Formulations of anti-LAG3 antibodies and co-formulations of anti-LAG3 antibodies and anti-PD-1 antibodies

1. A formulation that comprises an anti-LAG3 antibody at a concentration of about 20-220 mg/ml, wherein the anti-LAG3 antibody comprises two heavy chains and two light chains, each light chain comprises SEQ ID NO: 35 and each heavy chain comprises a heavy chain variable region sequence of SEQ ID NO: 58 and an IgG4 constant region, and an excipient which is 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, LiCl, or a combination thereof at a total concentration of about 40-150 mM; or a combination of a) and b); and a buffer that maintains the pH of the formulation at about 5.3 to 6.4.

2. The formulation of claim 1 , wherein the excipient is L-arginine or a pharmaceutically acceptable salt thereof at a concentration of about 40-150 mM.

3. The formulation of claim 2 further comprising about 30-120 mg/mL sucrose or trehalose; and about 0.05-1.5 mg/mL polysorbate 80 or 20;

wherein the buffer is about 3-150 mM L-histidine, acetate or citrate buffer.

4. The formulation of claim 3 , further comprising 3-150 mM L-methionine.

5. The formulation of claim 1 , wherein the excipient is L-arginine or a pharmaceutically acceptable salt thereof at a concentration of about 40-100 mM.

6. The formulation of claim 5 , wherein the anti-LAG3 antibody is at about 20-30 mg/ml; the excipient is about 40-100 mM L-arginine or a pharmaceutically acceptable salt thereof; the buffer is about 5-30 mM L-histidine, acetate or citrate buffer; and the formulation further comprises about 50-90 mg/mL sucrose or trehalose and about 0.05-1.0 mg/mL polysorbate 80.

7. The formulation of claim 6 , further comprising about 5-15 mM L-methionine.

8. The formulation of claim 1 , wherein the excipient is NaCl and L-arginine or a pharmaceutically acceptable salt thereof with a total concentration of about 70-100 mM.

9. The formulation of claim 1 , wherein the excipient is NaCl, KCl or LiCl at about 40-100 mM.

10. The formulation of claim 1 , wherein the excipient is L-histidine, L-aspartate, L-glutamine, or L-glycine at about 40-100 mM.

11. The formulation of claim 1 , wherein the excipient is L-histidine at about 40-100 mM.

12. The formulation of claim 1 , wherein the buffer is a histidine buffer, an acetate buffer or a citrate buffer.

13. The formulation of claim 12 , wherein the buffer has a concentration of about 1-300 mM.

14. The formulation of claim 13 , further comprising a surfactant selected from polysorbate 20 and polysorbate 80, and a sugar selected from sucrose and trehalose, or a combination thereof.

15. The formulation of claim 1 further comprising about 10-250 mg/mL sucrose, trehalose, mannitol, sorbitol, polyethylene glycol or glycerol; and about 0.005-2.0 mg/mL polysorbate 80 or 20; wherein the buffer is about 3-300 mM L-histidine, acetate or citrate buffer.

16. The formulation of claim 1 , wherein the excipient is about 40-100 mM L-glutamine, L-glycine, L-proline or L-methionine and about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof; the buffer is about 3-150 mM L-histidine, acetate or citrate buffer; and the formulation further comprises about 0.05-1.0 mg/mL polysorbate 80 or 20.

17. The formulation of claim 1 wherein the buffer is about 3-150 mM L-histidine, acetate or citrate buffer; and the excipient is about 40-150 mM NaCl; and wherein the formulation further comprises about 0.05-1.0 mg/mL polysorbate 80 or 20.

18. The formulation of claim 1 , wherein the anti-LAG3 antibody is at about 25 mg/mL; wherein the buffer is about 10 mM L-histidine buffer that maintains the pH at about 5.8; wherein the excipient is about 70 mM L-arginine or a pharmaceutically acceptable salt thereof; and the formulation further comprises about 50 mg/mL sucrose, about 0.2 mg/mL polysorbate 80 and about 10 mM L-methionine.

19. The formulation of claim 1 further comprising a sugar or polyol, and a non-ionic surfactant, or a combination thereof.

