IP Library › Granted Patent US 12,319,735
Granted Patent B2
US 12,319,735 · App. 17/291,701 · Granted Jun 3, 2025

Co-formulations of anti-LAG3 antibodies and anti-PD-1 antibodies

Inventors: Valentyn Antochshuk (Cranford, NJ); Preeti G. Desai (Westfield, NJ); Yogita Krishnamachari (Scotch Plains, NJ); Sahil S. Sangani (Rahway, NJ)
Assignee: Merck Sharp & Dohme LLC
C07K16/2818A61K39/00A61K47/10A61K47/12A61K47/183A61K47/22A61K47/26C07K16/2803C07K2317/565C07K2317/92C07K2317/94
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Quick Facts
Patent No.
US 12,319,735
App. No.
17/291,701
Granted
Jun 3, 2025
Kind
B2
Abstract

The present invention provides co-formulations of anti-PD-1 antibodies and anti-LAG3 antibodies, and their use in treating various disorders.

Claims (72)

1. A pharmaceutical formulation comprising:

about 16-22 mg/mL of an anti-LAG3 antibody; about 3-7 mg/mL of an anti-PD-1 antibody; about 30-120 mg/mL of a non-reducing disaccharide; about 0.02-2.0 mg/mL polysorbate 80 or polysorbate 20; a buffer that maintains the pH of the pharmaceutical formulation at about 5.0-6.5; and about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof, wherein the anti-LAG3 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 39, CDRL2 of SEQ ID NO: 40, and CDRL3 of SEQ ID NO: 41, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 42, CDRH2 of SEQ ID NO: 59, and CDRH3 of SEQ ID NO: 44, and the anti-PD-1 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 1, CDRL2 of SEQ ID NO: 2, and CDRL3 of SEQ ID NO: 3, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 6, CDRH2 of SEQ ID NO: 7, and CDRH3 of SEQ ID NO: 8; wherein the molar ratio of the anti-LAG3 antibody to anti-PD-1 antibody is 4:1.

2. The pharmaceutical formulation of claim 1 comprising about 18-22 mg/mL of the anti-LAG3 antibody; about 4-7 mg/mL of the anti-PD-1 antibody; about 50-90 mg/mL sucrose or trehalose; about 0.05-1.0 mg/mL polysorbate 80 or polysorbate 20; about 3-30 mM histidine buffer that maintains the pH of the pharmaceutical formulation at about 5.0-6.5; and about 40-100 mM L-arginine or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical formulation of claim 1 comprising about 18-20 mg/mL of the anti-LAG3 antibody; about 4-7 mg/mL of the anti-PD-1 antibody; about 50-60 mg/mL sucrose or trehalose; about 0.05-1.0 mg/mL polysorbate 80 or polysorbate 20; about 8-12 mM histidine buffer that maintains the pH of the pharmaceutical formulation at about 5.0-6.5; and about 40-70 mM L-arginine or a pharmaceutically acceptable salt thereof.

4. The formulation of any one of claims 1 to 3 , further comprising about 5-15 mM L-methionine.

5. The formulation of claim 2 , further comprising about 5-10 mM L-methionine.

6. A pharmaceutical formulation comprising about 20 mg/ml of an anti-LAG3 antibody; about 5 mg/ml of an anti-PD-1 antibody; about 54 mg/mL sucrose; about 0.2 mg/mL polysorbate 80; about 10 mM histidine buffer that maintains the pH of the pharmaceutical formulation at about 5.8; and about 56 mM L-arginine or a pharmaceutically acceptable salt thereof; and further comprising about 8 mM L-methionine, wherein the anti-LAG3 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 39, CDRL2 of SEQ ID NO: 40, and CDRL3 of SEQ ID NO: 41, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 42, CDRH2 of SEQ ID NO: 59, and CDRH3 of SEQ ID NO: 44, and the anti-PD-1 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 1, CDRL2 of SEQ ID NO: 2, and CDRL3 of SEQ ID NO: 3, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 6, CDRH2 of SEQ ID NO: 7, and CDRH3 of SEQ ID NO: 8.

7. A pharmaceutical formulation comprising about 18.02 mg/mL of an anti-LAG3 antibody; about 4.505 mg/ml of an anti-PD-1 antibody; about 50 mg/mL sucrose; about 0.2 mg/mL polysorbate 80; about 10 mM histidine buffer that maintains the pH of the pharmaceutical formulation at about 5.8; and about 70 mM L-arginine or a pharmaceutically acceptable salt thereof; and further comprising about 10 mM L-methionine, wherein the anti-LAG3 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 39, CDRL2 of SEQ ID NO: 40, and CDRL3 of SEQ ID NO: 41, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 42, CDRH2 of SEQ ID NO: 59, and CDRH3 of SEQ ID NO: 44, and the anti-PD-1 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 1, CDRL2 of SEQ ID NO: 2, and CDRL3 of SEQ ID NO: 3, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 6, CDRH2 of SEQ ID NO: 7, and CDRH3 of SEQ ID NO: 8.

