Antibodies specific to human poliovirus receptor (pvr)

Abstract

The present invention provides monoclonal antibodies that recognize poliovirus receptor (PVR) and inhibit its binding to T cell immunoreceptor with Ig and ITIM domains (TIGIT). The present invention further provides pharmaceutical compositions comprising the antibodies and methods for their use in cancer immunotherapy, treating infections and in diagnosis.

1 . A method of delivering an isolated monoclonal antibody or an antibody fragment thereof to a cell comprising contacting the cell with the isolated monoclonal antibody or antibody fragment thereof, wherein the isolated monoclonal antibody or antibody fragment thereof comprises a CDR set, the CDR set comprising a heavy chain (HC) CDR1, a heavy chain (HC) CDR2, a heavy chain (HC) CDR3, a light chain (LC) CDR1, a light chain (LC) CDR2, and a light chain (LC) CDR3 selected from the group consisting of:
 i. the HC CDR1 sequence comprises a sequence selected from the group consisting of GYTFSNYWIE (SEQ ID NO: 36) and SNYWIE (SEQ ID NO: 84); the HC CDR2 sequence comprises EIFPGSGRINFNEKFKG (SEQ ID NO: 38); the HC CDR3 sequence comprises TKIYGNSFDY (SEQ ID NO: 40); the LC CDR1 comprises a sequence selected from the group consisting of KASQDVGTAVV (SEQ ID NO: 44) and KASQDVGTAV (SEQ ID NO: 85); the LC CDR2 sequence comprises a sequence selected from the group consisting of: WASSRHN (SEQ ID NO: 46), WASSRHA (SEQ ID NO: 56), WASSRHR (SEQ ID NO: 57), WASSRHD (SEQ ID NO: 58), WASSRHE (SEQ ID NO: 59), WASSRHP (SEQ ID NO: 60), and WASSRHT (SEQ ID NO: 61); and the LC CDR3 sequence comprises QQYSRYPLT (SEQ ID NO: 48);   ii. the HC CDR1 sequence comprises a sequence selected from the group consisting of GFDFSRYW (SEQ ID NO: 4) and RYWMT (SEQ ID NO: 80); the HC CDR2 sequence comprises a sequence selected from the group consisting of EIHPDSSKINYTPSQ (SEQ ID NO: 6) and EIHPDSSKINYTPSQKD (SEQ ID NO: 81); the HC CDR3 sequence comprises a sequence selected from the group consisting of PDGNYNALDYW (SEQ ID NO: 8) and PDGNYNALDY (SEQ ID NO: 82); the LC CDR1 sequence comprises KASQDVGTAVT (SEQ ID NO: 12); LC CDR2 is WASTRHT (SEQ ID NO: 14); and the LC CDR3 sequence comprises QQYSRYPYT (SEQ ID NO: 16); and   iv. the HC CDR1 sequence comprises a sequence selected from the group consisting of GYTFTEYTMH (SEQ ID NO: 20) and EYTMH (SEQ ID NO: 83); the HC CDR2 sequence comprises GIDPNNGGTNYNQNFKG (SEQ ID NO: 22); the HC CDR3 sequence comprises VIPLEY (SEQ ID NO: 24); the LC CDR1 sequence comprises KASQNVYTNVA (SEQ ID NO: 28); the LC CDR2 sequence comprises SASYRYR (SEQ ID NO: 30); and the LC CDR3 sequence comprises QQYNSYPLA (SEQ ID NO: 32).   
     
     
         2 . The method of  claim 1 , wherein the HC CDR1 comprises the sequence SNYWIE (SEQ ID NO: 84); HC CDR2 comprises a sequence set forth in EIFPGSGRINFNEKFKG (SEQ ID NO: 38); and HC CDR3 comprises the sequence: TKIYGNSFDY (SEQ ID NO: 40). 
     
     
         3 . The method of  claim 2 , wherein the HC CDR1 sequence comprises GYTFSNYWIE (SEQ ID NO: 36); the HC CDR2 sequence comprises EIFPGSGRINFNEKFKG (SEQ ID NO: 38); the HC CDR3 comprises TKIYGNSFDY (SEQ ID NO: 40); the LC CDR1 sequence comprises KASQDVGTAVV (SEQ ID NO: 44); the LC CDR2 sequence comprises WASSRHE (SEQ ID NO: 59); and the LC CDR3 sequence comprises QQYSRYPLT (SEQ ID NO: 48). 
     
