What is claimed is:
1. A composition comprising (i) a therapeutically effective amount of a conjugate comprising an antibody chemically coupled to a maytansinoid, (ii) a buffering agent, (iii) a surfactant, (iv) a tonicifying amount of sodium chloride, and (v) water, wherein the composition has a pH of about 5-6.
2. The composition of claim 1, wherein the antibody is a monoclonal antibody.
3. The composition of claim 2, wherein the antibody is a humanized monoclonal antibody.
4. The composition of claim 2, wherein the antibody is selected from the group consisting of huN901, huMy9-6, huB4, huC242, trastuzumab, bivatuzumab, sibrotuzumab, and rituximab.
5. The composition of claim 1, wherein the maytansinoid comprises a thiol group.
6. The composition of claim 5, wherein the maytansinoid is DM1.
7. The composition of claim 5, wherein the maytansinoid is DM4.
8. The composition of claim 1, wherein the antibody is chemically coupled to the maytansinoid via chemical bonds selected from the group consisting of disulfide bonds, acid labile bonds, photolabile bonds, peptidase labile bonds, thioether bonds, and esterase labile bonds.
9. The composition of claim 1, wherein the concentration of the conjugate in the composition is about 0.1 mgmL to about 5 mgmL.
10. The composition of claim 9, wherein the concentration of the conjugate in the composition is about 1 mgmL or more.
11. The composition of claim 9 wherein the concentration of the conjugate in the composition is about 5 mgmL.
12. The composition of claim 1, wherein the buffering agent is selected from the group consisting of a citrate buffer, an acetate buffer, a succinate buffer, a phosphate buffer, and a histidine buffer.
13. The composition of claim 12, wherein the concentration of the buffering agent in the composition is about 2 mM to about 50 mM.
14. The composition of claim 13, wherein the composition comprises a sodium citrate buffer at a concentration of about 10 mM and the pH of the composition is about 5.5.
15. The composition of claim 1, wherein the surfactant is polysorbate 20 or polysorbate 80.
16. The composition of claim 15, wherein the concentration of the surfactant in the composition is about 0.002% to about 0.1% of the total volume of the composition.
17. The composition of claim 16, wherein the surfactant is polysorbate 20.
18. The composition of claim 17, wherein the concentration of polysorbate 20 in the composition is about 0.01% of the total volume of the composition.
19. The composition of claim 1, wherein the concentration of sodium chloride in the composition is about 50 mM to about 500 mM.
20. The composition of claim 19, wherein the concentration of sodium chloride in the composition is about 100 mM to about 200 mM.
21. The composition of claim 20, wherein the concentration of sodium chloride in the composition is about 120 mM.
22. The composition of claim 1, wherein the composition comprises (i) about 5 mgmL of a conjugate comprising huN901 chemically coupled to DM1, (ii) about 10 mM sodium citrate buffer, (iii) about 0.01% polysorbate 20, (iv) about 120 mM sodium chloride, and (v) water, wherein the pH of the composition is about 5.5.
23. The composition of claim 1, wherein the composition comprises (i) about 1 mgmL or more of a conjugate comprising huMy9-6 chemically coupled to DM1, (ii) about 10 mM sodium citrate buffer, (iii) about 0.01% polysorbate 20, (iv) about 135 mM sodium chloride, and (v) water, wherein the pH of the composition is about 5.5.
24. The composition of claim 1, wherein the composition comprises (i) about 1 mgmL or more of a conjugate comprising huMy9-6 chemically coupled to DM4, (ii) about 10 mM sodium citrate buffer, (iii) about 0.01% polysorbate 20, (iv) about 135 mM sodium chloride, and (v) water, wherein the pH of the composition is about 5.5.
25. The composition of claim 1, wherein the composition further comprises an antioxidant.
26. The composition of claim 25, wherein the concentration of the antioxidant in the composition is about 100 M to about 100 mM.
27. The composition of claim 26, wherein the antioxidant is selected from the group consisting of superoxide dismutase, glutathione peroxidase, tocotrienols, polyphenols, zinc, manganese, selenium, vitamin C, vitamin E, beta carotene, cysteine, and methionine.
28. The composition of claim 27, wherein the antioxidant is methionine.
29. The composition of claim 28, wherein the concentration of methionine in the composition is about 10 mM.
30. The composition of claim 1, wherein the composition comprises sucrose.
31. The composition of claim 30, wherein the concentration of sucrose in the composition is about 0.1% to about 10% of the total volume of the composition.
32. The composition of claim 31, wherein the concentration of sucrose in the composition is about 5% of the total volume of the composition.
33. A packaged composition comprising a sealed container and dispersed therein the composition of claim 1 and an inert gas overlay.
