Claims for Patent: 10,314,846

Summary for Patent: 10,314,846

Title:	Immunoconjugates comprising anti-HER2 antibodies and pyrrolobenzodiazepines
Abstract:	The invention provides immunoconjugates comprising anti-HER2 antibodies and methods of using the same.
Inventor(s):	Chen; Xiaocheng (Burlingame, CA), Dennis; Mark (San Carlos, CA), Junutula; Jagath Reddy (Fremont, CA), Phillips; Gail Lewis (San Carlos, CA), Pillow; Thomas Harden (San Francisco, CA), Sliwkowski; Mark X. (San Carlos, CA)
Assignee:	Genentech, Inc. (South San Francisco, CA)
Application Number:	15/438,418
Patent Claims:	1. An immunoconjugate comprising an antibody and a cytotoxic agent, wherein the immunoconjugate has the formula Ab-(L-D)p, wherein: (a) Ab is the antibody; (b) L is a linker; (c) D is a cytotoxic agent; and (d) p ranges from 1-8; and wherein D is a pyrrolobenzodiazepine and L-D is of Formula A: ##STR00031## wherein: R.sup.2 is ##STR00032## where R.sup.36a and R.sup.36b are independently selected from H, F, C.sub.1-4 saturated alkyl, C.sub.2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C.sub.1-4 alkyl amido and C.sub.1-4 alkyl ester; or, when one of R.sup.36a and R.sup.36b is H, the other is selected from nitrile and a C.sub.1-4 alkyl ester; R.sup.6 and R.sup.9 are independently selected from H, R, OH, OR, SH, SR, NH.sub.2, NHR, NRR', NO.sub.2, Me.sub.3Sn and halo; R.sup.7 is independently selected from H, R, OH, OR, SH, SR, NH.sub.2, NHR, NRR', NO.sub.2, Me.sub.3Sn and halo; Y has the formula: ##STR00033## G is a linker connected to the antibody; n is an integer selected in the range of 0 to 48; either: (a) R.sup.10 is H, and R.sup.11 is OH, OR.sup.A, where R.sup.A is C.sub.1-4 alkyl; or (b) R.sup.10 and R.sup.11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or (c) R.sup.10 is H and R.sup.11 is OSO.sub.zM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; R and R' are each independently selected from optionally substituted C.sub.1-12 alkyl, C.sub.3-20 heterocyclyl and C.sub.5-20 aryl groups, and optionally in relation to the group NRR', R and R' together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring; R.sup.16, R.sup.17, R.sup.19, R.sup.20, R.sup.21 and R.sup.22 are as defined for R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11 and R.sup.2 respectively; Z is CH or N; T and T'' are independently selected from a single bond or a C.sub.1-9 alkylene, which chain may be interrupted by one or more heteroatoms, e.g., O, S, N(H), NMe, provided that the number of atoms in the shortest chain of atoms between X and X' is 3 to 12 atoms; and X and X' are independently selected from O, S and N(H); and wherein the antibody is an antibody that binds HER2 comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:15; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:16; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:12; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:13; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:14. 2. The immunoconjugate of claim 1, wherein the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 11 and a light chain variable region comprising the sequence of SEQ ID NO: 10. 3. The immunoconjugate of claim 1, wherein the antibody is a monoclonal antibody. 4. The immunoconjugate of claim 3, wherein the antibody is a humanized or chimeric antibody. 5. The immunoconjugate of claim 1, wherein the antibody is an antibody fragment that binds HER2. 6. The immunoconjugate of claim 1, wherein HER2 is human HER2 comprising amino acids 23 to 1255 of SEQ ID NO: 1. 7. The immunoconjugate of claim 1, wherein the antibody binds to extracellular domain I of HER2. 8. The immunoconjugate of claim 7, wherein extracellular domain I of HER2 has the sequence of SEQ ID NO: 35. 9. The immunoconjugate of claim 4, wherein the antibody is an IgG1, IgG2a or IgG2b antibody. 10. The immunoconjugate of claim 1, wherein the antibody comprises one or more engineered free cysteine amino acids residues. 