Claims for Patent: 7,811,572

Summary for Patent: 7,811,572

Title:	Process for preparing purified drug conjugates
Abstract:	The invention provides a process for preparing a cell-binding agent chemically coupled to a drug. The process comprises covalently attaching a linker to a cell-binding agent, a purification step, conjugating a drug to the cell-binding agent and a subsequent purification step.
Inventor(s):	Dai; Yong (Newton, MA), Wang; Yong (North Attleboro, MA), Jin; Shengjin (Acton, MA), Meshulam; Deborah H. (Brookline, MA), Amphlett; Godfrey W. (Cambridge, MA)
Assignee:	ImmunoGen, Inc. (Waltham, MA)
Application Number:	11/503,781
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,811,572
Patent Claims:	1. A process for preparing a cell-binding agent-cytotoxic agent conjugate comprising the steps of: (a) contacting a cell-binding agent with a bifunctional crosslinking reagent to covalently attach a linker to the cell-binding agent and thereby prepare a first mixture comprising cell-binding agents having linkers bound thereto, wherein the cell-binding agent is selected from the group consisting of antibodies, interferons, interleukin 2 (IL-2), interleukin 3 (IL-3), interleukin 4 (IL-4), interleukin 6 (IL-6), insulin, EGF, TGF-.alpha., FGF, G-CSF, VEGF, MCSF, GM-CSF, and transferrin, (b) subjecting the first mixture to tangential flow filtration and thereby prepare a purified first mixture of cell-binding agents having linkers bound thereto, (c) conjugating a cytotoxic agent to the cell-binding agents having linkers bound thereto in the purified first mixture by reacting the cell-binding agents having linkers bound thereto with a cytotoxic agent in a solution having a pH of about 4 to about 9 to prepare a second mixture comprising (i) cell-binding agent chemically coupled through the linker to the cytotoxic agent, (ii) free cytotoxic agent, and (iii) reaction by-products produced during step (c), wherein the cytotoxic agent is selected from the group consisting of maytansinoids, taxanes, and CC1065, and (d) subjecting the second mixture to tangential flow filtration to purify the cell-binding agents chemically coupled through the linkers to the cytotoxic agent from the other components of the second mixture and thereby prepare a purified second mixture of cell-binding agents chemically coupled through the linkers to the cytotoxic agent. 2. The process of claim 1, wherein the solution in step (c) has a pH of from 4 to less than 6.0. 3. The process of claim 1, wherein the solution in step (c) has a pH of from greater than 6.5 to 9. 4. The process of claim 1, wherein the solution in step (c) has a pH of less than 6 or a pH of greater than 6.5. 5. The process of claim 1, wherein the cell-binding agent is an antibody. 6. The process of claim 5, wherein the antibody is a monoclonal antibody. 7. The process of claim 6, wherein the antibody is a humanized monoclonal antibody. 8. The process of claim 7, wherein the antibody is selected from the group consisting of huN901, huMy9-6, huB4, huC242, trastuzumab, bivatuzumab, sibrotuzumab, CNTO95, huDS6, and rituximab. 9. The process of claim 1, wherein the cytotoxic agent is a maytansinoid. 10. The process of claim 9, wherein the maytansinoid comprises a thiol group. 11. The process of claim 10, wherein the maytansinoid is DM1. 12. The process of claim 10, wherein the maytansinoid is DM4. 13. The process of claim 1, wherein the cell-binding agent is chemically coupled to the cytotoxic agent 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. 14. The process of claim 1, wherein the solution in step (c) comprises sucrose. 15. The process of claim 1, wherein the solution in step (c) further comprises a buffering agent selected from the group consisting of a citrate buffer, an acetate buffer, a succinate buffer, and a phosphate buffer. 16. The process of claim 1, further comprising (e) holding the mixture between at least one of steps a-b, steps b-c, and steps c-d to release the unstably bound linkers from the cell-binding agent. 