8. A pharmaceutical formulation comprising: about 18-22 mg/mL of an anti-LAG3 antibody and about 3-7 mg/ml of an anti-PD-1 antibody at a molar ratio of 4:1 anti-LAG3 antibody to anti-PD-1 antibody, an excipient selected from histidine, aspartate, glutamine, glycine, proline, methionine, arginine or a pharmaceutically acceptable salt thereof, NaCl, and KCl, or a combination thereof, at a total excipient concentration of about 25-250 mM, and a buffer that maintains the pH of the pharmaceutical formulation at about 4.5-8, wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO: 10 and a light chain sequence of SEQ ID NO: 5.

9. The pharmaceutical formulation of claim 8 , wherein the excipient is L-arginine or a pharmaceutically acceptable salt thereof at a concentration of about 25-250 mM.

10. The pharmaceutical formulation of claim 8 , wherein the excipient is L-arginine or a pharmaceutically acceptable salt thereof at a concentration of about 40-100 mM.

11. The pharmaceutical formulation of claim 8 , wherein the excipient is NaCl and L-arginine or a pharmaceutically acceptable salt thereof with a total excipient concentration of about 25-250 mM.

12. The pharmaceutical formulation of claim 11 , wherein the NaCl to L-arginine concentration ratio is 1:1.

13. The pharmaceutical formulation of claim 12 , wherein the NaCl concentration is about 35 mM and the L-arginine concentration is about 35 mM.

14. The pharmaceutical formulation of claim 12 , wherein the NaCl concentration is about 50 mM and the L-arginine concentration is about 50 mM.

15. The pharmaceutical formulation of claim 8 , further comprising a non-ionic surfactant that is a polysorbate.

16. The pharmaceutical formulation of claim 15 , wherein the non-ionic surfactant is polysorbate 80 or polysorbate 20.

17. The pharmaceutical formulation of claim 8 , further comprising a sugar that is a non-reducing disaccharide.

18. The pharmaceutical formulation of claim 17 , wherein the sugar is trehalose or sucrose, or a combination thereof.

19. The pharmaceutical formulation of claim 18 , wherein the sugar is at a concentration of about 10-200 mg/ml.

20. The pharmaceutical formulation of claim 8 , further comprising a polyol selected from the group consisting of mannitol, sorbitol, glycerol and polyethylene glycol.

21. The pharmaceutical formulation of claim 20 , wherein the polyol is at a concentration of about 10-200 mg/ml.

22. The pharmaceutical formulation of claim 8 , further comprising about 10-250 mg/mL sucrose, trehalose, mannitol, sorbitol, polyethylene glycol or glycerol; about 0.005-2.0 mg/mL polysorbate 80 or polysorbate 20; and wherein the buffer is about 3-300 mM L-histidine, acetate or citrate buffer that maintains the pH of the pharmaceutical formulation at about 5.0-6.5.

23. The pharmaceutical formulation of claim 9 or 11 , further comprising about 30-120 mg/mL sucrose or trehalose and about 0.05-1.5 mg/ml polysorbate 80 or polysorbate 20; and wherein the buffer is about 3-150 mM L-histidine, acetate or citrate buffer that maintains the pH of the pharmaceutical formulation at about 5.0-6.5.

24. The pharmaceutical formulation of claim 8 , further comprising about 50-90 mg/mL sucrose or trehalose and about 0.05-1.0 mg/mL polysorbate 80; and wherein the buffer is about 5-30 mM L-histidine, acetate or citrate buffer that maintains the pH of the pharmaceutical formulation at about 5.0-6.5.

25. The pharmaceutical formulation of claim 8 comprising about 20 mg/mL of the anti-LAG3 antibody; and further comprising about 50-90 mg/mL sucrose or trehalose and about 0.05-1.0 mg/mL polysorbate 80 or polysorbate 20; wherein the buffer is about 5-20 mM L-histidine, acetate or citrate buffer that maintains the pH of the pharmaceutical formulation at about 5.0-6.5; and wherein the excipient is about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof.

26. The pharmaceutical formulation of claim 8 comprising about 20 mg/mL of the anti-LAG3 antibody; and further comprising about 20-200 mg/mL glycerol, sorbitol or PEG400 and about 0.05-1.0 mg/ml polysorbate 80 or polysorbate 20; wherein the buffer is about 3-150 mM L-histidine, acetate or citrate buffer that maintains the pH of the pharmaceutical formulation at about 5.0-6.5; and wherein the excipient is about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof.

