Antibodies specific to human poliovirus receptor (pvr)

Abstract

The present invention provides monoclonal antibodies that recognize polio virus 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 - 50 . (canceled) 
     
     
         51 . A method of treating cancer, comprising administering to a subject in need thereof, a therapeutically effective amount of a pharmaceutical composition comprising at least one isolated monoclonal antibody or an antibody fragment, comprising 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   iii. 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).   
     
     
         52 . The method of  claim 51 , 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). 
     
     
         53 . The method of  claim 51 , 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). 
     
     
         54 . The method of  claim 51 , wherein the isolated monoclonal antibody is capable of inhibiting the binding of PVR to T cell immunoreceptor with Ig and ITIM domains (TIGIT). 
     
     
         55 . The method of  claim 51 , wherein the subject is a human subject. 
     
     
         56 . The method of  claim 51 , wherein the cancer overexpresses PVR. 
     
     
         57 . The method of  claim 51 , wherein the cancer is a solid cancer. 
     
     
         58 . The method of  claim 51 , wherein the cancer is a hematologic cancer. 
     
     
         59 . The method of  claim 51 , wherein the cancer is 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. 
     
     
         60 . The method of  claim 51 , wherein the monoclonal antibody is a chimeric antibody. 
     
     
         61 . The method of  claim 51 , wherein the monoclonal antibody is attached to a cytotoxic moiety, a radioactive moiety, or an identifiable moiety. 
     
     
         62 . The method of  claim 51 , further comprising an additional anti-cancer therapy selected from surgery, chemotherapy, radiotherapy, and immunotherapy. 
     
     
         63 . The method of  claim 51 , further comprising administering to said subject an additional immuno-modulator, activated lymphocyte cell, kinase inhibitor, chemotherapeutic agent or any other anti-cancer agent. 
     
     
         64 . The method of  claim 63 , 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. 
     
     
         65 . The method of  claim 63 , 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. 
     
     
         66 . The method of  claim 63 , 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. 
     
     
         67 . The method of  claim 51 , wherein treating results in preventing or reducing metastases formation, growth or spread in a subject. 
     
     
         68 . A method of diagnosing or prognosing cancer or infectious disease in a subject, the method comprising contacting a biological sample with an antibody or antibody fragment, comprising 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), WAS SRHP (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   iii. 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).   
     
     
         69 . The method of  claim 68 , further comprising determining the expression or activity of PVR in a sample from the subject and comparing the expression or activity of PVR to a reference amount obtained from a sample taken from a normal subject, from the same subject while being in a different stage of the disease or determined from clinical data of a large population of subjects. 
     
     
         70 . A method of treating a viral infection, comprising administering to a subject in need thereof, a therapeutically effective amount of a pharmaceutical composition comprising at least one antibody or antibody fragment comprising 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   iii. 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).   
     
     
         71 . The method of  claim 70 , wherein the virus is selected from the group consisting of: polio virus, coxsackie virus, adeno virus and human deficiency virus (HIV).