PHARMACEUTICAL COMPOSITIONS OF MOSUNETUZUMAB AND METHODS OF THEIR USE

Claims

1. A pharmaceutical composition comprising mosunetuzumab, polysorbate 20 (PS20), methionine, a buffering agent and a carrier, wherein the concentration of PS20 is from 0.01% to 0.1% weight / volume (w / v), the concentration of methionine is from 1 mM to 50 mM and the concentration of the buffering agent is from 5 mM to 20 mM.

2. The pharmaceutical composition of claim 1, wherein the concentration of mosunetuzumab is approximately 15 mg / mL or less.

3. The pharmaceutical composition according to claim 1 or 2, wherein the molar ratio of PS20 to mosunetuzumab is less than 100.

4. The pharmaceutical composition according to claim 3, wherein the molar ratio of PS20 to mosunetuzumab is from 50 to 100.

5. The pharmaceutical composition of claim 4, wherein the molar ratio of PS20 to mosunetuzumab is approximately 71.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the concentration of mosunetuzumab is from about 0.5 mg / mL to about 2 mg / mL.

7. The pharmaceutical composition of claim 6, wherein the concentration of mosunetuzumab is approximately 1 mg / ml.

8. A pharmaceutical composition according to any one of paragraphs 1-7, wherein the pharmaceutical composition is formulated in the form of a medicinal product (MP).

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the concentration of methionine is from about 2.5 mM to about 20 mM.

10. The pharmaceutical composition according to claim 9, wherein the concentration of methionine is approximately 10 mM.

11. A pharmaceutical composition according to any one of claims 1-10, wherein the buffering agent is histidine, phosphate, succinate, acetate, or a combination thereof.

12. The pharmaceutical composition according to claim 11, wherein the buffering agent is histidine.

13. The pharmaceutical composition according to claim 12, wherein the histidine is histidine acetate.

14. The pharmaceutical composition of any one of claims 1 to 13, wherein the concentration of the buffering agent is from about 8 mM to about 12 mM.

15. The pharmaceutical composition of claim 14, wherein the concentration of the buffering agent is approximately 10 mM.

16. The pharmaceutical composition of any one of claims 1 to 15, wherein the buffering agent is histidine acetate at a concentration of from about 8 mM to about 12 mM.

17. The pharmaceutical composition according to claim 16, wherein the concentration of histidine acetate is approximately 10 mM.

18. A pharmaceutical composition according to any one of claims 1-17, additionally containing a tonicity regulating agent.

19. The pharmaceutical composition according to claim 18, wherein the tonicity regulating agent is a sugar, amino acid or salt.

20. The pharmaceutical composition according to claim 19, wherein the tonicity regulating agent is sugar.

21. The pharmaceutical composition according to claim 20, wherein the sugar is sucrose, glucose, glycerol or trehalose.

22. The pharmaceutical composition according to claim 21, wherein the sugar is sucrose.

23. The pharmaceutical composition of any one of claims 18-22, wherein the concentration of the tonicity adjusting agent is from about 100 mM to about 500 mM.

24. The pharmaceutical composition of claim 23, wherein the concentration of the tonicity regulating agent is from about 200 mM to about 300 mM.

25. The pharmaceutical composition of claim 24, wherein the concentration of the tonicity regulating agent is approximately 240 mM.

26. The pharmaceutical composition of any one of claims 1-25, wherein the pharmaceutical composition has a pH level from about 4.5 to about 8.

27. The pharmaceutical composition of claim 26, wherein the pH of the pharmaceutical composition is from about 5.5 to about 6.

1.

28. The pharmaceutical composition of claim 27, wherein the pH level of the pharmaceutical composition is approximately 5.

8.

29. The pharmaceutical composition of any one of claims 1 to 28, wherein mosunetuzumab comprises methionine at position 257 of the Fc region (EU numbering), and wherein the oxidation of methionine at position 257 of the Fc region is less than about 10% over two weeks at 40°C.

30. The pharmaceutical composition of claim 29, wherein the oxidation of methionine at position 257 of the Fc region is no more than about 6% over two weeks at 40°C.