27. The pharmaceutical formulation of claim 8 comprising about 20 mg/mL of the anti-LAG3 antibody; and further comprising about 0.05-1.0 mg/mL polysorbate 80 or polysorbate 20; wherein the buffer is about 3-150 mM L-histidine, acetate or citrate buffer that maintains the pH of the pharmaceutical formulation at about 5.0-6.5; and wherein the excipient is about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof and about 40-100 mM L-glutamine, L-glycine, L-proline or L-methionine.

28. The pharmaceutical formulation of claim 25 , further comprising about 5-15 mM L-methionine.

29. The pharmaceutical formulation of claim 24 , further comprising about 5-15 mM L-methionine.

30. The pharmaceutical formulation of claim 8 or 29 comprising about 20 mg/mL of the anti-LAG3 antibody; further comprising about 50 mg/mL sucrose and about 0.2 mg/mL polysorbate 80; wherein the buffer is about 10 mM L-histidine buffer that maintains the pH of the pharmaceutical formulation at about 5.8-6.0; and wherein the excipient is about 70 mM L-arginine or L-arginine-HCl.

31. The pharmaceutical formulation of claim 1 that is a liquid formulation.

32. The pharmaceutical formulation of claim 1 that is frozen to at least below −70° C.

33. The pharmaceutical formulation of claim 1 that is a reconstituted solution from a lyophilized formulation.

34. The pharmaceutical formulation of claim 1 , wherein the anti-LAG3 antibody comprises: a light chain variable region sequence of SEQ ID NO: 37 and a heavy chain variable region sequence of SEQ ID NO: 58, and the anti-PD-1 antibody thereof comprises a heavy chain variable region of SEQ ID NO: 9 and a light chain variable region of SEQ ID NO: 4.

35. The pharmaceutical formulation of claim 34 , wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO: 10 and a light chain sequence of SEQ ID NO: 5.

36. The pharmaceutical formulation of claim 1 , wherein the anti-LAG3 antibody is Ab6 variant, and the anti-PD-1 antibody is pembrolizumab or pembrolizumab variant.

37. The pharmaceutical formulation of claim 2 , wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO: 10 and a light chain sequence of SEQ ID NO: 5.

38. The pharmaceutical formulation of claim 3 , wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO: 10 and a light chain sequence of SEQ ID NO: 5.

39. The pharmaceutical formulation of claim 4 , wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO: 10 and a light chain sequence of SEQ ID NO: 5.

40. The pharmaceutical formulation of claim 5 , wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO: 10 and a light chain sequence of SEQ ID NO: 5.

41. The pharmaceutical formulation of claim 6 , wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO: 10 and a light chain sequence of SEQ ID NO: 5.

42. The pharmaceutical formulation of claim 7 , wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO: 10 and a light chain sequence of SEQ ID NO: 5.

43. The pharmaceutical formulation of claim 37 that is a liquid formulation.

44. The pharmaceutical formulation of claim 38 that is a liquid formulation.

45. The pharmaceutical formulation of claim 39 that is a liquid formulation.

46. The pharmaceutical formulation of claim 40 that is a liquid formulation.

47. The pharmaceutical formulation of claim 41 that is a liquid formulation.

48. The pharmaceutical formulation of claim 42 that is a liquid formulation.

49. The pharmaceutical formulation of claim 8 that is a liquid formulation.

50. The pharmaceutical formulation of claim 22 that is a liquid formulation.

51. The pharmaceutical formulation of claim 23 that is a liquid formulation.

52. The pharmaceutical formulation of claim 24 that is a liquid formulation.

53. The pharmaceutical formulation of claim 25 that is a liquid formulation.

54. The pharmaceutical formulation of claim 26 that is a liquid formulation.

55. The pharmaceutical formulation of claim 27 that is a liquid formulation.

56. The pharmaceutical formulation of claim 30 that is a liquid formulation.

57. The pharmaceutical formulation of claim 8 , wherein the excipient is selected from a) histidine, aspartate, glutamine, glycine, proline, methionine, or a combination thereof, at a total concentration of about 40-100 mM; b) arginine or a pharmaceutically acceptable salt thereof, NaCl, KCl, or a combination thereof at a total concentration of about 40-150 mM; or a combination of a) and b).

58. The pharmaceutical formulation of claim 22 , wherein the excipient is selected from a) histidine, aspartate, glutamine, glycine, proline, methionine, or a combination thereof, at a total concentration of about 40-100 mM; b) arginine or a pharmaceutically acceptable salt thereof, NaCl, KCl, or a combination thereof at a total concentration of about 40-150 mM; or a combination of a) and b).

