Claims for Patent: 9,856,320

Summary for Patent: 9,856,320

Title:	Cancer immunotherapy by disrupting PD-1/PD-L1 signaling
Abstract:	The disclosure provides a method for immunotherapy of a cancer patient, comprises administering to the patient an Ab that inhibits signaling from the PD-1/PD-L1 signaling pathway, or a combination of such Ab and an anti-CTLA-4 Ab. This disclosure also provides a method for immunotherapy of a cancer patient comprising selecting a patient who is a suitable candidate for immunotherapy based on an assessment that the proportion of cells in a test tissue sample from the patient that express PD-L1 on the cell surface exceeds a predetermined threshold level, and administering an anti-PD-1 Ab to the selected subject. The disclosure additionally provides rabbit mAbs that bind specifically to a cell surface-expressed PD-L1 antigen in a FFPE tissue sample, and an automated IHC method for assessing cell surface expression in FFPE tissues using the provided anti-PD-L1 Abs.
Inventor(s):	Cogswell; John P. (Yardley, PA), Goldberg; Stacie M. (Potomac, MD), Gupta; Ashok Kumar (Clarksburg, MD), Jure-Kunkel; Maria (Plainsboro, NJ), Wang; Xi-Tao (Wellesley, MA), Wigginton; Jon M. (Rockville, MD)
Assignee:	Bristol-Myers Squibb Company (Princeton, NJ)
Application Number:	14/400,667
Patent Claims:	1. A method of treating a human subject afflicted with a cancer comprising administering to the subject: (a) an antibody or an antigen-binding portion thereof that specifically binds to and inhibits Programmed Death-1 (PD-1) ("anti-PD-1 antibody"); and (b) an antibody or an antigen-binding portion thereof that specifically binds to and inhibits Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) ("anti-CTLA-4 antibody"); (i) an induction dosing schedule comprising administration of the anti-PD-1 antibody and the anti-CTLA-4 antibody at a dosing frequency of once every 2, 3 or 4 weeks, or once a month, for 2, 4, 6, 8, 10, or 12 doses, followed by administration of the anti-PD-1 antibody alone at a dosing frequency of once every 2, 3 or 4 weeks, or once a month, for 2, 4, 6, 8, 10, or 12 doses; followed by (ii) a maintenance dosing schedule comprising administration of the anti-PD-1 antibody and the anti-CTLA-4 antibody at a dosing frequency of once every 8, 12 or 16 weeks, or once a quarter, for 4, 6, 8, 10, 12 or 16 doses; and wherein the anti-PD-1 antibody and the anti-CTLA-4 antibody are administered in the induction dosing schedule at the following dosages: (a) 0.1 mg/kg anti-PD-1 antibody and 3 mg/kg of anti-CTLA-4 antibody; (b) 5 mg/kg anti-PD-1 antibody and 3 mg/kg of anti-CTLA-4 antibody; (c) 10 mg/kg anti-PD-1 antibody and 3 mg/kg of anti-CTLA-4 antibody; (d) 0.1 mg/kg anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody; (e) 0.3 mg/kg anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody; (f) 1 mg/kg anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody; (g) 3 mg/kg anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody; (h) 5 mg/kg anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody; (i) 10 mg/kg anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody; (j) 0.1 mg/kg anti-PD-1 antibody and 0.1 mg/kg of anti-CTLA-4 antibody; (k) 0.3 mg/kg anti-PD-1 antibody and 0.3 mg/kg of anti-CTLA-4 antibody; (l) 0.5 mg/kg anti-PD-1 antibody and 0.5 mg/kg of anti-CTLA-4 antibody; or (m) 5 mg/kg anti-PD-1 antibody and 5 mg/kg of anti-CTLA-4 antibody. 2. The method of claim 1, wherein the anti-PD-1 antibody is nivolumab. 3. The method of claim 1, wherein the anti-CTLA-4 antibody is ipilimumab. 4. The method of claim 1, wherein the anti-CTLA-4 antibody is administered during the induction dosing schedule once every 3 weeks for a total of 4 doses. 5. A method of treating a human subject afflicted with a cancer comprising administering to the subject 1 mg/kg of an anti-PD-1 antibody and 3 mg/kg of an anti-CTLA-4 antibody every 3 weeks for 4 doses, followed by subsequently administering the anti-PD-1 antibody alone at a dosing frequency of once every 2 weeks. 6. The method of claim 1, wherein the administering comprises: (i) an induction dosing schedule comprising administration of the anti-PD-1 antibody and the anti-CTLA-4 antibody at a dosing frequency of once every 3 weeks for 4 doses, followed by administration of the anti-PD-1 antibody alone at a dosing frequency of once every 3 weeks for 4 doses; followed by (ii) a maintenance dosing schedule comprising administration of the anti-PD-1 antibody and the anti-CTLA-4 antibody at a dosing frequency of once every 2 to 12 weeks for up to 8 doses. 7. The method of claim 1, wherein the treatment provides a reduction in tumor size, reduction in tumor growth, elimination of the tumor, reduction in number of metastatic lesions over time, complete response, partial response, or stable disease. 