Claims for Patent: 10,072,082

Summary for Patent: 10,072,082

Title:	Cancer immunotherapy by disrupting PD-1/PD-L1 signaling
Abstract:	The disclosure provides a method for immunotherapy of a subject afflicted with cancer, comprises administering to the subject a composition comprising a therapeutically effective amount of an antibody that inhibits signaling from the PD-1/PD-L1 signaling pathway. This disclosure also provides a method for immunotherapy of a subject afflicted with cancer comprising selecting a subject that is a suitable candidate for immunotherapy based on an assessment that the proportion of cells in a test tissue sample from the subject that express PD-L1 on the cell surface exceeds a predetermined threshold level, and administering a therapeutically effective amount of an anti-PD-1 antibody to the selected subject. The invention 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 K. (Clarksburg, MD), Jure-Kunkel; Maria (Plainsboro, NJ), Wang; Xi-Tao (Wellesley, MA), Wigginton; Jon M. (Collegeville, PA)
Assignee:	Bristol-Myers Squibb Company (Princeton, NJ)
Application Number:	14/950,748
Patent Claims:	1. A method for treating a human subject afflicted with cancer using an immunotherapy, which method comprises: (a) selecting a human subject who is a suitable candidate for immunotherapy, wherein the selecting comprises: assessing the proportion of cells in a test tissue sample that express PD-L1 on the cell surface as determined by immunohistochemistry (IHC) using an anti-PD-L1 antibody, wherein the test tissue sample is obtained from a tumor of the subject and wherein the proportion of cells that express PD-L1 on the cell surface is .gtoreq.1%; and (b) administering a composition comprising a therapeutically effective amount of an anti-PD-1 antibody to the subject; wherein the anti-PD-L1 antibody comprises: (a) a heavy chain (HC) complementarity determining region (CDR) 1 comprising the amino acid sequence set forth in the HC-CDR1 of SEQ ID NO: 35; (b) an HC-CDR2 comprising the amino acid sequence set forth in the HC-CDR2 of SEQ ID NO: 35; (c) an HC-CDR3 comprising the amino acid sequence set forth in the HC-CDR3 of SEQ ID NO: 35; (d) a light chain (LC) CDR1 comprising the amino acid sequence set forth in the LC-CDR1 of SEQ ID NO: 36; (e) an LC-CDR2 comprising the amino acid sequence set forth in the LC-CDR2 of SEQID NO: 36; and (f) an LC-CDR3 comprising the amino acid sequence set forth in the LC-CDR3 of SEQ ID NO: 36. 2. The method of claim 1, wherein the test tissue sample is a formalin-fixed paraffin-embedded (FFPE) tissue sample. 3. The method of claim 1, wherein the anti-PD -L1 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 35 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 36. 4. 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. 5. The method of claim 1, wherein the cancer is a hematologic malignancy 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. 6. The method of claim 1, wherein the cancer is melanoma, renal cell carcinoma, NSCLC, castration-resistant prostate cancer (CRPC), or colorectal cancer (CRC). 7. The method of claim 1, wherein the cancer is an advanced, recurring, metastatic, and/or refractory cancer. 8. The method of claim 1, wherein the anti-PD-1 antibody cross-competes with a reference antibody, wherein the reference antibody comprises: (a) an HC-CDR1 comprising the amino acid sequence of the HC-CDR1 of SEQ ID NO: 4; (b) an HC-CDR2 comprising the amino acid sequence of the HC-CDR2 of SEQ ID NO: 4; (c) an HC-CDR3 comprising the amino acid sequence of the HC-CDR3 of SEQ ID NO: 4; (d) an LC-CDR1 comprising the amino acid sequence of the LC-CDR1 of SEQ ID NO: 11; (e) an LC-CDR2 comprising the amino acid sequence of the LC-CDR2 of SEQ ID NO: 11; and (f) an LC-CDR3 comprising the amino acid sequence of the LC-CDR3 of SEQ ID NO: 11. 9. The method of claim 8, wherein the reference antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 4 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 11. 