11. The immunoconjugate of claim 10, wherein the one or more engineered free cysteine amino acids residues are located in the heavy chain. 12. The immunoconjugate of claim 10, wherein the one or more engineered free cysteine amino acids residues are located in the light chain. 13. The immunoconjugate of claim 11, wherein the antibody comprises at least one mutation in the heavy chain constant region selected from A118C and S400C. 14. The immunoconjugate of claim 12, wherein the antibody comprises at least one mutation in the light chain constant region selected from K149C and V205C. 15. The immunoconjugate of claim 1, wherein the antibody comprises: a) a heavy chain comprising the sequence of SEQ ID NO: 19 and a light chain comprising the sequence of SEQ ID NO: 18; or b) a heavy chain comprising the sequence of SEQ ID NO: 19 and a light chain comprising the sequence of SEQ ID NO: 23; or c) a heavy chain comprising the sequence of SEQ ID NO: 24 and a light chain comprising the sequence of SEQ ID NO: 18. 16. The immunoconjugate of claim 1, wherein the antibody comprises the heavy chain constant region of SEQ ID NO: 28. 17. The immunoconjugate of claim 1, wherein the antibody comprises the light chain constant region of SEQ ID NO: 25. 18. The immunoconjugate of claim 1, wherein R.sup.9 is H and R.sup.19 is H. 19. The immunoconjugate of claim 1, wherein R.sup.6 is H and R.sup.16 is H. 20. The immunoconjugate of claim 1, wherein R.sup.7 is OR and R.sup.17 is OR, where each R is optionally substituted C.sub.1-4 alkyl. 21. The immunoconjugate of claim 20, wherein each R is Me. 22. The immunoconjugate of claim 1, wherein X is O and X' is O. 23. The immunoconjugate of claim 1, wherein T is a single bond or is selected from a C.sub.1 alkylene group and a C.sub.2 alkylene group and wherein T' is a single bond or is selected from a C.sub.1 alkylene group and a C.sub.2 alkylene group. 24. The immunoconjugate of claim 1, wherein T is a C.sub.1 alkylene group and T' is a C.sub.1 alkylene group. 25. The immunoconjugate of claim 1, wherein R.sup.36a and R.sup.36b are both H. 26. The immunoconjugate of claim 1, wherein R.sup.36a and R.sup.36b are both methyl. 27. The immunoconjugate of claim 1, wherein one of R.sup.36a and R.sup.36b is H, and the other is selected from C.sub.1-4 saturated alkyl, C.sub.2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted. 28. The immunoconjugate of claim 1, wherein one of R.sup.36a and R.sup.36b is H, and the other is selected from methyl and ethyl. 29. The immunoconjugate of claim 1, wherein R.sup.10 is H, R.sup.11 is OH, R.sup.20 is H, and R.sup.21 is OH. 30. The immunoconjugate of claim 1, wherein R.sup.10 and R.sup.11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound, and wherein R.sup.20 and R.sup.21 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound. 31. The immunoconjugate of claim 1, wherein R.sup.16, R.sup.17, R.sup.19, R.sup.20, R.sup.21, R.sup.22, X' and T' are the same as R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11, R.sup.2, X and T, respectively. 32. The immunoconjugate of claim 1, comprising the structure: ##STR00034## 33. The immunoconjugate of claim 32, comprising the structure: ##STR00035## 34. The immunoconjugate of claim 1, wherein p ranges from 1.3-2 or from 2-5. 35. A pharmaceutical formulation comprising the immunoconjugate of claim 1 and a pharmaceutically acceptable carrier. 36. The pharmaceutical formulation of claim 35, further comprising an additional therapeutic agent. 37. The pharmaceutical formulation of claim 36, wherein the additional therapeutic agent is an antibody or immunoconjugate that binds HER2. 38. The pharmaceutical formulation of claim 37, wherein the additional therapeutic agent is (i) an antibody or immunoconjugate that binds to domain II of HER2, and/or (ii) an antibody or immunoconjugate that binds to domain IV or HER2. 