Claims for Patent: 9,862,769

Summary for Patent: 9,862,769

Title:	Monoclonal antibodies against HER2
Abstract:	Isolated monoclonal antibodies which bind to human epidermal growth factor receptor 2 (HER2), and related anti-body-based compositions and molecules, are disclosed. Pharmaceutical compositions comprising the antibodies and therapeutic and diagnostic methods for using the antibodies are also disclosed.
Inventor(s):	De Goeij; Bart (Utrecht, NL), De Haij; Simone (Weesp, NL), Riedl; Thilo (Utrecht, NL), Hoet; Rene (Boxmeer, NL), Baadsgaard; Ole (Hellerup, DK), Van De Winkel; Jan (Utrecht, NL), Satijn; David (Utrecht, NL), Parren; Paul (Utrecht, NL), Labrijn; Aran Frank (Utrecht, NL), Meesters; Joyce (Utrecht, NL), Schuurman; Janine (Utrecht, NL), Van Den Brink; Edward N. (Utrecht, NL)
Assignee:	GENMAB A/S (Copenhagen V, DK)
Application Number:	13/700,341
Patent Claims:	1. An isolated antibody which binds to human epidermal growth factor receptor 2 (HER2) and comprises a VH region and a VL region selected from the group consisting of a) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:2, 3 and 4, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:6, DAS, and SEQ ID NO:7, respectively; b) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:9, 10 and 11, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:13, AAS, and SEQ ID NO:14, respectively; c) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:16, 17 and 18, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:20, VAS, and SEQ ID NO:21, respectively; d) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:23, 24 and 25, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:27, AAS, and SEQ ID NO:28, respectively; e) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:30, 163 and 31, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:33, AAS, and SEQ ID NO:34, respectively; f) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:36, 37 and 38, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:40, DAS, and SEQ ID NO:41, respectively; g) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:43, 44 and 45, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:47, AAS, and SEQ ID NO:48, respectively; h) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:50, 51 and 52, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:54, AAS, and SEQ ID NO:55, respectively; i) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:57, 58 and 59, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:61, AAS, and SEQ ID NO:6462, respectively; j) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:64, 65 and 66, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:68, DAS, and SEQ ID NO:69, respectively; and k) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:71, 72 and 73, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:75, DAS, and SEQ ID NO:76, respectively. 2. The antibody of claim 1, wherein the antibody comprises a VH region and a VL region selected from the group consisting of: a) a VH region comprising the sequence of SEQ ID NO:1 and a VL region comprising the sequence of SEQ ID NO:5; b) a VH region comprising the sequence of SEQ ID NO:8 and a VL region comprising the sequence of SEQ ID NO:12; c) a VH region comprising the sequence of SEQ ID NO:15 and a VL region comprising the sequence of SEQ ID NO:19; d) a VH region comprising the sequence of SEQ ID NO:22 and a VL region comprising the sequence of SEQ ID NO:26; e) a VH region comprising the sequence of SEQ ID NO:29 and a VL region comprising the sequence of SEQ ID NO:32; f) a VH region comprising the sequence of SEQ ID NO:35 and a VL region comprising the sequence of SEQ ID NO:39; g) a VH region comprising the sequence of SEQ ID NO:42 and a VL region comprising the sequence of SEQ ID NO:46; h) a VH region comprising the sequence of SEQ ID NO:49 and a VL region comprising the sequence of SEQ ID NO:53; i) a VH region comprising the sequence of SEQ ID NO:56 and a VL region comprising the sequence of SEQ ID NO:60; j) a VH region comprising the sequence of SEQ ID NO:63 and a VL region comprising the sequence of SEQ ID NO:67; k) a VH region comprising the sequence of SEQ ID NO:70 and a VL region comprising the sequence of SEQ ID NO:74; and l) a variant of any of said antibodies, wherein said variant has at most 1, 2 or 3 amino acid substitutions. 