10. The method of claim 1, wherein the anti-PD-1 antibody comprises: (a) an HC-CDR1 comprising the amino acid sequence set forth in the HC-CDR1 of SEQ ID NO: 4; (b) an HC-CDR2 comprising the amino acid sequence set forth in the HC-CDR2 of SEQ ID NO: 4; (c) an HC-CDR3 comprising the amino acid sequence set forth in the HC-CDR3 of SEQ ID NO: 4; (d) an LC-CDR1 comprising the amino acid sequence set forth in the LC-CDR1 of SEQ ID NO: 11; (e) an LC-CDR2 comprising the amino acid sequence set forth in the LC-CDR2 of SEQ ID NO: 11; and (f) an LC-CDR3 comprising the amino acid sequence set forth in the LC-CDR3 of SEQ ID NO: 11. 11. The method of claim 10, wherein the anti-PD-1 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 4 and a variable light chain region comprising the amino acid sequence set forth in SEQ ID NO: 11. 12. The method of claim 1, wherein the anti-PD-1 antibody is an IgG1, IgG2, IgG3, or IgG4 isotype. 13. The method of claim 12, wherein the anti-PD-1 antibody is an IgG4 isotype. 14. The method of claim 1, wherein the anti-PD-1 antibody is a human antibody. 15. The method of claim 1, wherein the anti-PD-1 antibody is a humanized antibody. 16. The method of claim 1, wherein the anti-PD-1 antibody is nivolumab. 17. The method of claim 1, further comprising administering a second therapeutic agent. 18. The method of claim 17, wherein the second therapeutic agent comprises a second immunotherapeutic antibody. 19. The method of claim 18, wherein the second immunotherapeutic antibody is selected from the group consisting of an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-LAG-3 antibody, and any combination thereof. 20. The method of claim 18, wherein the second immunotherapeutic antibody is an anti-CTLA-4 antibody. 21. The method of claim 20, wherein the anti-CTLA-4 antibody is ipilimumab. 22. The method of claim 18, wherein the anti-PD-1 antibody and the second immunotherapeutic antibody are administered simultaneously. 23. The method of claim 18, wherein the anti-PD-1 antibody and the second immunotherapeutic antibody are administered sequentially. 24. The method of claim 17, wherein the second therapeutic agent comprises a chemotherapy. 25. The method of claim 1, wherein the proportion of cells that express PD-L1 on the cell surface is .gtoreq.5%. 26. The method of claim 1, wherein the proportion of cells that express PD-L1 on the cell surface is .gtoreq.10%. 27. The method of claim 7, wherein the cancer s melanoma, renal cell carcinoma, or NSCLC. 28. A method for treating a human subject afflicted with NSCLC using an immunotherapy, which method comprises: (a) selecting a human subject who is a suitable candidate for immunotherapy, wherein the selecting comprises assessing the proportion of cells in the test tissue sample that express PD-L1 on the cell surface as determined by immunohistochemistry (IHC) using an anti-PD-L1 antibody, wherein the test tissue sample is obtained from a tumor of the subject and wherein the proportion of cells that express PD-L1 on the cell surface is .gtoreq.1%; and (b) administering a composition comprising a therapeutically effective amount of an anti-PD-1 antibody and an anti-CTLA-4 antibody to the subject; wherein the anti-PD-L1 antibody comprises: (a) an HC-CDR1 comprising the amino acid sequence set forth in the HC-CDR1 of SEQ ID NO: 35; (b) an HC-CDR2 comprising the amino acid sequence set forth in the HC-CDR2 of SEQ ID NO: 35; (c) an HC-CDR3 comprising the amino acid sequence set forth in the HC-CDR3 of SEQ ID NO: 35; (d) an LC-CDR1 comprising the amino acid sequence set forth in the LC-CDR1 of SEQ ID NO: 36; (e) an LC-CDR2 comprising the amino acid sequence set forth in the LC-CDR2 of SEQ ID NO: 36; and (f) an LC-CDR3 comprising the amino acid sequence set forth in the LC-CDR3 of SEQ ID NO: 36.

Details for Patent 10,072,082

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