Claims for Patent: 9,233,171

Summary for Patent: 9,233,171

Title:	Method of treatment of tumors that are resistant to EGFR antibody therapies by EGFR antibody cytotoxic agent conjugate
Abstract:	The present invention relates to the identification that EGFR antibody immunoconjugates are effective in inhibiting the growth of tumor cells that have developed EGFR and/or ALK resistance mechanisms. Methods of administering the EGFR antibody immunoconjugates to patients having resistant tumor cells is also disclosed.
Inventor(s):	Setiady; Julianto (Waltham, MA), Park; Peter U. (Somerville, MA), Chittenden; Thomas (Sudbury, MA)
Assignee:	ImmunoGen, Inc. (Waltham, MA)
Application Number:	13/682,948
Patent Claims:	1. A method of treating cancer in a human patient comprising administering an amount of an epidermal growth factor receptor (EGFR) antibody immunoconjugate to a human patient with a tumor comprising tumor cells that are resistant or refractory to an EGFR antibody therapy, effective to inhibit growth of the tumor; wherein the immunoconjugate has the formula (A)-(L)-(C), wherein: (A) is an antibody or antigen binding fragment thereof that specifically binds EGFR and comprises the heavy chain variable region of SEQ ID NO:1 and the light chain variable region of SEQ ID NO:2 or SEQ ID NO:3; (L) is a linker; and (C) is a maytansinoid or maytansinoid analog; and wherein said linker (L) links (A) to (C). 2. The method of claim 1, wherein the cancer is a squamous cell cancer, lung cancer, head and neck cancer, or an EGFR-positive cancer. 3. The method of claim 2, wherein the cancer is a squamous cell cancer. 4. The method of claim 2, wherein the cancer is lung cancer. 5. The method of claim 2, wherein the cancer is head and neck cancer. 6. The method of claim 2, wherein the cancer is an EGFR-positive cancer. 7. The method of claim 1, wherein at least one of the tumor cells: (1) contains one or more mutations in an EGFR-encoding gene; (2) contains one or more mutations in a PIK3CA, RAS, or PTEN encoding gene; (3) has an activated MET pathway; (4) has mesenchymal histology or has undergone epithelial-mesenchymal transition; or (5) has ERBB2 gene amplification or increased production of HER2 protein. 8. The method of claim 7, wherein the at least one of the tumor cells contains one or more mutations in an EGFR-encoding gene. 9. The method of claim 8, wherein the Mutated EGFR gene comprises a EGFRvIII mutation. 10. The method of claim 7, wherein the at least one of the tumor cells contains one or more mutations in a PIK3CA, RAS, or PTEN encoding gene. 11. The method of claim 7, wherein the at least one of the tumor cells has an activated MET pathway. 12. The method of claim 11, wherein said MET pathway activation is caused by MET gene amplification. 13. The method of claim 7, wherein the at least one of the tumor cells has mesenchymal histology or has undergone epithelial-mesenchymal transition. 14. The method of claim 7, wherein the at least one of the tumor cells has ERBB2 gene amplification. 15. The method of claim 7, wherein the at least one of the tumor cells has increased production of HER2 protein. 16. The method of claim 1, wherein the EGFR antibody therapy to which the cells are resistant or refractory is selected from the group consisting of: cetuximab, panitumumab, zalutumumab, necitumumab, and nimotuzumab. 17. The method of claim 1, wherein the human patient previously failed or is currently failing an EGFR therapy comprising administration of an EGFR antibody. 18. The method of claim 17, wherein the EGFR antibody is cetuximab. 19. The method of claim 17, wherein the EGFR antibody is panitumumab. 20. The method of claim 1, wherein the linker is selected from the group consisting of a cleavable linker, a non-cleavable linker, a hydrophilic linker, and a dicarboxylic acid based linker. 21. The method of claim 20, wherein the linker is a non-cleavable linker. 22. The method of claim 1, wherein the linker is selected from the group consisting of: N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP); N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB) or N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB); N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC); N-sulfosuccinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (sulfo SMCC); N-succinimidyl-4-(iodoacetyl)-aminobenzoate (SIAB); N-succinimidyl-[(N-maleimidopropionamido)-tetraethyleneglycol]ester (NHS-PEG4-maleimide); N-(beta-maleimidopropyloxy)succinimide ester (BMPS); and gamma-maleimidobutyric acid N-succinimidyl ester (GMBS). 23. The method of claim 1, wherein the cytotoxic agent is a maytansinoid analog. 24. The method of claim 1, wherein the cytotoxic agent is a maytansinoid. 