     
         4 . The method of  claim 1 , wherein the isolated monoclonal antibody is capable of inhibiting the binding of PVR to T cell immunoreceptor with Ig and ITIM domains (TIGIT). 
     
     
         5 . The method of  claim 1 , wherein the cells are tumor cells. 
     
     
         6 . The method of  claim 1 , comprising administering the isolated monoclonal antibody or antibody fragment thereof to cells of a subject. 
     
     
         7 . The method of  claim 6 , wherein the subject is a human subject. 
     
     
         8 . The method of  claim 6 , wherein the cells are of a cancer overexpressing PVR. 
     
     
         9 . The method of  claim 6 , wherein the cells are of a cancer selected from the group consisting of a melanoma, a breast cancer, an ovarian cancer, a pancreatic cancer, a colorectal cancer, a colon cancer, a cervical cancer, a kidney cancer, a lung cancer, a thyroid cancer, a prostate cancer, a brain cancer, a renal cancer, a throat cancer, a laryngeal carcinoma, a bladder cancer, a hepatic cancer, a fibrosarcoma, an endometrial cells cancer, a glioblastoma, sarcoma, a myeloid, a leukemia and a lymphoma. 
     
     
         10 . The method of  claim 6 , further comprising administering to said subject an additional immuno-modulator, activated lymphocyte cell, kinase inhibitor, chemotherapeutic agent or any other anti-cancer agent. 
     
     
         11 . The method of  claim 10 , wherein the additional immune-modulator is an antibody against an immune checkpoint molecule selected from the group consisting of PD-1, CTLA-4, PDL-1, CEACAM1, NKG2A, B7-H3, B7-H4, VISTA, CD112R, lymphocyte activation gene 3 (LAG3), CD137, OX40 (also referred to as CD134), killer cell immunoglobulin-like receptors (KIR), TIGIT, and any combination thereof. 
     
     
         12 . The method of  claim 10 , wherein the anti-cancer agent is selected from the group consisting of an anti PD-1 antibody, anti CTLA-1 antibody and an epidermal growth factor receptor (EGFR) inhibitor. 
     
     
         13 . The method of  claim 10 , wherein the anti-cancer agent is selected from the group consisting of: Erbitux, cytarabine, fludarabine, fluorouracil, mercaptopurine, methotrexate, thioguanine, gemcitabine, vincristine, vinblastine, vinorelbine, carmustine, lomustine, chlorambucil, cyclophosphamide, cisplatin, carboplatin, ifosfamide, mechlorethamine, melphalan, thiotepa, dacarbazine, bleomycin, dactinomycin, daunorubicin, doxorubicin, idarubicin, mitomycin, mitoxantrone, plicamycin, etoposide, teniposide and any combination thereof. 
     
     
         14 . The method of  claim 1 , wherein the monoclonal antibody is a chimeric antibody. 
     
     
         15 . The method of  claim 1 , wherein the monoclonal antibody is attached to a cytotoxic moiety, a radioactive moiety, or an identifiable moiety. 
     
     
         16 . An isolated monoclonal antibody or an antibody fragment thereof comprising a heavy chain variable region selected from the group consisting of SEQ ID NO: 34 and SEQ ID NO: 77, or an analog having at least 95% sequence similarity with said heavy chain variable region sequence, and a light chain variable sequence selected from the group consisting of SEQ ID NO: 42 and SEQ ID NO: 79, or an analog having at least 95% sequence similarity with said light chain variable region sequence. 
     
     
         17 . The isolated monoclonal antibody of  claim 16 , wherein the antibody is a chimeric antibody comprising a heavy chain variable region of SEQ ID NO: 77 and a light chain variable region of SEQ ID NO: 79. 
     
     
         18 . A method of delivering the isolated monoclonal antibody or an antibody fragment thereof of  claim 16  to a cell of a subject, said method comprising administering the isolated monoclonal antibody to the subject.