34. The packaged composition of claim 33, wherein the inert gas is nitrogen or argon.
35. A method for killing a cell in a human comprising administering to the human a composition comprising (i) a therapeutically effective amount of a conjugate comprising an antibody chemically coupled to a maytansinoid, (ii) a buffering agent, (iii) a surfactant, (iv) a tonicifying amount of sodium chloride, and (v) water, wherein the composition has a pH of about 5-6, such that the antibody binds to the surface of the cell and the cytotoxicity of the maytansinoid is activated, whereby the cell is killed.
36. The method of claim 35, wherein the cell is a tumor cell.
37. The method of claim 35, wherein the antibody is a monoclonal antibody.
38. The method of claim 37, wherein the antibody is a humanized monoclonal antibody.
39. The method of claim 37, wherein the antibody is selected from the group consisting of huN901, huMy9-6, huB4, huC242, trastuzumab, bivatuzumab, sibrotuzumab, and rituximab.
40. The method of claim 35, wherein the maytansinoid comprises a thiol group.
41. The method of claim 40, wherein the maytansinoid is DM1.
42. The method of claim 40, wherein the maytansinoid is DM4.
43. The method of claim 35, wherein the antibody is chemically coupled to the maytansinoid via chemical bonds selected from the group consisting of disulfide bonds, acid labile bonds, photolabile bonds, peptidase labile bonds, thioether bonds, and esterase labile bonds.
44. The method of claim 35, wherein the antibody binds to an antigen present on the surface of the cell.
45. The method of claim 44, wherein the antigen is selected from the group consisting of NCAMCD56, CD33, CD19, GD3, CanAg, PSMA, alpha-folate receptor, Her2neu, CD44v6, fetoacinar pancreatic (FAP) antigen, Cripto-1, CA6, CD20, CA55.1, MNCA IX, and chondroitin sulfate proteoglycan.
46. The method of claim 35, wherein the concentration of the conjugate in the composition is about 0.1 mgmL to about 5 mgmL.
47. The method of claim 46, wherein the concentration of the conjugate in the composition is about 1 mgmL or more.
48. The method of claim 46, wherein the concentration of the conjugate in the composition is about 5 mgmL.
49. The method of claim 35, wherein the buffering agent is selected from the group consisting of a citrate buffer, an acetate buffer, a succinate buffer, a phosphate buffer, and a histidine buffer.
50. The method of claim 35, wherein the surfactant is polysorbate 20 or polysorbate 80.
51. The method of claim 50, wherein the surfactant is polysorbate 20.
52. The method of claim 35, wherein the composition further comprises an antioxidant.
53. The method of claim 52, wherein the antioxidant is selected from the group consisting of superoxide dismutase, glutathione peroxidase, tocotrienols, polyphenols, zinc, manganese, selenium, vitamin C, vitamin E, beta carotene, cysteine, and methionine.
54. The method of claim 53, wherein the antioxidant is methionine.
55. The method of claim 35, wherein the composition comprises sucrose.
56. The method of claim 35, wherein the composition is administered to the human intravenously, intraperitoneally, or intratumorally.
57. A lyophilized composition comprising (i) a therapeutically effective amount of a conjugate comprising an antibody chemically coupled to a maytansinoid, (ii) a buffering agent, (iii) a surfactant, (iv) a cryoprotectant, and (v) a bulking agent, wherein the composition has a pH of about 5-6 when reconstituted with water.
58. The composition of claim 56, wherein the antibody is a monoclonal antibody.
59. The composition of claim 58, wherein the antibody is a humanized monoclonal antibody.
60. The composition of claim 58, wherein the antibody is selected from the group consisting of huN901, huMy9-6, huB4, huC242, trastuzumab, bivatuzumab, sibrotuzumab, and rituximab.
61. The composition of claim 57, wherein the maytansinoid comprises a thiol group.
62. The composition of claim 61, wherein the maytansinoid is DM1.
63. The composition of claim 61, wherein the maytansinoid is DM4.
64. The composition of claim 57, wherein the antibody is chemically coupled to the maytansinoid via chemical bonds selected from the group consisting of disulfide bonds, acid labile bonds, photolabile bonds, peptidase labile bonds, thioether bonds, and esterase labile bonds.
65. The composition of claim 57, wherein the buffering agent is selected from the group consisting of a citrate buffer, an acetate buffer, a succinate buffer, a phosphate buffer, and a histidine buffer.
66. The composition of claim 65, wherein the composition comprises about 0.1 mg to about 2 mg of the buffering agent per mg of the conjugate.
67. The composition of claim 66, wherein the composition comprises about 0.3 mg sodium succinate buffer per mg of the conjugate.
