Anti-ASIC1 Antibodies and Uses Thereof

Abstract

The present invention provides antibodies and antigen-binding fragments thereof that specifically bind to cells expressing acid-sensing ion channel-1 (ASIC1). According to certain embodiments of the invention, the antibodies inhibit acid-induced, ASIC1-mediated ion currents in cells expressing human ASIC1. The antibodies of the invention are useful for the treatment of pain, including pain associated with surgical intervention and various diseases and disorders.

What is claimed is: 
     
         1 . An isolated antibody or antigen-binding fragment thereof that specifically binds cell surface-expressed acid sensing ion channel 1 (ASIC1) (SEQ ID NO:401). 
     
     
         2 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment thereof specifically binds cell surface-expressed ASIC1 with an EC 50  of 1 nM or less as measured using fluorescence activated cell sorting (FACS). 
     
     
         3 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody or antigen-binding fragment thereof inhibits acid-induced, ASIC1-mediated ion currents in cells expressing human ASIC1. 
     
     
         4 . The antibody or antigen-binding fragment of  claim 3 , wherein the antibody or antigen-binding fragment thereof inhibits acid-induced cellular calcium flux in cells expressing ASIC1 at pH of about 5.0 to about 6.0 with an IC 50  of 6 nM or less as measured using a FLIPR assay. 
     
     
         5 . The antibody or antigen-binding fragment of  claim 3 , wherein the antibody or antigen-binding fragment thereof inhibits acid-induced ion currents at pH of about 5.0 to about 6.0 with an IC 50  of 10 nM or less as measured using a patch-clamp assay. 
     
     
         6 . The antibody or antigen-binding fragment of  claim 5 , wherein the antibody or antigen-binding fragment thereof comprises: (a) three 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, 34, 50, 66, 114, 130, 146, 162, 194, 210, 242, 258, and 274; and (b) three CDRs of a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 42, 58, 74, 122, 138, 154, 170, 202, 218, 250, 266, and 282. 
     
     
         7 . The antibody or antigen-binding fragment of  claim 6 , wherein the antibody or antigen-binding fragment thereof comprises a HCVR/LCVR amino acid sequence pair selected from the group consisting of: SEQ ID NOs: 2/10; 34/42; 50/58; 66/74; 114/122; 130/138; 146/154; 162/170; 194/202; 210/218; 242/250; 258/266; and 274/282. 
     
     
         8 . The antibody or antigen-binding fragment of  claim 7 , wherein the antibody or antigen-binding fragment thereof comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains, respectively, selected from the group consisting of: SEQ ID NOs: 4-6-8-12-14-16; 36-38-40-44-46-48; 52-54-56-60-62-64; 68-70-72-76-78-80; 116-118-120-124-126-128; 132-134-136-140-142-144; 148-150-152-156-158-160; 164-166-168-172-174-176; 196-198-200-204-206-208; 212-214-216-220-222-224; 244-246-248-252-254-256; 260-262-264-268-270-272; and 276-278-280-284-286-288.