20. The formulation of claim 19 , wherein the sugar is a non-reducing disaccharide.

21. The formulation of claim 20 , wherein the sugar is trehalose or sucrose, or a combination thereof.

22. The formulation of claim 19 , wherein the polyol is selected from the group consisting of mannitol, sorbitol, glycerol and polyethylene glycol.

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

24. The formulation of claim 19 , wherein the non-ionic surfactant is a polysorbate.

25. The formulation of claim 19 , wherein the polyol is about 20-200 mg/mL glycerol, sorbitol or PEG400; the non-ionic surfactant is about 0.05-1.0 mg/mL polysorbate 80 or 20; the buffer is about 3-150 mM L-histidine, acetate or citrate buffer; and the excipient is about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof.

26. The formulation of claim 19 , wherein the anti-LAG3 antibody is at about 20-30 mg/mL; the sugar is about 50-90 mg/mL sucrose or trehalose; the non-ionic surfactant is about 0.05-1.0 mg/mL polysorbate 80 or 20; the buffer is about 5-20 mM L-histidine, acetate or citrate buffer; and the excipient is about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof.

27. The formulation of claim 26 , further comprising 1-30 mM L-methionine.

28. The formulation of claim 26 that is a liquid formulation.

29. The formulation of claim 28 , wherein at 5° C., the % monomer of the anti-LAG3 antibody is ≥95% after 3 months as measured by size exclusion chromatography.

30. The formulation of claim 28 , wherein at 5° C., the % acidic variant of the anti-LAG3 antibody is less than 15% after 3 months as measured by ion exchange chromatography.

31. The formulation of claim 26 that is frozen to at least below −70° C.

32. The formulation of claim 26 that is a reconstituted solution from a lyophilized formulation.

33. The formulation of claim 20 , 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.

34. The formulation of claim 26 , further comprising an anti-PD-1 antibody that comprises two heavy chains and two light chains, wherein each light chain comprises SEQ ID NO: 5, and each heavy chain comprises a heavy chain variable region sequence of SEQ ID NO: 9 and an IgG4 constant region.

35. The formulation of claim 34 , wherein 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 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.

37. A method for the treatment of cancer or infection in a patient comprising administering to the patient the formulation of claim 1 .

38. A formulation comprising about 15-50 mg/mL of an anti-LAG3 antibody that comprises two heavy chains and two light chains, each light chain comprises SEQ ID NO: 35 and each heavy chain comprises a heavy chain variable region sequence of SEQ ID NO: 58 and an IgG4 constant region, about 50-90 mg/mL sucrose or trehalose; about 0.05-1.0 mg/mL polysorbate 80 or 20; about 5-20 mM L-histidine, acetate or citrate buffer that maintains the pH of the formulation at about 5.3 to 6.4; and about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof; and an anti-PD-1 antibody that comprises two heavy chains and two light chains, wherein each light chain comprises SEQ ID NO: 5, and each heavy chain comprises a heavy chain variable region sequence of SEQ ID NO: 9 and an IgG4 constant region.

39. The formulation of claim 38 , comprising about 20-30 mg/ml of the anti-LAG3 antibody, about 50-90 mg/mL sucrose or trehalose; about 0.05-1.0 mg/mL polysorbate 80; about 5-20 mM L-histidine buffer; and about 40-100 mM L-arginine or a pharmaceutically acceptable salt thereof.

40. The formulation of claim 39 , further comprising about 5-15 mM L-methionine.

41. The formulation of claim 40 , 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 formulation of claim 39 wherein the pharmaceutically acceptable salt of L-arginine is L-arginine-hydrochloride.

43. The formulation of claim 42 , 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.

44. The formulation of claim 39 , 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.

45. The formulation of claim 38 , 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.

46. A formulation that comprises:

an anti-LAG3 antibody at a concentration of about 20-220 mg/ml, wherein the anti-LAG3 antibody comprises two heavy chains and two light chains, each light chain comprises SEQ ID NO: 35 and each heavy chain comprises SEQ ID NO: 57;

an excipient which is 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, LiCl, or a combination thereof at a total concentration of about 40-150 mM; or a combination of a) and b);

a buffer that maintains the pH of the formulation at about 5.3 to 6.4;

and an anti-PD-1 antibody that comprises two heavy chains and two light chains, each heavy chain comprises SEQ ID NO: 10 and each light chain comprises SEQ ID NO: 5.

