Mosnetuzumab pharmaceutical composition and method of use
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- GENENTECH INC
- Filing Date
- 2026-01-16
- Publication Date
- 2026-06-16
Smart Images
Figure 2026097792000024 
Figure 2026097792000025 
Figure 2026097792000026
Abstract
Claims
1. A pharmaceutical composition comprising mosnetuzumab, polysorbate 20 (PS20), methionine, a buffer, and a carrier, wherein the concentration of PS20 is 0.01% by weight / volume to 0.1% by weight / volume (w / v), the concentration of methionine is 1 mM to 50 mM, and the concentration of the buffer is 5 mM to 20 mM.
2. The pharmaceutical composition according to claim 1, wherein the concentration of mosnetuzumab is approximately 15 mg / ml or less.
3. The pharmaceutical composition according to claim 1 or 2, wherein the molar ratio of PS20 to mosnetuzumab is less than 100.
4. The pharmaceutical composition according to claim 3, wherein the molar ratio of PS20 to mosnetuzumab is 50 to 100.
5. The pharmaceutical composition according to claim 4, wherein the molar ratio of PS20 to mosnetuzumab is approximately 71.
6. A pharmaceutical composition according to any one of claims 1 to 5, wherein the concentration of mosnetuzumab is approximately 0.5 mg / ml to approximately 2 mg / ml.
7. The pharmaceutical composition according to claim 6, wherein the concentration of mosnetuzumab is approximately 1 mg / ml.
8. A pharmaceutical composition according to any one of claims 1 to 7, formulated as a pharmaceutical product (DP).
9. A pharmaceutical composition according to any one of claims 1 to 8, wherein the concentration of methionine is approximately 2.5 mM to approximately 20 mM.
10. The pharmaceutical composition according to claim 9, wherein the concentration of methionine is approximately 10 mM.
11. The pharmaceutical composition according to any one of claims 1 to 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 histidine is histidine acetate.
14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the concentration of the buffering agent is approximately 8 mM to approximately 12 mM.
15. The pharmaceutical composition according to claim 14, wherein the concentration of the buffering agent is approximately 10 mM.
16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the buffering agent is histidine acetate at a concentration of 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 to 17, further comprising an isotonic agent.
19. The pharmaceutical composition according to claim 18, wherein the isotonic agent is a sugar, an amino acid, or a salt.
20. The pharmaceutical composition according to claim 19, wherein the isotonic agent is a 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 according to any one of claims 18 to 22, wherein the concentration of the isotonic agent is about 100 mM to about 500 mM.
24. The pharmaceutical composition according to claim 23, wherein the concentration of the isotonic agent is about 200 mM to about 300 mM.
25. The pharmaceutical composition according to claim 24, wherein the concentration of the isotonic agent is approximately 240 mM.
26. A pharmaceutical composition according to any one of claims 1 to 25, having a pH of approximately 4.5 to approximately 8.
27. The pharmaceutical composition according to claim 26, wherein the pH is approximately 5.5 to approximately 6.
1.
28. The pharmaceutical composition according to claim 27, wherein the pH is approximately 5.
8.
29. The pharmaceutical composition according to any one of claims 1 to 28, wherein mosnetuzumab has methionine at position 257 (EU numbering) of the Fc region, and 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 according to claim 29, wherein the oxidation of methionine at position 257 of the Fc region is approximately 6% or less over a period of two weeks at 40°C.
31. A pharmaceutical composition comprising mosnetuzumab, a surfactant, methionine, and a carrier, wherein the pharmaceutical composition has a pH of about 5.
8. (i) The concentration of mosnetuzumab is approximately 10 mg / ml or less, (ii) The concentration of the surfactant is approximately 0.05% to approximately 0.1% (w / v), (iii) A pharmaceutical composition having a methionine concentration of approximately 10 mM.
32. The pharmaceutical composition according to claim 31, wherein the molar ratio of the surfactant to mosnetuzumab 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 according to claim 33, wherein the surfactant is PS20 and the concentration of PS20 is about 0.06% (w / v).
