Anti-prokineticin receptor (prokr) antibodies and uses thereof

Abstract

The present invention provides antibodies that bind to prokineticin receptors (PROKRs) and methods of using same. According to certain embodiments of the invention, the antibodies are fully human antibodies that bind to human PROKR1 and/or PROKR2. The present invention includes antibodies that bind cell surface-expressed PROKR1 and/or PROKR2. In certain embodiments, the antibodies of the present invention are capable of blocking prokineticin (PK)-mediated activation of one or more PROKR. The antibodies of the invention are useful for the treatment of various diseases and disorders mediated by prokineticin signaling.

What is claimed is: 
     
         1 . An isolated antibody or antigen-binding fragment thereof that specifically binds a prokineticin receptor (PROKR) and blocks prokineticin-mediated activation of the PROKR. 
     
     
         2 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment thereof specifically binds cell surface-expressed PROKR1. 
     
     
         3 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment thereof specifically binds cell surface-expressed PROKR2. 
     
     
         4 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment thereof specifically binds cell surface-expressed PROKR1 and cell surface-expressed PROKR2. 
     
     
         5 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment thereof specifically binds cell surface-expressed PROKR1 but does not bind cell surface-expressed PROKR2. 
     
     
         6 . The antibody of antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment thereof blocks prokineticin-1 (PK1)-mediated activation of PROKR1. 
     
     
         7 . The antibody of antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment thereof blocks prokineticin-2 (PK2)-mediated activation of PROKR1. 
     
     
         8 . The antibody of antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment thereof blocks prokineticin-1 (PK1)-mediated activation of PROKR1 and prokineticin-2 (PK2)-mediated activation of PROKR1. 
     
     
         9 . The antibody or antigen-binding fragment of  claim 6 , wherein the antibody or antigen-binding fragment thereof blocks PK1-mediated activation of PROKR1 with an IC 50  of less than 20 nM, as measured in a calcium mobilization assay using PROKR1-expressing cells stimulated with 1 to 20 nM PK1 in vitro. 
     
     
         10 . The antibody or antigen-binding fragment of  claim 9 , wherein the antibody or antigen-binding fragment thereof blocks PK1-mediated activation of PROKR1 with an IC 50  of less than 10 nM, as measured in a calcium mobilization assay using PROKR1-expressing cells stimulated with 1 to 20 nM PK1 in vitro. 
     
     
         11 . The antibody or antigen-binding fragment of  claim 7 , wherein the antibody or antigen-binding fragment thereof blocks PK2-mediated activation of PROKR1 with an IC 50  of less than 60 nM, as measured in a calcium mobilization assay using PROKR1-expressing cells stimulated with 1 to 20 nM PK2 in vitro. 
     
     
         12 . The antibody or antigen-binding fragment of  claim 11 , wherein the antibody or antigen-binding fragment thereof blocks PK2-mediated activation of PROKR1 with an IC 50  of less than 20 nM, as measured in a calcium mobilization assay using PROKR1-expressing cells stimulated with 1 to 20 nM PK2 in vitro. 
     
     
         13 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment thereof competes for binding to cell surface-expressed PROKR1 or to cell surface-expressed PROKR2 with a reference antibody comprising an HCVR/LCVR sequence pair selected from the group consisting of SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/122, 130/138, 146/154, and 162/170. 
     
     
         14 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment comprises: (a) the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, 114, 130, 146, and 162; and (b) the CDRs of a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 122, 138, 154, and 170. 
     
     
         15 . The isolated antibody or antigen-binding fragment of  claim 14 , wherein the antibody or antigen-binding fragment comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair selected from the group consisting of: SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/122, 130/138, 146/154, and 162/170. 
     
     
         16 . The isolated antibody or antigen-binding fragment of  claim 15 , wherein the antibody or antigen-binding fragment comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains, respectively, selected from the group consisting of: SEQ ID NOs: 4-6-8-12-14-16; 20-22-24-28-30-32; 36-38-40-44-46-48; 52-54-56-60-62-64; 68-70-72-76-78-80; 84-86-88-92-94-96; 100-102-104-108-110-112; 116-118-120-124-126-128; 132-134-136-140-142-144; 148-150-152-156-158-160; and 164-166-168-172-174-176. 
     
     
         17 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, 114, 130, 146, and 162; and (b) a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 122, 138, 154, and 170. 
     
     
         18 . The isolated antibody or antigen-binding fragment of  claim 17 , wherein the antibody or antigen-binding fragment comprises a HCVR/LCVR amino acid sequence pair selected from the group consisting of: SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/122, 130/138, 146/154, and 162/170. 
     
     
         19 . A pharmaceutical composition comprising the antibody or antigen-binding fragment of  claim 18 , and a pharmaceutically acceptable carrier or diluent. 
     
     
         20 . A method for treating or attenuating pain, the method comprising administering the pharmaceutical composition of  claim 19  to a subject in need thereof. 
     
     
         21 . The method of  claim 20 , wherein the pain is nociceptive pain, visceral pain, or inflammatory pain. 
     
     
         22 . The method of  claim 21 , wherein the pain is associated with a condition selected from the group consisting of inflammation, post-operative incision, neuropathy, bone fracture, burn, osteoporotic fracture, bone cancer, gout, migraine headache, and fibromyalgia. 
     
     
         23 . The method of  claim 20 , wherein the pain is cancer-associated pain.