Claims for Patent: 10,131,712

Summary for Patent: 10,131,712

Title:	Combination therapy with T-cell redirecting bispecific antibodies and checkpoint inhibitors
Abstract:	The present invention concerns compositions and methods of use of bispecific antibodies comprising at least one binding site for a tumor-associated antigen (TAA) and at least one binding site for an antigen expressed on an effector T cell, NK cell, monocyte or neutrophil. The bispecific antibodies are of use for inducing an immune response against a TAA-expressing tumor. The methods may comprising administering the bispecific antibody in combination with one or more therapeutic agents such as antibody-drug conjugates, interferons (preferably interferon-.alpha.), and/or checkpoint inhibitor antibodies. The bispecific antibody is capable of targeting effector T cells, NK cells, monocytes or neutrophils to induce leukocyte-mediated cytotoxicity of cancer cells. The cytotoxic immune response is enhanced by co-administration of interferon, checkpoint inhibitor antibody and/or ADC. In preferred embodiments, the checkpoint inhibitor is a chimeric or humanized anti-PD1 antibody as described herein.
Inventor(s):	Rossi; Edmund A. (Woodland Park, NJ), Chang; Chien-Hsing (Downingtown, PA), Goldenberg; David M. (Mendham, NJ)
Assignee:	IBC Pharmaceuticals, Inc. (Morris Plains, NJ)
Application Number:	15/604,153
Patent Claims:	1. A method of inducing an immune response to a cancer cell that expresses a tumor-associated antigen (TAA) selected from the group consisting of CD19, CD20, CD22, CEACAM5, CEACAM6, HLA-DR, MUC5ac, and Trop-2 comprising: a) administering to the cancer cell a bispecific antibody that comprises (i) a first binding site for CD3; and (ii) a second binding site for a TAA selected from the group consisting of CD19, CD20, CD22, CEACAM5, CEACAM6, HLA-DR, MUC5ac, and Trop-2, wherein the first binding site comprises an Okt3 antibody or antigen-binding fragment thereof and the second binding site comprises an antibody or antigen-binding antibody fragment thereof selected from the group consisting of hPAM4, hA20, hA19, hLL2, hL243, hMN-14, hMN-15, hRS7, and hMN-3; and b) administering to the cancer cell an anti-PD1 checkpoint inhibitor antibody comprising the heavy chain CDR sequences GFAFSSNDMS (SEQ ID NO:42), TISGGGINTYYPDSVKG (SEQ ID NO:43) and RSNYAWFAY (SEQ ID NO:44) and the light chain CDR sequences RASESVDTYGISFMN (SEQ ID NO:45), PNQGS (SEQ ID NO:46) and QQSKEVPWT (SEQ ID NO:47). 2. The method of claim 1, wherein the anti-PD1 antibody increases the efficacy of the bispecific antibody. 3. The method of claim 1, wherein the anti-PD1 antibody is a chimeric antibody comprising the light chain amino acid sequence SEQ ID NO:40 and the heavy chain amino acid sequence SEQ ID NO:41. 4. The method of claim 1, wherein the anti-PD1 antibody is a humanized antibody comprising the light chain amino acid sequence SEQ ID NO:48 and the heavy chain amino acid sequence SEQ ID NO:49. 5. The method of claim 1, wherein the bispecific antibody is an anti-Trop-2.times.anti-CD3 bispecific antibody. 6. The method of claim 1, wherein the bispecific antibody comprises a humanized RS7 antibody or antigen-binding fragment thereof. 7. The method of claim 1, wherein the bispecific antibody comprises the amino acid sequence of SEQ ID NO:107. 8. The method of claim 1, wherein the bispecific antibody comprises at least one antibody fragment selected from the group consisting of a scFv, a Fab and a dAb. 9. The method of claim 1, wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia, acute myelogenous leukemia, biliary cancer, B-cell leukemia, B-cell lymphoma, biliary cancer, bone cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer glioma, hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma, liver cancer, lung cancer, medullary thyroid cancer, melanoma, multiple myeloma, ovarian cancer, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, renal cancer, sarcoma, testicular cancer, urothelial cancer, and urinary bladder cancer. 10. The method of claim 1, further comprising administering to the cancer cell a therapeutic agent selected from the group consisting of a second antibody or antigen-binding fragment thereof, a drug, a toxin, an enzyme, a cytotoxic agent, an anti-angiogenic agent, a pro-apoptotic agent, an antibiotic, a hormone, an immunomodulator, a cytokine, a chemokine, an antisense oligonucleotide, a small interfering RNA (siRNA), and a radioisotope. 