35. The pharmaceutical composition according to claim 34, wherein the molar ratio of PS20 to mosnetuzumab is about 50 to about 100.
36. The pharmaceutical composition according to claim 35, wherein the molar ratio of PS20 to mosnetuzumab is approximately 71.
37. The pharmaceutical composition according to claim 33, wherein the surfactant is P188 and the concentration of P188 is about 0.1% (w / v).
38. The pharmaceutical composition according to claim 37, wherein the molar ratio of P188 to mosnetuzumab is about 5 to about 25.
39. The pharmaceutical composition according to claim 38, wherein the molar ratio of P188 to mosnetuzumab is approximately 17.
40. The pharmaceutical composition according to any one of claims 31 to 39, wherein the concentration of mosnetuzumab is approximately 0.5 mg / ml to approximately 2 mg / ml.
41. The pharmaceutical composition according to claim 40, wherein the concentration of mosnetuzumab is approximately 1 mg / ml.
42. A pharmaceutical composition according to any one of claims 35 to 41, formulated as DP.
43. The pharmaceutical composition according to any one of claims 31 to 42, further comprising histidine acetate at a concentration of about 10 mM and / or sucrose at a concentration of about 240 mM.
44. A pharmaceutical composition according to any one of claims 1 to 43, which is a unit dosage form.
45. The pharmaceutical composition according to claim 44, wherein the unit dosage form is a liquid formulation for dilution.
46. The pharmaceutical composition according to claim 45, wherein the liquid preparation for dilution is supplied to a container having a volume of approximately 50 ml.
47. The pharmaceutical composition according to claim 45, wherein the liquid formulation for dilution is supplied to a container having a volume of about 2 ml.
48. The pharmaceutical composition according to claim 45 or 46, wherein the volume of the liquid formulation for dilution is 20 to 40 ml.
49. The pharmaceutical composition according to claim 48, wherein the volume of the liquid preparation for dilution is approximately 30 ml.
50. The pharmaceutical composition according to claim 45 or 47, wherein the volume of the liquid formulation for dilution is 0.2 to 2 ml.
51. The pharmaceutical composition according to claim 50, wherein the volume of the liquid preparation for dilution is approximately 1 ml.
52. The pharmaceutical composition according to any one of claims 45 to 51, wherein the liquid formulation is intended for dilution with ordinary physiological saline containing 0.45% or 0.9% (w / v) NaCl.
53. A pharmaceutical composition according to any one of claims 1 to 52, comprising 1,000 or fewer particles having a diameter of 2 μm or more per 1 ml, as detected by high-precision liquid particle counting (HIAC).
54. A pharmaceutical composition according to any one of claims 1 to 53, wherein the carrier is water.
55. A pharmaceutical composition according to any one of claims 1 to 54, having a shelf life of at least 36 months when stored at 5°C ± 3°C and protected from light.
56. A pharmaceutical composition according to any one of claims 1 to 55, which is stable through one or more freeze-thaw cycles.
57. The pharmaceutical composition according to claim 56, which is stable through three or more freeze-thaw cycles.
58. A pharmaceutical composition according to any one of claims 1 to 57, which is stable at approximately 25°C for approximately two weeks or more.
59. The pharmaceutical composition according to claim 58, which is stable at approximately 25°C for approximately 4 weeks or more.
60. A pharmaceutical composition according to any one of claims 1 to 59, which is stable at -20°C for approximately 48 months or more.
61. The pharmaceutical composition according to any one of claims 56 to 60, wherein the stability is evaluated by size exclusion high-performance liquid chromatography (SE-HPLC).
62. The pharmaceutical composition according to claim 61, which is determined to be stable when it maintains a purity that changes by less than 5% as measured by SE-HPLC.
63. The pharmaceutical composition according to any one of claims 56 to 60, wherein its stability is evaluated by a non-reducing capillary electrophoresis sodium dodecyl sulfate (CE-SDS) assay.