47. The formulation of claim 46 , wherein the anti-LAG3 antibody is at a concentration of about 20-30 mg/ml.

48. The formulation of claim 47 , wherein the excipient is L-arginine or a pharmaceutically acceptable salt thereof at a concentration of about 40-150 mM.

49. The formulation of claim 47 , wherein the excipient is NaCl and L-arginine or a pharmaceutically acceptable salt thereof with a total concentration of about 70-100 mM.

50. The formulation of claim 47 , wherein the excipient is NaCl, KC 1 or LiCl at about 40-100 mM.

51. The formulation of claim 47 , wherein the excipient is L-histidine, L-aspartate, L-glutamine, or L-glycine at about 40-100 mM.

52. The formulation of claim 47 , wherein the buffer is about 3-300 mM L-histidine, acetate or citrate buffer; and wherein the formulation further comprises about 10-250 mg/mL sucrose, trehalose, mannitol, sorbitol, polyethylene glycol or glycerol and about 0.005-2.0 mg/mL polysorbate 80 or 20.

53. The formulation of claim 47 , wherein the excipient is L-arginine or a pharmaceutically acceptable salt thereof at a concentration of about 40-150 mM; the buffer is about 3-150 mM L-histidine, acetate or citrate buffer; and wherein the formulation further comprises about 30-120 mg/mL sucrose or trehalose and about 0.05-1.5 mg/mL polysorbate 80 or 20.

54. The formulation of claim 47 , wherein the excipient is about 40-100 mM L-arginine or a pharmaceutically acceptable salt thereof; the buffer is about 5-30 mM L-histidine, acetate or citrate buffer; and wherein the formulation further comprises about 50-90 mg/mL sucrose or trehalose and about 0.05-1.0 mg/mL polysorbate 80.

55. The formulation of claim 47 , wherein the buffer is about 8-6 mM L-histidine, acetate or citrate buffer; and the excipient is about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof; and the formulation further comprises about 50-90 mg/mL sucrose or trehalose and about 0.05-1.0 mg/mL polysorbate 80 or 20.

56. The formulation of claim 47 , wherein the buffer is about 3-150 mM L-histidine, acetate or citrate buffer; the excipient is about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof; and the formulation further comprises about 20-200 mg/mL glycerol, sorbitol or PEG400 and about 0.05-1.0 mg/mL polysorbate 80 or 20.

57. The formulation of claim 47 , wherein the excipient is about 40-100 mM L-glutamine, L-glycine, L-proline or L-methionine and about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof; the buffer is about 3-150 mM L-histidine, acetate or citrate buffer; and the formulation further comprises about 0.05-1.0 mg/mL polysorbate 80 or 20.

58. The formulation of claim 47 , wherein the buffer is about 3-150 mM L-histidine, acetate or citrate buffer; the excipient is about 40-150 mM NaCl; and the formulation further comprises about 0.05-1.0 mg/mL polysorbate 80 or 20.

59. A formulation comprising:

about 15-50 mg/mL of an anti-LAG3 antibody that comprises two heavy chains and two light chains, and each light chain comprises SEQ ID NO: 35 and each heavy chain comprises SEQ ID NO: 57;

about 50-90 mg/mL sucrose or trehalose;

about 0.05-1.0 mg/mL polysorbate 80 or 20;

about 5-20 mM L-histidine, acetate or citrate buffer that maintains the pH of the formulation at about 5.3 to 6.4;

about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof; and

an anti-PD-1 antibody that comprises two heavy chains and two light chains, and each heavy chain comprises SEQ ID NO: 10 and each light chain comprises SEQ ID NO: 5.

60. The formulation of claim 59 , comprising about 20-30 mg/ml of the anti-LAG3 antibody, about 50-90 mg/mL sucrose; about 0.05-1.0 mg/mL polysorbate 80; about 5-20 mM L-histidine buffer; and about 40-100 mM L-arginine or a pharmaceutically acceptable salt thereof.

61. The formulation of claim 60 , further comprising about 8-23 mM L-methionine.