25. The method of claim 24, wherein the cytotoxic agent is N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N(2')-deacetyl-N2'-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4). 26. The method of claim 1, wherein the EGFR antibody immunoconjugate comprises the linker SMCC and the maytansinoid DM1. 27. The method of claim 1, wherein the EGFR antibody immunoconjugate is administered with an additional anti-neoplastic agent. 28. The method of claim 27, wherein the EGFR antibody immunoconjugate is administered simultaneously with the anti-neoplastic agent. 29. The method of claim 27, wherein the EGFR antibody immunoconjugate and anti-neoplastic agent are administered in any temporal order. 30. The method of claim 16, wherein the EGFR therapy to which the cells are resistant or refractory is panitumumab. 31. The method of claim 16, wherein the EGFR therapy to which the cells are resistant or refractory is zalutumumab. 32. The method of claim 16, wherein the EGFR therapy to which the cells are resistant or refractory is necitumumab. 33. The method of claim 16, wherein the EGFR therapy to Which the cells are resistant or refractory is nimotuzumab. 34. The method of claim 16, wherein the EGFR therapy to which the cells are resistant or refractory is cetuximab. 35. The method of claim 17, wherein the EGFR antibody is zalutumumab. 36. The method of claim 17, wherein the EGFR antibody is necitumumab. 37. The method of claim 17, wherein the EGFR antibody is nimotuzumab. 38. A method of treating cancer in a human patient comprising administering an amount of an epidermal growth factor receptor (EGFR) antibody immunoconjugate to a human patient with a tumor comprising tumor cells that are resistant or refractory to an EGFR antibody therapy, effective to inhibit growth of the tumor; wherein the immunoconjugate has the formula (A)-(L)-(C), wherein: (A) is an antibody or antigen binding fragment thereof that specifically binds EGFR and comprises the heavy chain variable region of SEQ ID NO: 1 and the light chain variable region of SEQ ID NO:2 or SEQ ID NO:3; (L) is a non-cleavable linker; and (C) is a cytotoxic agent; and wherein said linker (L) links (A) to (C). 39. The method of claim 38, wherein the cancer is a squamous cell cancer, lung cancer, head and neck cancer, or an EGFR-positive cancer. 40. The method of claim 38, wherein at least one of the tumor cells: (1) contains one or more mutations in an EGFR-encoding gene; (2) contains one or more mutations in a PIK3CA, RAS, or PTEN encoding gene; (3) has an activated MET or IGF1R pathway; (4) has mesenchymal histology or has undergone epithelial-mesenchymal transition; or (5) has ERBB2 gene amplification or increased production of HER2 protein. 41. The method of claim 40, wherein the mutated EGFR gene comprises a EGFRvIII mutation. 42. The method of claim 40, wherein the at least one of the tumor cells has an activated MET pathway, and wherein said MET pathway activation is caused by MET gene amplification. 43. The method of claim 38, wherein the EGFR antibody therapy to which the cells are resistant or refractory is selected from the group consisting of: cetuximab, panitumumab, zalutumumab, necitumumab, and nimotuzumab. 44. The method of claim 38, wherein the human patient previously failed or is currently failing an EGFR therapy comprising administration of an EGFR antibody selected from the group consisting of: cetuximab, panitumumab, zalutumumab, necitumumab, and nimotuzumab. 45. The method of claim 38, wherein the linker is selected from the group consisting: SMCC, sulfoSMCC, NHS-PEG4-maleimide, BMPS, and GMBS. 46. The method of claim 45, wherein the non-cleavable linker is SMCC. 47. The method of claim 38, wherein the cytotoxic agent is selected from the group consisting of: a maytansinoid, maytansinoid analog, doxorubicin, a modified doxorubicin, benzodiazepine, taxoid, CC-1065, CC-1065 analog, duocarmycin, duocarmycin analog, calicheamicin, dolastatin, dolastatin analog, auristatin, tomaymycin derivative, and leptomycin derivative or a prodrug of the agent. 48. The method of claim 47, wherein the cytotoxic agent is a maytansinoid. 49. The method of claim 48, wherein the cytotoxic agent is DM1 or DM4. 50. The method of claim 38, wherein the EGFR antibody immunoconjugate comprises the linker SMCC and the maytansinoid DM1. 51. The method of claim 38, wherein the EGFR antibody immunoconjugate is administered with an additional anti-neoplastic agent.

Details for Patent 9,233,171

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2031-11-21
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2031-11-21
Amgen, Inc.	VECTIBIX	panitumumab	Injection	125147	09/27/2006		2031-11-21