68. The composition of claim 57, wherein the surfactant is polysorbate 20 or polysorbate 80.
69. The composition of claim 68, wherein the composition comprises about 0.005 mg to about 0.1 mg of the surfactant per mg of the conjugate.
70. The composition of claim 69, wherein the surfactant is polysorbate 20.
71. The composition of claim 70, wherein the composition comprises about 0.02 mg polysorbate 20 per mg of the conjugate.
72. The composition of claim 57, wherein the composition comprises about 0.5 mg to about 5 mg of the cryoprotectant per mg of the conjugate.
73. The composition of claim 70, wherein the cyroprotectant is sucrose.
74. The composition of claim 73, wherein the composition comprises about 1 mg sucrose per mg of the conjugate.
75. The composition of claim 57, wherein the composition comprises about 2 mg to about 20 mg of the bulking agent per mg of the conjugate.
76. The composition of claim 75, wherein the bulking agent is glycine.
77. The composition of claim 76, wherein the composition comprises about 3.8 mg glycine per mg of the conjugate.
78. The composition of claim 57, wherein the composition comprises (i) a conjugate comprising huN901 chemically coupled to DM1, (ii) about 0.3 mg sodium succinate buffer per mg of the conjugate, (iii) about 0.02 mg polysorbate 20 per mg of the conjugate, (iv) about 1 mg sucrose per mg of the conjugate, and (v) about 3.8 mg glycine per mg of the conjugate.
79. A method for killing a cell in a human comprising (a) providing the lyophilized composition of claim 57, (b) adding water to the lyophilized composition to provide a reconstituted composition, and (c) administering the reconstituted composition to the human such that the antibody binds to the surface of the cell and the cytotoxicity of the maytansinoid is activated, whereby the cell is killed.
80. The method of claim 79, wherein the cell is a tumor cell.
81. The method of claim 79, wherein the antibody is a monoclonal antibody.
82. The method of claim 81, wherein the antibody is a humanized monoclonal antibody.
83. The method of claim 81, wherein the antibody is selected from the group consisting of huN901, huMy9-6, huB4, huC242, trastuzumab, bivatuzumab, sibrotuzumab, and rituximab.
84. The method of claim 79, wherein the maytansinoid comprises a thiol group.
85. The method of claim 84, wherein the maytansinoid is DM1.
86. The method of claim 84, wherein the maytansinoid is DM4.
87. The method of claim 79, wherein the antibody is chemically coupled to the maytansinoid via chemical bonds selected from the group consisting of disulfide bonds, acid labile bonds, photolabile bonds, peptidase labile bonds, thioether bonds, and esterase labile bonds.
88. The method of claim 79, wherein the antibody binds to an antigen present on the surface of the cell.
89. The method of claim 88, wherein the antigen is selected from the group consisting of NCAMCD56, CD33, CD19, GD3, CanAg, PSMA, alpha-folate receptor, Her2neu, CD44v6, fetoacinar pancreatic (FAP) antigen, Cripto-1, CA6, CD20, CA55.1, MNCA IX, and chondroitin sulfate proteoglycan.
90. The method of claim 79, wherein the concentration of the conjugate in the reconstituted composition is about 0.1 mgmL to about 5 mgmL.
91. The method of claim 90, wherein the concentration of the conjugate in the composition is about 1 mgmL or more.
92. The method of claim 90, wherein the concentration of the conjugate in the reconstituted composition is about 5 mgmL.
93. The method of claim 79, wherein the buffering agent is selected from the group consisting of a citrate buffer, an acetate buffer, a succinate buffer, a phosphate buffer, and a histidine buffer.
94. The method of claim 93, wherein the concentration of the buffering agent in the reconstituted composition is about 2 mM to about 50 mM.
95. The method of claim 94, wherein the reconstituted composition comprises a sodium succinate buffer at a concentration of about 10 mM and the pH of the reconstituted composition is about 5.5.
96. The method of claim 79, wherein the surfactant is polysorbate 20 or polysorbate 80.
97. The method of claim 96, wherein the concentration of the surfactant in the reconstituted composition is about 0.002% to about 0.1% of the total volume of the reconstituted composition.
98. The method of claim 97, wherein the surfactant is polysorbate 20.
99. The method of claim 98, wherein the concentration of polysorbate 20 in the reconstituted composition is about 0.01% of the total volume of the reconstituted composition.
100. The method of claim 79, wherein the concentration of the cryoprotectant in the reconstituted composition is about 0.1% to about 3% of the total volume of the reconstituted composition.
101. The method of claim 100, wherein the cyroprotectant is sucrose.
102. The method of claim 101, wherein the concentration of sucrose in the reconstituted composition is about 0.5% of the total volume of the reconstituted composition.
103. The method of claim 79, wherein the concentration of the bulking agent in the reconstituted composition is about 50 mM to about 500 mM.