64. The pharmaceutical composition according to claim 63, which is determined to be stable when it maintains a purity that changes by less than 5% as measured by a non-reducing CE-SDS assay.
65. The pharmaceutical composition according to claim 63 or 64, wherein the non-reducing CE-SDS assay is a microchip CE-SDS (mCE-SDS) assay.
66. A pharmaceutical composition according to any one of claims 1 to 65, having a purity of approximately 85% or more as evaluated by SE-HPLC.
67. The pharmaceutical composition according to claim 66, having a purity of approximately 90% or more as evaluated by SE-HPLC.
68. The pharmaceutical composition according to claim 67, having a purity of approximately 95% or more as evaluated by SE-HPLC.
69. The pharmaceutical composition according to any one of claims 66 to 68, wherein the purity evaluated by SE-HPLC is maintained substantially the same for approximately 36 months or more at approximately 5°C.
70. The pharmaceutical composition according to claim 69, wherein the purity evaluated by SE-HPLC is maintained substantially the same for approximately 42 months or more at approximately 5°C.
71. The pharmaceutical composition according to claim 70, wherein the purity evaluated by SE-HPLC is maintained substantially the same for approximately 64 months or more at approximately 5°C.
72. The pharmaceutical composition according to any one of claims 1 to 71, having a purity of approximately 75% or more when evaluated by a non-reducing CE-SDS assay.
73. The pharmaceutical composition according to claim 72, having a purity of approximately 80% or more when evaluated by a non-reducing CE-SDS assay.
74. The pharmaceutical composition according to claim 73, having a purity of approximately 85% or more when evaluated by a non-reducing CE-SDS assay.
75. The pharmaceutical composition according to any one of claims 72 to 74, wherein the purity, as evaluated by a non-reducing CE-SDS assay, is maintained for about 36 months or more at about 5°C.
76. The pharmaceutical composition according to claim 75, wherein the purity, as evaluated by a non-reducing CE-SDS assay, is maintained for about 42 months or more at about 5°C.
77. The pharmaceutical composition according to any one of claims 72 to 76, wherein the non-reducing CE-SDS assay is a microchip CE-SDS (mCE-SDS) assay.
78. A pharmaceutical composition according to any one of claims 1 to 77, formulated for intravenous administration.
79. A pharmaceutical composition according to any one of claims 1 to 78, which does not contain a preservative.
80. A pharmaceutical composition according to any one of claims 1 to 79, comprising 1 mg / ml mosnetuzumab, 10 mM L-histidine acetate, 240 mM sucrose, 0.06% (w / v) PS20, and 10 mM methionine, pH 5.8, which is formulated for administration by infusion after dilution with ordinary physiological saline containing 0.45% or 0.9% NaCl.
81. A pharmaceutical composition according to any one of claims 1 to 80, for use as a pharmaceutical.
82. A pharmaceutical composition according to any one of claims 1 to 80, for use in the treatment or delay of the progression of cancer in subjects requiring treatment or delay of the progression of cancer.
83. A pharmaceutical composition according to any one of claims 1 to 80 for use in enhancing immune function in subjects with cancer.