8. The method of claim 1, wherein the cancer is selected from liver cancer, hepatocellular carcinoma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, breast cancer, lung cancer, squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, cutaneous or intraocular malignant melanoma, renal cancer, renal cell carcinoma, uterine cancer, ovarian cancer, colorectal cancer, colon cancer, colorectal cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, castration-resistant prostate cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, gastric cancer, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, solid tumors of childhood, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the CNS, primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, asbestos-induced cancers, and a hematologic malignancy. 9. The method of claim 8, wherein the hematologic malignancy is selected from multiple myeloma, B-cell lymphoma, Hodgkin lymphoma/primary mediastinal B-cell lymphoma, non-Hodgkin's lymphomas, acute myeloid lymphoma, chronic myelogenous leukemia, chronic lymphoid leukemia, lymphocytic lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, acute lymphoblastic leukemia, mycosis fungoides, anaplastic large cell lymphoma, T-cell lymphoma, and precursor T-lymphoblastic lymphoma. 10. The method of claim 1, wherein the cancer is the cancer is an advanced, recurring, metastatic, and/or refractory cancer. 11. The method of claim 1, wherein the treatment is further combined with one of more of chemotherapy, radiation, surgery, hormone deprivation, angiogenesis inhibitors, and an anti-PD-L1 antibody or antigen-binding portion thereof. 12. The method of claim 1, wherein the anti-PD-1 antibody and the anti-CTLA-4 antibody are administered in the maintenance dosing schedule at the following dosages: (a) 0.1 mg/kg anti-PD-1 antibody and 3 mg/kg of anti-CTLA-4 antibody; (b) 5 mg/kg anti-PD-1 antibody and 3 mg/kg of anti-CTLA-4 antibody; (c) 10 mg/kg anti-PD-1 antibody and 3 mg/kg of anti-CTLA-4 antibody; (d) 0.1 mg/kg anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody; (e) 0.3 mg/kg anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody; (f) 1 mg/kg anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody; (g) 3 mg/kg anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody; (h) 5 mg/kg anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody; (i) 10 mg/kg anti-PD-1 antibody and 1 mg/kg of anti-CTLA-4 antibody; (j) 0.1 mg/kg anti-PD-1 antibody and 0.1 mg/kg of anti-CTLA-4 antibody; (k) 0.3 mg/kg anti-PD-1 antibody and 0.3 mg/kg of anti-CTLA-4 antibody; (l) 0.5 mg/kg anti-PD-1 antibody and 0.5 mg/kg of anti-CTLA-4 antibody; or (m) 5 mg/kg anti-PD-1 antibody and 5 mg/kg of anti-CTLA-4 antibody. 13. The method of claim 5, wherein the anti-PD-1 antibody subsequently administered alone is administered at a dosage of 3 mg/kg. 14. The method of claim 1, wherein 5 mg/kg of the anti-PD-1 antibody and 3 mg/kg of the anti-CTLA-4 antibody are administered to a human subject every 3 weeks for 4 doses in the induction dosing schedule. 15. The method of claim 1, wherein 1 mg/kg of the anti-PD-1 antibody and 1 mg/kg of the anti-CTLA-4 antibody are administered to a human subject every 3 weeks for 4 doses in the induction dosing schedule. 16. The method of claim 1, wherein 3 mg/kg of the anti-PD-1 antibody and 1 mg/kg of the anti-CTLA-4 antibody are administered to a human subject every 3 weeks for 4 doses in the induction dosing schedule. 17. The method of claim 1, wherein 5 mg/kg of the anti-PD-1 antibody and 1 mg/kg of the anti-CTLA-4 antibody are administered to a human subject every 3 weeks for 4 doses in the induction dosing schedule. 18. The method of claim 5, wherein the treatment provides a reduction in tumor size, reduction in tumor growth, elimination of the tumor, reduction in number of metastatic lesions over time, complete response, partial response, or stable disease. 19. The method of claim 5, wherein the cancer is selected from liver cancer, hepatocellular carcinoma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, breast cancer, lung cancer, squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, melanoma, renal cancer, renal cell carcinoma, uterine cancer, ovarian cancer, colorectal cancer, colon cancer, colorectal cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, castration-resistant prostate cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, gastric cancer, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, solid tumors of childhood, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the CNS, primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, asbestos-induced cancers, and a hematologic malignancy. 20. The method of claim 5, wherein the cancer is melanoma. 21. The method of claim 5, wherein the cancer is an advanced, recurring, metastatic, and/or refractory cancer. 22. The method of claim 5, wherein the treatment is further combined with one of more of chemotherapy, radiation, surgery, hormone deprivation, angiogenesis inhibitors, and an anti-PD-L1 antibody or antigen-binding portion thereof.

Details for Patent 9,856,320

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bristol-myers Squibb Company	YERVOY	ipilimumab	Injection	125377	03/25/2011		2032-05-15
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	12/22/2014		2032-05-15
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	10/04/2017		2032-05-15
Bristol-myers Squibb Company	OPDIVO	nivolumab	Injection	125554	08/27/2021		2032-05-15