comprises a heavy chain variable region amino acid sequence of SEQ ID NO: 13; or a heavy chain variable region amino acid sequence of SEQ ID NO: 37.

38. The antibody-drug conjugate of claim 37 , wherein Ab comprises a heavy chain amino acid sequence of SEQ ID NO: 33; or a heavy chain amino acid sequence of SEQ ID NO: 57.

39. The antibody-drug conjugate of claim 36 , wherein Ab comprises a light chain variable region amino acid sequence of SEQ ID NO: 25 or a light chain variable region amino acid sequence of SEQ ID NO: 49.

40. The antibody-drug conjugate of claim 39 , wherein Ab comprises a light chain amino acid sequence of SEQ ID NO: 35; or a light chain amino acid sequence of SEQ ID NO: 59.

41. An antibody-drug conjugate of the formula:

Ab-(L-D) p,

wherein:

(a) Ab is an antibody, or antigen-binding fragment thereof, that binds to Notch3 comprising a VH CDR1, a VH CDR2 and a VH CDR3 of a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 13 and a VL CDR1, a VL CDR2 and VL CDR3 of a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 25;

(b) L-D is a linker-drug moiety, wherein L is a linker, and D is a drug; and

42. The antibody-drug conjugate of claim 41 , wherein L is selected from the group consisting of maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (vc), maleimidocaproyl (mc), maleimido-heptanoyl (me) and maleimido-Peg6C2 (MalPeg6C2).

43. The antibody-drug conjugate of claim 42 , wherein D is selected from the group consisting of:

(a) 0101 having the formula:

(b) 6780 having the formula:

(d) 3377 having the formula:

and

(e) 8261 having the formula:

44. The antibody-drug conjugate of claim 41 , wherein L-D is selected from the group consisting of:

vc0101 having the formula:

and vc6780 having the formula:

45. A pharmaceutical composition comprising the antibody-drug conjugate of claim 41 and a pharmaceutically acceptable carrier.

46. The antibody-drug conjugate of claim 41 , wherein Ab comprises:

47. The antibody-drug conjugate of claim 41 , wherein Ab comprises a heavy chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 13 or a light chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 25.

48. The antibody-drug conjugate of claim 47 , wherein Ab comprises a heavy chain variable region amino acid sequence of SEQ ID NO: 13.

49. The antibody-drug conjugate of claim 48 , wherein Ab comprises a heavy chain amino acid sequence of SEQ ID NO: 33.

50. The antibody-drug conjugate of claim 47 , wherein Ab comprises a light chain variable region amino acid sequence of SEQ ID NO: 25.

51. The antibody-drug conjugate of claim 50 , wherein Ab comprises a light chain amino acid sequence of SEQ ID NO: 35.

52. An antibody-drug conjugate of the formula:

Ab-(L-D) p,

wherein:

(a) Ab is an antibody, or antigen-binding fragment thereof, that binds to Notch3 comprising a VH CDR1, a VH CDR2, and a VH CDR3 of a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 37; and a VL CDR1, a VL CDR2, and a VL CDR3 of a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 49;

(b) L-D is a linker-drug moiety, wherein L is a linker, and D is a drug; and

53. The antibody-drug conjugate of claim 52 , wherein L is selected from the group consisting of maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (vc), maleimidocaproyl (mc), maleimido-heptanoyl (me) and maleimido-Peg6C2 (MalPeg6C2).

54. The antibody-drug conjugate of claim 53 , wherein D is selected from the group consisting of:

(a) 0101 having the formula:

(b) 6780 having the formula:

(d) 3377 having the formula:

and

(e) 8261 having the formula:

55. The antibody-drug conjugate of claim 52 , wherein L-D is selected from the group consisting of:

vc0101 having the formula:

and vc6780 having the formula:

56. The antibody-drug conjugate of claim 52 , wherein Ab comprises:

57. The antibody-drug conjugate of claim 52 , wherein Ab comprises a heavy chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 37 or a light chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 49.

58. The antibody-drug conjugate of claim 57 , wherein Ab comprises a heavy chain variable region amino acid sequence of SEQ ID NO: 37.

59. The antibody-drug conjugate of claim 58 , wherein Ab comprises a heavy chain amino acid sequence of SEQ ID NO: 57.

60. The antibody-drug conjugate of claim 57 , wherein Ab comprises a light chain variable region amino acid sequence of SEQ ID NO: 49.

61. The antibody-drug conjugate of claim 60 , wherein Ab comprises a light chain amino acid sequence of SEQ ID NO: 59.

62. A pharmaceutical composition comprising the antibody-drug conjugate of claim 52 and a pharmaceutically acceptable carrier.

63. An antibody-drug conjugate of the formula:

Ab-(L-D) p,

wherein:

(a) Ab is an antibody, or antigen-binding fragment thereof, comprising a heavy chain variable region amino acid sequence of SEQ ID NO: 13 and a light chain variable region amino acid sequence of SEQ ID NO 25;

(b) L-D is a linker-drug moiety, wherein L is a linker, and D is a drug, wherein the L-D is vc0101 having the formula

and

64. A pharmaceutical composition comprising the antibody-drug conjugate of claim 63 and a pharmaceutically acceptable carrier.

Continuity (3)

Provisional Application 61889744 · Oct 11, 2013

Provisional Application 61723772 · Nov 7, 2012

Related Publication 20140127211A1 · May 8, 2014