84. A pharmaceutical composition according to any one of claims 1 to 80 for use in the treatment or delaying the progression of cancer, or for use in enhancing immune function in a subject having cancer, wherein the cancer is chronic lymphocytic leukemia (CLL), B-cell lymphoma, splenic diffuse red myelin small B-cell lymphoma, B-cell lymphoma having intermediate characteristics between diffuse large B-cell lymphoma and Burkitt lymphoma, and diffuse large B-cell lymphoma and classical Hodgkin lymphoma. B-cell lymphoma, germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL), activated B-cell-like (ABC) DLBCL, primary cutaneous follicular lymphoma, T-cell / histiocyte-rich large cell lymphoma, primary central nervous system DLBCL, primary cutaneous DLBCL (leg 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 cell B-cell lymphoma, large B-cell lymphoma caused by 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), Waldenström macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt lymphoma (BL), B-cell prelymphocytic leukemia, splenic marginal zone A pharmaceutical composition comprising a non-Hodgkin lymphoma selected from the group consisting of lymphoma, hairy cell leukemia, splenic lymphoma / leukemia, hairy cell leukemia variant, alpha-heavy chain disease, gamma-heavy chain disease, muco-heavy chain disease, plasmacytoma, solitary plasmacytoma of bone, extraskeletal plasmacytoma, extranodal marginal zone lymphoma (MALT lymphoma) of mucosa-associated lymphoid tissue, nodular marginal zone lymphoma, pediatric nodular marginal zone lymphoma, pediatric follicular lymphoma, lymphomatoid granulomatosis, plasmablastic lymphoma, and primary exudative 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 recurrent and / or refractory (R / R).
88. A pharmaceutical composition for use according to claim 87, wherein a subject having R / R FL has relapsed or become resistant to at least two prior systemic therapies.
89. The pharmaceutical composition for use according to claim 88, wherein the subject has previously received systemic therapy containing an anti-CD20 monoclonal antibody.
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 to 90, wherein mosnetuzumab is formulated for administration to a subject in a dose of about 0.1 mg to about 100 mg.
92. The pharmaceutical composition for use according to claim 91, wherein mosnetuzumab is formulated for administration to a subject in a dose of approximately 1 mg to approximately 60 mg.
93. The pharmaceutical composition for use according to claim 92, wherein mosnetuzumab is formulated for administration to a subject in doses of approximately 1 mg, 2 mg, 6 mg, 9 mg, 13.5 mg, 20 mg, 30 mg, or 60 mg.
94. The pharmaceutical composition for use according to claim 93, wherein mosnetuzumab is formulated for administration to a subject in doses of approximately 1 mg, 2 mg, 30 mg, or 60 mg.
95. A pharmaceutical composition for use according to any one of claims 82 to 94, which is formulated for administration to a subject after being diluted with ordinary physiological saline containing 0.45% or 0.9% (w / v) NaCl.
96. The pharmaceutical composition for use according to claim 95, wherein, after dilution with normal physiological saline, the concentration of mosnetuzumab is approximately 0.01 mg / ml to approximately 0.3 mg / ml.
97. The pharmaceutical composition for use according to claim 96, wherein, after dilution with normal physiological saline, the concentration of mosnetuzumab is approximately 0.01 mg / ml, approximately 0.02 mg / ml, approximately 0.04 mg / ml, approximately 0.12 mg / ml, approximately 0.24 mg / ml, or approximately 0.3 mg / ml.
98. A method for treating or delaying the progression of cancer in a subject requiring treatment or delaying the progression of cancer, comprising administering an effective amount of the pharmaceutical composition described in any one of claims 1 to 80 to the subject.
99. A method for enhancing immune function in a subject with cancer, comprising administering an effective amount of the pharmaceutical composition described in any one of claims 1 to 80 to the subject.
100. A method for treating or delaying the progression of cancer in a subject requiring treatment or delaying the progression of cancer, or for enhancing immune function in a subject having cancer, comprising administering an effective amount of the pharmaceutical composition described in any one of claims 1 to 80 to the subject, wherein the cancer is CLL, B-cell lymphoma, diffuse red pulp small B-cell lymphoma of the spleen, B-cell lymphoma having intermediate characteristics between diffuse large B-cell lymphoma and Burkitt lymphoma, B-cell lymphoma having intermediate characteristics between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, GCB DLBCL, ABC DLBCL, primary cutaneous follicular lymphoma, T-cell / histiocyte-rich large cell lymphoma, primary DLBCL of the central nervous system, primary cutaneous DLBCL (leg type), 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 resulting from HHV8-associated multicentric Castleman disease, B-cell leukemia, FL, MCL, AML, MZL, SLL, A method comprising NHL selected from the group consisting of LL, WM, CNSL, BL, B-cell prelymphocytic 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, plasmacytosis myeloma, solitary plasmacytoma of bone, extraskeletal plasmacytoma, MALT lymphoma, nodular marginal zone lymphoma, pediatric nodular marginal zone lymphoma, pediatric follicular lymphoma, lymphomatoid granulomatosis, plasmablastic lymphoma, and primary exudative lymphoma.