59. The pharmaceutical formulation of claim 24 , wherein the excipient is selected from a) histidine, aspartate, glutamine, glycine, proline, methionine, or a combination thereof, at a total concentration of about 40-100 mM; b) arginine or a pharmaceutically acceptable salt thereof, NaCl, KCl, or a combination thereof at a total concentration of about 40-150 mM; or a combination of a) and b).

60. A pharmaceutical formulation comprising 20 mg/mL of an anti-LAG3 antibody; 5 mg/mL of an anti-PD-1 antibody; about 54 mg/mL sucrose; about 0.2 mg/mL polysorbate 80; about 10 mM histidine buffer that maintains the pH of the pharmaceutical formulation at about 5.8; and about 56 mM L-arginine or a pharmaceutically acceptable salt thereof; and further comprising about 8 mM L-methionine, wherein the anti-LAG3 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 39, CDRL2 of SEQ ID NO: 40, and CDRL3 of SEQ ID NO: 41, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 42, CDRH2 of SEQ ID NO: 59, and CDRH3 of SEQ ID NO: 44, and the anti-PD-1 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 1, CDRL2 of SEQ ID NO: 2, and CDRL3 of SEQ ID NO: 3, and a variable heavy chain region comprising CDRH1 of SEO ID NO: 6, CDRH2 of SEQ ID NO: 7, and CDRH3 of SEQ ID NO: 8.

61. A pharmaceutical formulation comprising 20 mg/mL of an anti-LAG3 antibody; 5 mg/mL of an anti-PD-1 antibody; 54 mg/mL sucrose; 0.2 mg/mL polysorbate 80; 10 mM histidine buffer that maintains the pH of the pharmaceutical formulation at 5.8; and 56 mM L-arginine or a pharmaceutically acceptable salt thereof; and further comprising 8 mM L-methionine, wherein the anti-LAG3 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 39, CDRL2 of SEQ ID NO: 40, and CDRL3 of SEQ ID NO: 41, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 42, CDRH2 of SEQ ID NO: 59, and CDRH3 of SEQ ID NO: 44, and the anti-PD-1 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 1, CDRL2 of SEQ ID NO: 2, and CDRL3 of SEQ ID NO: 3, and a variable heavy chain region comprising CDRHI of SEO ID NO: 6, CDRH2 of SEQ ID NO: 7, and CDRH3 of SEQ ID NO: 8.

62. The pharmaceutical formulation of claim 60 , wherein the anti-LAG3 antibody comprises: a light chain variable region sequence of SEQ ID NO: 37 and a heavy chain variable region sequence of SEQ ID NO: 58, and the anti-PD-1 antibody comprises a heavy chain variable region of SEQ ID NO: 9 and a light chain variable region of SEQ ID NO: 4.

63. The pharmaceutical formulation of claim 61 , wherein the anti-LAG3 antibody comprises: a light chain variable region sequence of SEQ ID NO: 37 and a heavy chain variable region sequence of SEQ ID NO: 58, and the anti-PD-1 antibody comprises a heavy chain variable region of SEQ ID NO: 9 and a light chain variable region of SEQ ID NO: 4.

64. The pharmaceutical formulation of claim 60 , wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO: 10 and a light chain sequence of SEQ ID NO: 5.

65. The pharmaceutical formulation of claim 61 , wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO: 10 and a light chain sequence of SEQ ID NO: 5.

66. The pharmaceutical formulation of claim 60 that is a liquid formulation.

67. The pharmaceutical formulation of claim 61 that is a liquid formulation.

68. The pharmaceutical formulation of claim 62 that is a liquid formulation.

69. The pharmaceutical formulation of claim 63 that is a liquid formulation.

70. The pharmaceutical formulation of claim 64 that is a liquid formulation.

71. The pharmaceutical formulation of claim 65 that is a liquid formulation.

Assignments (4)
MERGER Recorded Aug 8, 2022
From: MERCK SHARP & DOHME CORP.
To: MERCK SHARP & DOHME LLC
Reel/Frame 061102/0145 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 6, 2021
From: ANTOCHSHUK, VALENTYN; DESAI, PREETI G.; KRISHNAMACHARI, YOGITA
To: MERCK SHARP & DOHME CORP.
Reel/Frame 056155/0364 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 6, 2021
From: SANGANI, SAHIL S.
To: EUROFINS LANCASTER LABORATORIES PROFESSIONAL SCIENTIFIC SERVICES LLC.
Reel/Frame 056155/0752 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 6, 2021
From: EUROFINS LANCASTER LABORATORIES PROFESSIONAL SCIENTIFIC SERVICES LLC.
To: MERCK SHARP & DOHME CORP.
Reel/Frame 056155/0916 →
Continuity (2)
Provisional Application 62756678 · Nov 7, 2018
Related Publication 20220002410A1 · Jan 6, 2022
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