104. The method of claim 103, wherein the bulking agent is glycine.
105. The method of claim 104, wherein the concentration of glycine in the reconstituted composition is about 250 mM.
106. The method of claim 79, wherein the composition is administered to the human intravenously, intraperitoneally, or intratumorally.
107. A composition comprising (i) a therapeutically effective amount of a conjugate comprising an antibody chemically coupled to a maytansinoid, (ii) a buffering agent, (iii) a tonicifying amount of sodium chloride, and (iv) water, wherein the composition has a pH of about 5-6.
108. A method for killing a cell in a human comprising administering to the human a composition comprising (i) a therapeutically effective amount of a conjugate comprising an antibody chemically coupled to a maytansinoid, (ii) a buffering agent, (iii) a tonicifying amount of sodium chloride, and (iv) water, wherein the composition has a pH of about 5-6, such that the antibody binds to the surface of the cell and the cytotoxicity of the maytansinoid is activated, whereby the cell is killed.
109. A lyophilized composition comprising (i) a therapeutically effective amount of a conjugate comprising an antibody chemically coupled to a maytansinoid, (ii) a buffering agent, (iii) a cryoprotectant, and (iv) a bulking agent, wherein the composition has a pH of about 5-6 when reconstituted with water.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A seal assembly between a door and a rear-quarter window of an automotive vehicle comprising:
a molding portion operatively attached to a front portion of the rear-quarter window, the molding portion including a U-shaped base and a support member; and
a seal portion operatively attached to the molding portion, the seal portion including a first stationary base, a second stationary base, and a resilient portion,
wherein the first stationary base, the second stationary base and the resilient portion define a cavity, where the resilient portion deforms into the cavity and the first stationary base and the second stationary base remain stationary when the door is in a closed position.
2. The seal assembly of claim 1, wherein the first stationary base is operatively attached to the U-shaped base of the molding portion, and wherein the first stationary base is integrally joined to the second stationary base such that the first stationary base is generally perpendicular to the second stationary base.
3. The seal assembly of claim 2, wherein a first end of the resilient portion is integrally joined to the first stationary base and a second end of the resilient portion is integrally joined to the second stationary base such that the first end of the resilient portion is generally perpendicular to the first stationary base and the second end of the resilient portion is generally perpendicular to the second stationary base.
4. The seal assembly of claim 1, wherein the U-shaped base includes an inner leg, an outer leg, and a connecting leg, wherein an outer surface of the molding portion is angled such that a thickness of the outer leg increases as the outer leg extends toward the door, wherein the support member integrally extends from the outer leg toward the door at the same angle as the outer surface of the molding portion.
5. The seal assembly of claim 4, wherein the connecting leg extends along a front edge of the rear-quarter window and integrally joins the inner leg and the outer leg and wherein the integrally joined inner leg, outer leg, and connecting leg define a recess that receives a front portion of the rear-quarter window.
6. A combination seal and molding for an automotive vehicle comprising:
a seal having a first base portion, a second base portion, and an arc portion; and
a molding having an inner leg, an outer leg, a connecting leg, and a support member,
wherein the first base portion is operatively attached to the inner leg of the molding, and
wherein the first base portion, the second base portion, and the arc portion cooperate to define a cavity where the arc portion resiliently deforms into the cavity while the first and second base portions remain stationary when the door is in a closed position.
7. The combination of claim 6, wherein an outer surface of the molding is angled such that a thickness of the outer leg increases as the outer leg extends toward the door and wherein the support member integrally extends from the outer leg toward the door at the same angle as the outer surface of the molding and overlies the second base portion.
8. The combination of claim 7, wherein the first base portion includes a first straight member, a second straight member, and a curved member, wherein the first straight member defines a first plane and the second straight member defines second plane, wherein the first plane and second plane are generally parallel to each other, and wherein the curved member joins the first straight member and the second straight member.
9. The combination of claim 8, wherein a second end of the first straight member is integrally joined to a first end of the second base portion and the second base portion is generally perpendicular to the first straight member.
10. The combination of claim 9, wherein a first end of the arc portion is joined to a second end of the second straight member such that the second end of the arc portion is substantially perpendicular to the second straight member, and wherein a second end of the arc portion is joined to a second end of the second base portion such that the second end of the arc portion is substantially perpendicular to the second base portion.
11. The combination of claim 10, wherein the inner leg is operatively attached to an inner surface of the rear-quarter window, the outer leg is operatively attached to an outer surface of the rear-quarter window, and the connecting leg extends between a front edge of the rear-quarter window and the second base portion of the seal, and wherein the connecting leg integrally joins the inner leg to the outer leg to define a recess that receives a front portion of the rear-quarter window.