31. A pharmaceutical composition comprising mosunetuzumab, a surfactant, methionine and a carrier, wherein the pharmaceutical composition has a pH of approximately 5.8, and wherein: (i) the mosunetuzumab concentration is approximately 10 mg / mL or less, (ii) the concentration of surfactant is from about 0.05% to about 0.1% (w / v), and (iii) the concentration of methionine is approximately 10 mM.

32. The pharmaceutical composition of claim 31, wherein the molar ratio of surfactant to mosunetuzumab is 100 or less.

33. The pharmaceutical composition according to claim 31 or 32, wherein the surfactant is PS20 or poloxamer 188 (P188).

34. The pharmaceutical composition of claim 33, wherein the surfactant is PS20 and the concentration of PS20 is approximately 0.06% (w / v).

35. The pharmaceutical composition of claim 34, wherein the molar ratio of PS20 to mosunetuzumab is from about 50 to about 100.

36. The pharmaceutical composition of claim 35, wherein the molar ratio of PS20 to mosunetuzumab is approximately 71.

37. The pharmaceutical composition of claim 33, wherein the surfactant is P188 and the concentration of P188 is approximately 0.1% (w / v).

38. The pharmaceutical composition of claim 37, wherein the molar ratio of P188 to mosunetuzumab is from about 5 to about 25.

39. The pharmaceutical composition of claim 38, wherein the molar ratio of P188 to mosunetuzumab is approximately 17.

40. The pharmaceutical composition of any one of claims 31-39, wherein the concentration of mosunetuzumab is from about 0.5 mg / mL to about 2 mg / mL.

41. The pharmaceutical composition of claim 40, wherein the concentration of mosunetuzumab is approximately 1 mg / ml.

42. A pharmaceutical composition according to any one of paragraphs 35-41, wherein the pharmaceutical composition is formulated in the form of a medicinal product.

43. The pharmaceutical composition according to any one of claims 31-42, further comprising histidine acetate at a concentration of approximately 10 mM and / or sucrose at a concentration of approximately 240 mM.

44. A pharmaceutical composition according to any one of claims 1-43, wherein the pharmaceutical composition is in a single dosage form.

45. The pharmaceutical composition according to claim 44, wherein the unit dosage form is a liquid composition for dilution.

46. The pharmaceutical composition according to claim 45, wherein the liquid composition for dilution is supplied in a container having a volume of approximately 50 ml.

47. The pharmaceutical composition according to claim 45, wherein the liquid composition for dilution is supplied in a container having a volume of approximately 2 ml.

48. A pharmaceutical composition according to claim 45 or 46, wherein the volume of the liquid composition for dilution is 20-40 ml.

49. The pharmaceutical composition according to claim 48, wherein the volume of the liquid composition for dilution is approximately 30 ml.

50. A pharmaceutical composition according to claim 45 or 47, wherein the volume of the liquid composition for dilution is 0.2-2 ml.

51. The pharmaceutical composition according to claim 50, wherein the volume of the liquid composition for dilution is approximately 1 ml.

52. A pharmaceutical composition according to any one of claims 45-51, wherein the liquid composition is intended for dilution with a physiological solution containing 0.45% or 0.9% (w / v) NaCl.

53. The pharmaceutical composition of any one of claims 1 to 52, wherein the pharmaceutical composition contains no more than 1000 particles having a diameter ≥2 μm per ml, detected by high-accuracy liquid particle counting (HIAC).

54. A pharmaceutical composition according to any one of claims 1-53, wherein the carrier is water.

55. A pharmaceutical composition according to any one of claims 1-54, wherein the pharmaceutical composition has a shelf life of at least 36 months when stored at a temperature of 5°C±3°C and in a place protected from light.

56. The pharmaceutical composition according to any one of claims 1-55, wherein the pharmaceutical composition is stable during one or more freeze-thaw cycles.

57. The pharmaceutical composition according to claim 56, wherein the pharmaceutical composition is stable for three or more freeze-thaw cycles.

58. The pharmaceutical composition of any one of claims 1-57, wherein the pharmaceutical composition is stable for about two weeks or longer at about 25°C.

59. The pharmaceutical composition of claim 58, wherein the pharmaceutical composition is stable for about four weeks or longer at about 25°C.