11. The method of claim 10, wherein the drug is selected from the group consisting of 5-fluorouracil, afatinib, aplidin, azaribine, anastrozole, axitinib, AVL-101, AVL-291, bendamustine, bleomycin, bortezomib, bosutinib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celecoxib, chlorambucil, cisplatin (CDDP), Cox-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dasatinib, dinaciclib, docetaxel, dactinomycin, daunorubicin, doxorubicin, 2-pyrrolinodoxorubicine (2P-DOX), cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, erlotinib, estramustine, epipodophyllotoxin, erlotinib, entinostat, etoposide (VP16), etoposide glucuronide, etoposide phosphate, exemestane, fingolimod, floxuridine (FUdR), dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, farnesyl-protein transferase inhibitors, flavopiridol, fostamatinib, ganetespib, GDC-0834, GS-1101, gefitinib, gemcitabine, hydroxyurea, ibrutinib, idarubicin, idelalisib, ifosfamide, imatinib, L-asparaginase, lapatinib, lenolidamide, leucovorin, LFM-A13, lomustine, mechlorethamine, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, navelbine, neratinib, nilotinib, nitrosurea, olaparib, plicomycin, procarbazine, paclitaxel, PCI-32765, pentostatin, Pro-2-P-Dox, PSI-341, raloxifene, semustine, sorafenib, streptozocin, SU11248, sunitinib, tamoxifen, temazolomide, transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vatalanib, vinorelbine, vinblastine, vincristine, and ZD1839. 12. The method of claim 10, wherein the chemokine is selected from the group consisting of RANTES, MCAF, MIP1-alpha, MIP1-Beta and IP-10. 13. The method of claim 10, wherein the immunomodulator is selected from the group consisting of a stem cell growth factor, a lymphotoxin, a hematopoietic factor, a colony stimulating factor (CSF), and an interferon (IFN). 14. The method of claim 10, wherein the cytokine is selected from the group consisting of human growth hormone, N-methionyl human growth hormone, bovine growth hormone, parathyroid hormone, thyroxin, insulin, proinsulin, relaxin, prorelaxin, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), hepatic growth factor, prostaglandin, fibroblast growth factor, prolactin, placental lactogen, OB protein, tumor necrosis factor-.alpha., tumor necrosis factor-.beta., mullerian-inhibiting substance, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, integrin, thrombopoietin (TPO), NGF-.beta., platelet-growth factor, TGF-.alpha. (transforming growth factor-.alpha.), TGF-.beta., insulin-like growth factor-I, insulin-like growth factor-II, erythropoietin (EPO), an osteoinductive factor, interferon-.alpha., interferon-.beta., interferon-.lamda., macrophage-colony stimulating factor (M-CSF), granulocyte-macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF), interleukin-1 (IL-1), IL-1.alpha., IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-21, LIF, kit-ligand, FLT-3, angiostatin, thrombospondin, endostatin, tumor necrosis factor and LT (lymphotoxin). 15. The method of claim 1, wherein the bispecific antibody comprises (i) a first antibody moiety conjugated to an AD (anchoring domain) moiety from an AKAP protein; and (ii) a second antibody moiety conjugated to a DDD (dimerization and docking domain) moiety from protein kinase A (PKA) regulatory subunit RI.alpha., RI.beta., RII.alpha. or RII.beta.; wherein two copies of the DDD moiety form a dimer that binds to one copy of the AD moiety to form a complex. 16. An isolated anti-PD1 antibody comprising the heavy chain CDR sequences GFAFSSNDMS (SEQ ID NO:42), TISGGGINTYYPDSVKG (SEQ ID NO:43) and RSNYAWFAY (SEQ ID NO:44) and the light chain CDR sequences RASESVDTYGISFMN (SEQ ID NO:45), PNQGS (SEQ ID NO:46) and QQSKEVPWT (SEQ ID NO:47). 17. The anti-PD1 antibody of claim 16, wherein the antibody is a murine, chimeric, humanized or human antibody. 18. The anti-PD1 antibody of claim 16, wherein the antibody is a chimeric antibody comprising the light chain amino acid sequence SEQ ID NO:40 and the heavy chain amino acid sequence SEQ ID NO:41. 19. The anti-PD1 antibody of claim 16, wherein the antibody is a is a humanized antibody comprising the light chain amino acid sequence SEQ ID NO:48 and the heavy chain amino acid sequence SEQ ID NO:49. 20. A composition comprising an anti-PD1 antibody according to claim 16. 21. A kit comprising: a) an anti-PD1 antibody according to claim 16; and b) at least one container. 22. A method of treating a PD1-expressing cancer, comprising administering to a patient with cancer an anti-PD1 antibody according to claim 16.

Details for Patent 10,131,712

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2032-08-14
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2032-08-14