3. The antibody of claim 2, comprising the VH and VL region sequences of (a), (c), (d), (e), (g), (h), (i), (j), or (k). 4. The antibody of claim 1, which has an EC.sub.50 value for binding to HER2-expressing cells lower than 0.80 .mu.g/ml, when determined by flow cytometry. 5. The antibody of claim 1, which induces antibody-dependent cell-mediated cytotoxicity, when determined under the following conditions: (a).sup.51Cr-labeled SK-BR-3 cells are pre-incubated with the antibody, (b) peripheral blood mononuclear cells are added to the cells of step (a) at an effector to target ratio of 100:1; and (c) cell lysis is determined based on .sup.51Cr released into supernatant. 6. The antibody of claim 1, which promotes ligand-independent proliferation of HER2-expressing cells less than F5, when determined under the following conditions: (a) AU565 cells are seeded in the presence of HER2 antibody in serum-free cell culture medium and (b) viable cells after 3 days are quantified using a fluorescence-based viability assay. 7. The antibody of claim 1, which inhibits ligand-independent proliferation of HER2-expressing cells, when determined under the following conditions: (a) AU565 cells are seeded in the presence of HER2 antibody in serum-free cell culture medium and (b) viable cells after 3 days are quantified using a fluorescence-based viability assay. 8. The antibody of claim 1, which does not promote ligand-induced proliferation of HER2-expressing cells, when determined under the following conditions: (a) MCF7 cells are seeded in complete culture medium for 4 hours, (b) the cell culture medium is replaced with starvation medium and HER2 antibody; (c) heregulin-.beta.1 is added to the starvation medium; and (d) cell viability is determined after 4 days using a fluorescence-based viability assay. 9. The antibody of claim 1, which inhibits ligand-induced proliferation of HER2-expressing cells, when determined under the following conditions: (a) MCF7 cells are seeded in complete culture medium for 4 hours, (b) the cell culture medium is replaced with starvation medium and HER2 antibody; (c) heregulin-.beta.1 is added to the starvation medium; and (d) cell viability is determined after 4 days using a fluorescence-based viability assay. 10. The antibody of claim 1, which, when conjugated directly or indirectly to a therapeutic moiety, kills at least 49% of HER2-expressing cells, when determined under the following conditions: (a) a dilution series of HER2 antibodies are incubated with anti-kappa-ETA', (b) AU565 cells are incubated with the dilution series from part (a), and (c) cell viability is determined after 3 days using a fluorescence-based viability assay. 11. The antibody of claim 4, wherein the HER2-expressing cells express less than an average of about 30000 HER2 molecules per cell. 12. The antibody of claim 1, wherein a higher amount of the antibody than trastuzumab is internalized by a HER2-expressing tumor cell-line, when determined under the following conditions: (a) a dilution series of HER2 antibodies are incubated with anti-kappa-ETA', (b) AU565 cells are incubated with the dilution series from part (a), and (c) cell viability is determined after 3 days using a fluorescence-based viability assay. 13. A bispecific antibody comprising (i) a first antigen-binding region which binds to human HER2 and a (ii) second antigen-binding region, wherein the first antigen-binding region comprises a VH and VL region according to claim 1, and wherein the second antigen-binding region binds to a different epitope than the first antibody. 14. A bispecific antibody according to claim 13, wherein the second antibody is a CD3 antibody. 15. A bispecific antibody according to claim 14, wherein the CD3 antibody comprises a) a VH region comprising the sequence of SEQ ID NO:171 and a VL region comprising the sequence of SEQ ID NO:172; or b) a VH region comprising the sequence of SEQ ID NO: 173 and a VL region comprising the sequence of SEQ ID NO: 174. 16. The antibody of claim 1, wherein the antibody is a full-length antibody. 17. The antibody of claim 1, wherein the antibody is conjugated to another moiety. 