60. The pharmaceutical composition of any one of claims 1-59, wherein the pharmaceutical composition is stable for about 48 months or longer at -20°C.

61. A pharmaceutical composition according to any one of claims 56-60, wherein stability is assessed using size exclusion high performance liquid chromatography (SE-HPLC).

62. The pharmaceutical composition of claim 61, wherein the pharmaceutical composition is defined as stable if the pharmaceutical composition maintains a purity that changes by less than 5% when measured using SE-HPLC.

63. The pharmaceutical composition according to any one of claims 56-60, wherein the stability is assessed using a capillary electrophoresis assay in the presence of sodium dodecyl sulfate (CE-SDS) under non-reducing conditions.

64. The pharmaceutical composition of claim 63, wherein the pharmaceutical composition is defined as stable if the pharmaceutical composition maintains a purity that changes by less than 5% when measured using a CE-SDS-based assay under non-reducing conditions.

65. The pharmaceutical composition of claim 63 or 64, wherein the CE-SDS-based assay under non-reducing conditions is a microarray CE-SDS (mCE-SDS) assay.

66. The pharmaceutical composition of any one of claims 1-65, wherein the pharmaceutical composition has a purity of about 85% or greater as assessed by SE-HPLC.

67. The pharmaceutical composition of claim 66, wherein the pharmaceutical composition has a purity of approximately 90% or greater as assessed by SE-HPLC.

68. The pharmaceutical composition of claim 67, wherein the pharmaceutical composition has a purity of approximately 95% or greater as assessed by SE-HPLC.

69. The pharmaceutical composition of any one of claims 66-68, wherein the purity of the pharmaceutical composition, as assessed by SE-HPLC, remains approximately the same for about 36 months or longer at about 5°C.

70. The pharmaceutical composition of claim 69, wherein the purity of the pharmaceutical composition, as assessed by SE-HPLC, remains approximately the same for about 42 months or longer at about 5°C.

71. The pharmaceutical composition of claim 70, wherein the purity of the pharmaceutical composition, as assessed by SE-HPLC, remains approximately the same for about 64 months or longer at about 5°C.

72. The pharmaceutical composition of any one of claims 1-71, wherein the pharmaceutical composition has a purity of about 75% or greater as assessed by CE-SDS analysis under non-reducing conditions.

73. The pharmaceutical composition of claim 72, wherein the pharmaceutical composition has a purity of approximately 80% or greater as assessed by CE-SDS analysis under non-reducing conditions.

74. The pharmaceutical composition of claim 73, wherein the pharmaceutical composition has a purity of approximately 85% or greater as assessed by CE-SDS analysis under non-reducing conditions.

75. The pharmaceutical composition of any one of claims 72-74, wherein the purity of the pharmaceutical composition, as assessed by CE-SDS analysis under non-reducing conditions, is maintained for about 36 months or longer at about 5°C.

76. The pharmaceutical composition of claim 75, wherein the purity of the pharmaceutical composition, as assessed by CE-SDS analysis under non-reducing conditions, is maintained for about 42 months or longer at about 5°C.

77. The pharmaceutical composition of any one of claims 72 to 76, wherein the CE-SDS assay under non-reducing conditions is a microarray CE-SDS (mCE-SDS) assay.

78. A pharmaceutical composition according to any one of claims 1-77, wherein the pharmaceutical composition is formulated for intravenous administration.

79. A pharmaceutical composition according to any one of claims 1-78, wherein the pharmaceutical composition does not contain a preservative.

80. The pharmaceutical composition of any one of claims 1 to 79, wherein the pharmaceutical composition comprises 1 mg / ml mosunetuzumab, 10 mM L-histidine acetate, 240 mM sucrose, 0.06% (w / v) PS20 and 10 mM methionine, a pH of 5.8, and wherein the pharmaceutical composition is formulated for administration by infusion after dilution with a saline solution containing 0.45% or 0.9% NaCl.

81. A pharmaceutical composition according to any one of claims 1-80 for use as a medicinal product.

82. A pharmaceutical composition according to any one of claims 1-80 for use in treating or slowing the progression of cancer in a subject in need thereof.