17. The process of claim 16, wherein the mixture is held between steps a-b. 18. The process of claim 16, wherein the mixture is held between steps b-c. 19. The process of claim 16, wherein the mixture is held between steps c-d. 20. A process for preparing a cell-binding agent cytotoxic agent conjugate comprising the steps of: (a) contacting a cell-binding agent with a bifunctional crosslinking reagent to covalently attach a linker to the cell-binding agent and thereby prepare a first mixture comprising cell-binding agents having linkers bound thereto, wherein the cell-binding agent is selected from the group consisting of antibodies, interferons, interleukin 2 (IL-2), interleukin 3 (IL-3), interleukin 4 (IL-4), interleukin 6 (IL-6), insulin, EGF, TGF-.alpha., FGF, G-CSF, VEGF, MCSF, GM-CSF, and transferrin, (b) conjugating a cytotoxic agent to the cell-binding agents having linkers bound thereto in the first mixture by reacting the cell-binding agent having linkers bound thereto with a cytotoxic agent in a solution having a pH of about 4 to about 9 to prepare a second mixture comprising (i) cell-binding agent chemically coupled through the linker to the cytotoxic agent, (ii) free cytotoxic agent, and (iii) reaction by-products produced during step (b), and (c) subjecting the second mixture to tangential flow filtration, selective precipitation, adsorptive filtration, adsorptive chromatography, or a combination thereof, to purify the cell-binding agents chemically coupled through the linkers to the cytotoxic agent from the other components of the second mixture and thereby prepare a purified second mixture of cell-binding agents chemically coupled through the linkers to the cytotoxic agent with the proviso that the first mixture is not subjected to tangential flow filtration, selective precipitation, adsorptive filtration, or adsorptive chromatography. 21. The process of claim 20, wherein the first mixture is not subjected to purification. 22. The process of claim 20, wherein the adsorptive chromatography is selected from the group consisting of hydroxyapatite chromatography, hydrophobic charge induction chromatography (HCIC), hydrophobic interaction chromatography (HIC), ion exchange chromatography, mixed mode ion exchange chromatography, immobilized metal affinity chromatography (IMAC), dye ligand chromatography, affinity chromatography, reversed phase chromatography, and combinations thereof. 23. The process of claim 20, wherein the solution in step (b) has a pH of from about 4 to about 6. 24. The process of claim 20, wherein the solution in step (b) has a pH of from about 6.5 to about 9. 25. The process of claim 20, wherein the solution in step (b) has a pH of less than 6.0 or a pH of greater than 6.5. 26. The process of claim 20, wherein the cell-binding agent is an antibody. 27. The process of claim 26, wherein the antibody is a monoclonal antibody. 28. The process of claim 26, wherein the antibody is a humanized monoclonal antibody. 29. The process of claim 28, wherein the antibody is selected from the group consisting of huN901, huMy9-6, huB4, huC242, trastuzumab, bivatuzumab, sibrotuzumab, CNTO95, huDS6, and rituximab. 30. The process of claim 20, wherein the cytotoxic agent is selected from the group consisting of maytansinoids, taxanes, and CC1065. 31. The process of claim 30, wherein the cytotoxic agent is a maytansinoid. 32. The process of claim 31, wherein the maytansinoid comprises a thiol group. 33. The process of claim 32, wherein the maytansinoid is DM1. 34. The process of claim 32, wherein the maytansinoid is DM4. 35. The process of claim 20, wherein the cell-binding agent is chemically coupled to the cytotoxic agent 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. 36. The process of claim 20, wherein the solution in step (b) comprises sucrose. 37. The process of claim 20, wherein the solution in step (b) further comprises a buffering agent selected from the group consisting of a citrate buffer, an acetate buffer, a succinate buffer, and a phosphate buffer. 38. The process of claim 20, further comprising (e) holding the mixture between at least one of steps a-b and steps b-c to release the unstably bound linkers from the cell-binding agent. 39. The process of claim 38, wherein the mixture is held between steps a-b. 40. The process of claim 38, wherein the mixture is held between steps b-c.

Details for Patent 7,811,572

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2025-08-24
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2025-08-24
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2025-08-24
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2025-08-24
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2025-08-24