18. The antibody of claim 17, wherein the moiety is selected from the group consisting of taxol; cytochalasin B; gramicidin D; ethidium bromide; emetine; mitomycin; etoposide; tenoposide; vincristine; vinblastine; colchicin; doxorubicin; daunorubicin; dihydroxy anthracin dione; a tubulin-inhibitor; mitoxantrone; mithramycin; actinomycin D; 1--dehydrotestosterone; a glucocorticoid; procaine; tetracaine; lidocaine; propranolol; puromycin; calicheamicin or an analog or derivative thereof; an antimetabolite; an alkylating agent; an antibiotic; an antimitotic agent; toxins; ribonuclease (RNase); DNase I, Staphylococcal enterotoxin A; pokeweed antiviral protein; diphtherin toxin; and Pseudomonas endotoxin. 19. The antibody of claim 17, wherein the moiety is selected from the group consisting of maytansine, calicheamicin, duocarmycin, rachelmycin (CC-1065), monomethyl auristatin E, monomethyl auristatin F or an analog, derivative, or prodrug of any thereof. 20. The antibody of claim 17, which is conjugated to a cytokine selected from the group consisting of IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, IL-13, IL-15, IL-18, IL-23, IL-24, IL-27, IL-28a, IL-28b, IL-29, KGF, IFN.alpha., IFN.beta., IFN.gamma., GM-CSF, CD40L, Flt3 ligand, stem cell factor, ancestim, and TNF.alpha.. 21. The antibody of claim 17, which is conjugated to a radioisotope. 22. A pharmaceutical composition comprising an antibody as defined in claim 1 and a pharmaceutically acceptable carrier. 23. A pharmaceutical composition comprising an antibody as defined in claim 17, and a pharmaceutically acceptable carrier. 24. A method for inhibiting growth and/or proliferation of one or more tumor cells expressing HER2, comprising administration, to an individual in need thereof, of an antibody according to claim 1. 25. The method of claim 24, wherein the one or more tumor cell coexpresses HER2 and EGFR and/or HER3. 26. A method for treating cancer, comprising selecting a subject suffering from a cancer comprising tumor cells co-expressing HER2 and EGFR and/or HER3, and administering to the subject the antibody according to claim 1. 27. The method of claim 26, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, endometrial/cervical cancer, lung cancer, malignant melanoma, ovarian cancer, pancreatic cancer, prostate cancer, testis cancer, a soft-tissue tumor such as synovial sarcoma, and bladder cancer. 28. A method for producing an antibody, said method comprising the steps of a) culturing a host cell expressing the antibody of claim 1, and b) purifying the antibody from the culture media. 29. A method for detecting the presence of HER2 in a sample, comprising: a) contacting the sample with the antibody of claim 1 under conditions that allow for formation of a complex between the antibody and HER2; and b) analyzing whether a complex has been formed. 30. A kit for detecting the presence of HER2 in a sample comprising the antibody of claim 1; and instructions for use of the kit. 31. An isolated antibody which binds human epidermal growth factor receptor 2 (HER2) comprising a VH region and a VL region selected from the group consisting of: a) a VH region comprising the sequence of SEQ ID NO:77 and a VL region comprising the sequence of SEQ ID NO:78; b) a VH region comprising the sequence of SEQ ID NO:79 and a VL region comprising the sequence of SEQ ID NO:80; c) a VH region comprising the sequence of SEQ ID NO:81 and a VL region comprising the sequence of SEQ ID NO:82; d) a VH region comprising the sequence of SEQ ID NO:83 and a VL region comprising the sequence of SEQ ID NO:84; e) a VH region comprising the sequence of SEQ ID NO:85 and a VL region comprising the sequence of SEQ ID NO:86; f) a VH region comprising the sequence of SEQ ID NO:87 and a VL region comprising the sequence of SEQ ID NO:88; g) a VH region comprising the sequence of SEQ ID NO:89 and a VL region comprising the sequence of SEQ ID NO:90; h) a VH region comprising the sequence of SEQ ID NO:91 and a VL region comprising the sequence of SEQ ID NO:92; i) a VH region comprising the sequence of SEQ ID NO:93 and a VL region comprising the sequence of SEQ ID NO:94; j) a VH region comprising the sequence of SEQ ID NO:95 and a VL region comprising the sequence of SEQ ID NO:96; k) a VH region comprising the sequence of SEQ ID NO:97 and a VL region comprising the sequence of SEQ ID NO:98; l) a