83. A pharmaceutical composition according to any one of claims 1-80 for use in enhancing immune function in a subject having cancer.

84. A pharmaceutical composition according to any one of claims. 1-80 for use in treating or slowing the progression of cancer or for use in enhancing immune function in a subject having a cancer, wherein the cancer is a non-Hodgkin's lymphoma selected from the group consisting of chronic lymphoid leukemia (CLL), B-cell lymphoma, diffuse small B-cell lymphoma of the splenic red pulp, B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and Burkitt's lymphoma, B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin's lymphoma, diffuse large B-cell lymphoma of germinal center (GCB)-like B-cell (DLBCL), activated B-cell (ABC) DLBCL, primary cutaneous follicular center lymphoma, large T-cell / histiocyte-rich B-cell lymphoma, primary central nervous system DLBCL,primary cutaneous DLBCL (lower extremity type), Epstein-Barr virus (EBV)-positive DLBCL in the elderly, DLBCL associated with chronic inflammation, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, large B-cell lymphoma associated with HHV8-associated multicentric Castleman disease, B-cell leukemia, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenstrom's macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt's lymphoma (BL), B-cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma / leukemia, hairy cell leukemia variant,α heavy chain disease, γ heavy chain disease, μ heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), nodular marginal zone lymphoma, nodular marginal zone lymphoma of childhood, follicular lymphoma of childhood, Hodgkin's disease, plasmablastic lymphoma, and primary effusion lymphoma.

85. A pharmaceutical composition for use according to claim 84, wherein NHL is GCB DLBCL, ABC DLBCL, FL, MCL, AML, CLL, MZL, SLL, LL, WM, CNSL or BL.

86. A pharmaceutical composition for use according to claim 85, wherein NHL is FL.

87. A pharmaceutical composition for use according to claim 86, wherein FL is relapsing and / or refractory (R / R).

88. A pharmaceutical composition for use according to claim 87, wherein the subject having R / R FL has relapsed after at least two previous systemic therapies or is refractory to them.

89. A pharmaceutical composition for use according to claim 88, wherein the subject has previously received systemic therapy containing a monoclonal antibody to CD20.

90. A pharmaceutical composition for use according to claim 88 or 89, wherein the subject has previously received systemic therapy containing an alkylating agent.

91. A pharmaceutical composition for use according to any one of claims 82-90, wherein mosunetuzumab is formulated for administration to a subject at a dose of from about 0.1 mg to about 100 mg.

92. A pharmaceutical composition for use according to claim 91, wherein mosunetuzumab is formulated for administration to a subject at a dose of from about 1 mg to about 60 mg.

93. A pharmaceutical composition for use according to claim 92, wherein mosunetuzumab is formulated for administration to a subject at a dose of about 1 mg, 2 mg, 6 mg, 9 mg, 13.5 mg, 20 mg, 30 mg, or 60 mg.

94. A pharmaceutical composition for use according to claim 93, wherein mosunetuzumab is formulated for administration to a subject at a dose of about 1 mg, 2 mg, 30 mg, or 60 mg.

95. A pharmaceutical composition for use according to any one of claims 82-94, wherein the pharmaceutical composition is formulated for administration to a subject after dilution with a physiological solution containing 0.45% or 0.9% (w / v) NaCl.

96. A pharmaceutical composition for use according to claim 95, wherein after dilution with saline, the concentration of mosunetuzumab is from about 0.01 mg / mL to about 0.3 mg / mL.

97. A pharmaceutical composition for use according to claim 96, wherein after dilution with saline, the concentration of mosunetuzumab is about 0.01 mg / ml, about 0.02 mg / ml, about 0.04 mg / ml, about 0.12 mg / ml, about 0.24 mg / ml, or about 0.3 mg / ml.

98. A method for treating or slowing the progression of cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition according to any one of claims 1-80.

99. A method for enhancing immune function in a subject having cancer, the method comprising administering to the subject an effective amount of a pharmaceutical composition according to any one of claims 1-80.