39. The pharmaceutical formulation of claim 38, wherein the additional therapeutic agent is (i) an antibody or immunoconjugate that binds to epitope 2C4, and/or (ii) an antibody or immunoconjugate that binds to epitope 4D5. 40. The pharmaceutical formulation of claim 36, wherein the additional therapeutic agent is trastuzumab, trastuzumab-MCC-DM1 (T-DM1), and/or pertuzumab. 41. The pharmaceutical formulation of claim 36, further comprising (1) trastuzumab or T-DM1, and (2) pertuzumab. 42. A method of treating an individual having a HER2-positive cancer, the method comprising administering to the individual an effective amount of the immunoconjugate of claim 1. 43. The method of claim 42, wherein the HER2-positive cancer is breast cancer or gastric cancer. 44. The method of claim 43, wherein the HER2-positive breast cancer is early-stage breast cancer. 45. The method of claim 43, wherein the HER2-positive breast cancer is metastatic breast cancer. 46. The method of claim 42, further comprising administering an additional therapeutic agent to the individual. 47. A method of treating an individual having a HER2-positive cancer, the method comprising administering to the individual an effective amount of the immunoconjugate of claim 1 and at least one additional therapeutic agent to the individual. 48. The method of claim 47, wherein the additional therapeutic agent is an antibody or immunoconjugate that binds HER2. 49. The method of claim 48, wherein the additional therapeutic agent is (i) an antibody or immunoconjugate that binds to domain II of HER2, and/or (ii) an antibody or immunoconjugate that binds to domain IV or HER2. 50. The method of claim 49, wherein the additional therapeutic agent is (i) an antibody or immunoconjugate that binds to epitope 2C4, and/or (ii) an antibody or immunoconjugate that binds to epitope 4D5. 51. The method of claim 47, wherein the additional therapeutic agent is selected from trastuzumab, trastuzumab-MCC-DM1 (T-DM1), and pertuzumab. 52. The method of claim 47, wherein the additional therapeutic agents are (1) trastuzumab or T-DM1, and (2) pertuzumab. 53. The method of claim 47, wherein the HER2-positive cancer is breast cancer or gastric cancer. 54. The method of claim 53, wherein the HER2-positive breast cancer is metastatic breast cancer. 55. The method of claim 53, wherein the HER2-positive breast cancer is early-stage breast cancer. 56. The method of claim 42, wherein the HER2-positive cancer is recurrent cancer. 57. The method of claim 56, wherein the recurrent cancer is locally recurrent cancer. 58. The method of claim 42, wherein the HER2-positive cancer is advanced cancer. 59. The method of claim 42, wherein the HER2-positive cancer is non-resectable. 60. A method of treating an individual having a HER2-positive cancer, comprising: a) subjecting the individual to neoadjuvant treatment with the immunoconjugate claim 1, b) removing the cancer by definitive surgery, and c) subjecting the individual to adjuvant treatment with the immunoconjugate of claim 1. 61. The method of claim 60, wherein the HER2-positive cancer is breast cancer or gastric cancer. 62. The method of claim 61, wherein the HER2-positive cancer is breast cancer. 63. A method of inhibiting proliferation of a HER2-positive cell, the method comprising exposing the cell to the immunoconjugate of claim 1 under conditions permissive for binding of the immunoconjugate to HER2 on the surface of the cell, thereby inhibiting proliferation of the cell. 64. The method of claim 63, wherein the cell is a breast cancer cell or a gastric cancer cell.

Details for Patent 10,314,846

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2034-09-17
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2034-09-17
Genentech, Inc.	PERJETA	pertuzumab	Injection	125409	06/08/2012		2034-09-17
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2034-09-17