VH region comprising the sequence of SEQ ID NO:99 and a VL region comprising the sequence of SEQ ID NO:100; m) a VH region comprising the sequence of SEQ ID NO:101 and a VL region comprising the sequence of SEQ ID NO:102; n) a VH region comprising the sequence of SEQ ID NO:103 and a VL region comprising the sequence of SEQ ID NO:104; o) a VH region comprising the sequence of SEQ ID NO:105 and a VL region comprising the sequence of SEQ ID NO:106; p) a VH region comprising the sequence of SEQ ID NO:107 and a VL region comprising the sequence of SEQ ID NO:108; q) a VH region comprising the sequence of SEQ ID NO:109 and a VL region comprising the sequence of SEQ ID NO:110; r) a VH region comprising the sequence of SEQ ID NO:111 and a VL region comprising the sequence of SEQ ID NO:112; s) a VH region comprising the sequence of SEQ ID NO:113 and a VL region comprising the sequence of SEQ ID NO:114; t) a VH region comprising the sequence of SEQ ID NO:115 and a VL region comprising the sequence of SEQ ID NO:116; u) a VH region comprising the sequence of SEQ ID NO:117 and a VL region comprising the sequence of SEQ ID NO:118; v) a VH region comprising the sequence of SEQ ID NO:119 and a VL region comprising the sequence of SEQ ID NO:120; w) a VH region comprising the sequence of SEQ ID NO:121 and a VL region comprising the sequence of SEQ ID NO:122; x) a VH region comprising the sequence of SEQ ID NO:123 and a VL region comprising the sequence of SEQ ID NO:124; and y) a VH region comprising the sequence of SEQ ID NO:125 and a VL region comprising the sequence of SEQ ID NO:126. 32. The antibody of claim 1, wherein the antibody comprises a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:2, 3 and 4, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:6, DAS, and SEQ ID NO:7, respectively. 33. The antibody of claim 1, wherein the antibody comprises a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:9, 10 and 11, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:13, AAS, and SEQ ID NO:14, respectively. 34. The antibody of claim 1, wherein the antibody comprises a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:16, 17 and 18, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:20, VAS, and SEQ ID NO:21, respectively. 35. The antibody of claim 1, wherein the antibody comprises a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:23, 24 and 25, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:27, AAS, and SEQ ID NO:28, respectively. 36. The antibody of claim 1, wherein the antibody comprises a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:30, 163 and 31, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:33, AAS, and SEQ ID NO:34, respectively. 37. The antibody of claim 1, wherein the antibody comprises a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:36, 37 and 38, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:40, DAS, and SEQ ID NO:41, respectively. 38. The antibody of claim 1, wherein the antibody comprises a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:43, 44 and 45, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:47, AAS, and SEQ ID NO:48, respectively. 39. The antibody of claim 1, wherein the antibody comprises a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:50, 51 and 52, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:54, AAS, and SEQ ID NO:55, respectively. 40. The antibody of claim 1, wherein the antibody comprises a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:57, 58 and 59, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:61, AAS, and SEQ ID NO:6462, respectively. 41. The antibody of claim 1, wherein the antibody comprises a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:64, 65 and 66, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:68, DAS, and SEQ ID NO:69, respectively. 42. The antibody of claim 1, wherein the antibody comprises a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs:71, 72 and 73, respectively; and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NO:75, DAS, and SEQ ID NO:76, respectively.

Details for Patent 9,862,769

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2030-05-27
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2030-05-27
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2030-05-27