100. A method for treating or slowing the progression of cancer in a subject in need thereof, or enhancing immune function in a subject having cancer, comprising administering to the subject an effective amount of a pharmaceutical composition according to any one of claims 1-80, wherein the cancer is an NHL selected from the group consisting of (CLL), B-cell lymphoma, diffuse small B-cell lymphoma of the splenic red pulp, B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and Burkitt's lymphoma, B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin's lymphoma, GCB DLBCL, ABC DLBCL, primary cutaneous follicular center lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, primary central nervous system DLBCL, primary cutaneous (lower extremity type) DLBCL, EBV-positive geriatric DLBCL,associated with chronic inflammation, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease, B-cell leukemia, FL, MCL, AML, MZL, SLL, LL, WM, CNSL, BL, B-cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma / leukemia, variant hairy cell leukemia, α heavy chain disorder, γ heavy chain disorder, μ heavy chain disorder, plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma, MALT lymphoma, nodular marginal zone lymphoma, nodular marginal zone lymphoma of children, follicular lymphoma of children, lymphogranulomatosis, plasmablastic lymphoma and primary effusion lymphoma., 101. The method of claim 100, wherein NHL is GCB DLBCL, ABC DLBCL, FL, MCL, AML, CLL, MZL, SLL, LL, WM, CNSL, or BL.

102. The method of claim 101, wherein NHL is FL.

103. The method of claim 102, wherein FL is recurrent and / or refractory (R / R).

104. The method of claim 103, wherein the subject having R / R FL has relapsed after at least two prior systemic therapies or is refractory to them.

105. The method of claim 104, wherein the subject has previously received systemic therapy comprising a monoclonal antibody to CD20.

106. The method of claim 104 or 105, wherein the subject has previously received systemic therapy containing an alkylating agent.

107. The method of any one of claims 98-106, wherein mosunetuzumab is administered to the subject at a dose of from about 0.1 mg to about 100 mg.

108. The method of claim 107, wherein mosunetuzumab is administered to the subject at a dose of from about 1 mg to about 60 mg.

109. The method of claim 108, wherein mosunetuzumab is administered to the subject at a dose of about 1 mg, 2 mg, 6 mg, 9 mg, 13.5 mg, 20 mg, 30 mg, or 60 mg.

110. The method of claim 109, wherein mosunetuzumab is formulated for administration to a subject at a dose of about 1 mg, 2 mg, 30 mg, or 60 mg.

111. The method according to any one of claims 98-110, wherein the pharmaceutical composition is administered to the subject after dilution with a physiological solution containing 0.45% or 0.9% (w / v) NaCl.

112. The method of claim 111, wherein after dilution with saline, the concentration of mosunetuzumab is from about 0.01 mg / mL to about 0.3 mg / mL.

113. The method of claim 112, wherein after dilution with saline, the concentration of mosunetuzumab is about 0.01 mg / mL, about 0.02 mg / mL, about 0.04 mg / mL, about 0.12 mg / mL, about 0.24 mg / mL, or about 0.3 mg / mL.

114. The method of any one of claims 98-113, wherein mosunetuzumab is administered to the subject in a dosing regimen comprising at least three 21-day dosing cycles, wherein: (a) the first 21-day dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered to the subject on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is approximately 1 mg, C1D2 is approximately 2 mg, and C1D3 is approximately 60 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered to the subject on Day 1 of the second dosing cycle, with C2D1 being approximately 60 mg; and (c) the third dosing cycle comprises a single dose (C3D1) of mosunetuzumab administered to the subject on day 1 of the third dosing cycle, with C3D1 being approximately 30 mg.

115. The method of claim 114, wherein the dosing regimen comprises one to fourteen additional dosing cycles, each of which comprises an additional single dose of approximately 30 mg of mosunetuzumab.

116. The method according to claim 115, wherein the dosing regimen includes from one to five additional dosing cycles.

117. The method according to claim 116, wherein the dosing regimen includes five additional dosing cycles.

118. The method of any one of claims 115-117, wherein each additional single dose of mosunetuzumab is administered to the subject on day 1 of each respective additional dosing cycle.

119. The method according to any one of paragraphs 98-118, wherein the pharmaceutical composition is administered intravenously.

120. The method according to any one of paragraphs 98-119, wherein the subject is a human being.