101. The method according to claim 100, wherein NHL is GCB DLBCL, ABC DLBCL, FL, MCL, AML, CLL, MZL, SLL, LL, WM, CNSL, or BL.
102. The method according to claim 101, wherein NHL is FL.
103. The method according to claim 102, wherein FL is recurrent and / or refractory (R / R).
104. The method according to claim 103, wherein a subject having R / R FL has relapsed or is resistant to at least two prior systemic therapies.
105. The method according to claim 104, wherein the subject has previously received systemic therapy including an anti-CD20 monoclonal antibody.
106. The method according to claim 104 or 105, wherein the subject has previously received systemic therapy containing an alkylating agent.
107. The method according to any one of claims 98 to 106, wherein mosnetuzumab is administered to the subject in a dose of approximately 0.1 mg to approximately 100 mg.
108. The method according to claim 107, wherein mosnetuzumab is administered to the subject in a dose of approximately 1 mg to approximately 60 mg.
109. The method according to claim 108, wherein mosnetuzumab is administered to the subject in a dose of approximately 1 mg, 2 mg, 6 mg, 9 mg, 13.5 mg, 20 mg, 30 mg, or 60 mg.
110. The method according to claim 109, wherein mosnetuzumab is formulated for administration to a subject in doses of approximately 1 mg, 2 mg, 30 mg, or 60 mg.
111. The method according to any one of claims 98 to 110, wherein the pharmaceutical composition is administered to a subject after being diluted with ordinary physiological saline containing 0.45% or 0.9% (w / v) NaCl.
112. The method according to claim 111, wherein, after dilution with normal physiological saline, the concentration of mosnetuzumab is approximately 0.01 mg / ml to approximately 0.3 mg / ml.
113. The method according to claim 112, wherein, after dilution with normal physiological saline, the concentration of mosnetuzumab is approximately 0.01 mg / ml, approximately 0.02 mg / ml, approximately 0.04 mg / ml, approximately 0.12 mg / ml, approximately 0.24 mg / ml, or approximately 0.3 mg / ml.
114. Mosnetuzumab is administered to the subjects in a dosing regimen that includes at least three 21-day dosing cycles. (a) The first 21-day administration cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab administered to the subject on days 1, 8, and 15 of the first administration cycle, respectively, with C1D1 being approximately 1 mg, C1D2 being approximately 2 mg, and C1D3 being approximately 60 mg; (b) The second administration cycle includes a single dose (C2D1) of mosnetuzumab administered to the subject on day 1 of the second administration cycle, with C2D1 being approximately 60 mg; (c) The method according to any one of claims 98 to 113, wherein the third administration cycle comprises a single dose (C3D1) of mosnetuzumab administered to the subject on day 1 of the third administration cycle, the amount of C3D1 being approximately 30 mg.
115. The method according to claim 114, wherein the administration regimen comprises one to fourteen additional administration cycles, each comprising an additional single dose of approximately 30 mg of mosnetuzumab.
116. The method according to claim 115, wherein the administration regimen includes one to five additional administration cycles.
117. The method according to claim 116, wherein the administration regimen includes five additional administration cycles.
118. The method according to any one of claims 115 to 117, wherein each additional single dose of mosnetuzumab is administered to the subject on day 1 of each additional dosing cycle.
119. The method according to any one of claims 98 to 118, wherein the pharmaceutical composition is administered intravenously.
120. The method according to any one of claims 98 to 119, wherein the subject is a human.