Antagonists of protease activated receptor-1 (par1)

Abstract

The present invention provides antibodies or antigen-binding molecules that specifically recognize and antagonize human PAR1 receptor. Also provided in the invention are polynucleotides and vectors that encode such molecules and host cells that harbor the polynucleotides or vectors.

1 . An antibody or antigen binding molecule that specifically binds to an epitope of human PAR1, wherein the epitope comprises the amino acid sequence SFLLRNPNDKYEPFWEDEEKNESGLTE (SEQ ID NO:38), and wherein the antibody or antigen binding molecule is a PAR1 antagonist. 
     
     
         2 . The antibody or antigen-binding molecule of  claim 1  which comprises a heavy chain complementarity determining region (CDR) sequence of SEQ ID NO:21, SEQ ID NO:22 or SEQ ID NO:23; or a light chain CDR sequence of SEQ ID NO:24, SEQ ID NO:25, or SEQ ID NO:26. 
     
     
         3 . The antibody or antigen-binding molecule of  claim 1  which comprises a heavy chain complementarity determining region (CDR) sequence of SEQ ID NO:27, SEQ ID NO:28 or SEQ ID NO:29; or a light chain CDR sequence of SEQ ID NO:30, SEQ ID NO:31, or SEQ ID NO:32. 
     
     
         4 . The antibody or antigen-binding molecule of  claim 1  which comprises (i) a heavy chain variable region amino acid sequence that is at least 85% identical to SEQ ID NO:5 and a light chain variable region amino acid sequence that is at least 85% identical to SEQ ID NO:6, or (ii) a heavy chain variable region amino acid sequence that is at least 85% identical to SEQ ID NO:7 and a light chain variable region amino acid sequence that is at least 85% identical to SEQ ID NO:8. 
     
     
         5 . The antibody or antigen-binding molecule of  claim 1  which comprises (i) a heavy chain variable region amino acid sequence of SEQ ID NO:5 and a light chain variable region amino acid sequence of SEQ ID NO:6, or (ii) a heavy chain variable region amino acid sequence of SEQ ID NO:7 and a light chain variable region amino acid sequence of SEQ ID NO:8. 
     
     
         6 . An isolated or recombinant polynucleotide which encodes an antibody or antigen binding molecule that specifically binds to an epitope of human PAR1, wherein the epitope comprises the amino acid sequence SFLLRNPNDKYEPFWEDEEKNESGLTE (SEQ ID NO:38), and wherein the antibody or antigen binding molecule is a PAR1 antagonist. 
     
     
         7 . The polynucleotide of  claim 6 , wherein the antibody or antigen-binding molecule comprises (i) heavy chain CDR1, CDR2, and CDR3 sequences, SEQ ID NO:21, SEQ ID NO:22 and SEQ ID NO:23, respectively; and light chain CDR1, CDR2, and CDR3 sequences, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; or (ii) heavy chain CDR1, CDR2, and CDR3 sequences, SEQ ID NO:27, SEQ ID NO:28 and SEQ ID NO:29, respectively; and light chain CDR1, CDR2, and CDR3 sequences, SEQ ID NO:30, SEQ ID NO:31, and SEQ ID NO:32, respectively. 
     
     
         8 . The polynucleotide of  claim 6 , wherein the antibody or antigen-binding molecule comprises (i) a mature heavy chain variable region sequence that is at least 90% identical to the mature region of SEQ ID NO:5, and a mature light chain variable region sequence that is at least 90% identical to the mature region of SEQ ID NO:6; or (ii) a mature heavy chain variable region amino acid sequence that is at least 90% identical to SEQ ID NO:7 and a mature light chain variable region amino acid sequence that is at least 90% identical to SEQ ID NO:8. 
     
     
         9 . The polynucleotide of  claim 6 , wherein the antibody or antigen-binding molecule comprises (i) a mature heavy chain variable region sequence that is identical to the mature region of SEQ ID NO:5 and a mature light chain variable region sequence that is identical to the mature region of SEQ ID NO:6; or (ii) a mature heavy chain variable region sequence that is identical to the mature region of SEQ ID NO:7 and a mature light chain variable region sequence that is identical to the mature region of SEQ ID NO:8. 
     
     
         10 . The polynucleotide of  claim 6  which is a DNA. 
     
     
         11 . An isolated host cell comprising (1) a recombinant DNA segment encoding a heavy chain of the antibody or antigen-binding molecule of  claims 1 , and (2) a second recombinant DNA segment encoding a light chain of the antibody or antigen-binding molecule; wherein said DNA segments are respectively operably linked to a first and a second promoter, and are capable of being expressed in said host cell. 
     
     
         12 . The host cell of  claim 11 , wherein the antibody or antigen-binding molecule comprises (i) heavy chain CDR1, CDR2, and CDR3 sequences, SEQ ID NO:21, SEQ ID NO:22 and SEQ ID NO:23, respectively; and light chain CDR1, CDR2, and CDR3 sequences, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively; or (ii) heavy chain CDR1, CDR2, and CDR3 sequences, SEQ ID NO:27, SEQ ID NO:28 and SEQ ID NO:29, respectively; and light chain CDR1, CDR2, and CDR3 sequences, SEQ ID NO:30, SEQ ID NO:31, and SEQ ID NO:32, respectively. 
     
     
         13 . The host cell of  claim 11 , wherein the antibody or antigen-binding molecule comprises (i) a mature heavy chain variable region sequence that is at least 90% identical to the mature region of SEQ ID NO:5, and a mature light chain variable region sequence that is at least 90% identical to the mature region of SEQ ID NO:6; or (ii) a mature heavy chain variable region amino acid sequence that is at least 90% identical to SEQ ID NO:7 and a mature light chain variable region amino acid sequence that is at least 90% identical to SEQ ID NO:8. 
     
     
         14 . The host cell of  claim 11 , wherein the antibody or antigen-binding molecule comprises (i) a mature heavy chain variable region sequence that is identical to the mature region of SEQ ID NO:5 and a mature light chain variable region sequence that is identical to the mature region of SEQ ID NO:6; or (ii) a mature heavy chain variable region sequence that is identical to the mature region of SEQ ID NO:7 and a mature light chain variable region sequence that is identical to the mature region of SEQ ID NO:8. 
     
     
         15 . A pharmaceutical composition comprising an antibody or antigen binding molecule that specifically binds to an epitope of human PAR1, wherein the epitope comprises the amino acid sequence SFLLRNPNDKYEPFWEDEEKNESGLTE (SEQ ID NO:38), and wherein the antibody or antigen binding molecule is a PAR1 antagonist. 
     
     
         16 . A method of amelioriating the symptoms of a disease condition mediated by aberrant intracellular signaling through PAR1 comprising administering to a subject in need thereof an antibody or antigen binding molecule that specifically binds to an epitope of human PAR1, wherein the epitope comprises the amino acid sequence SFLLRNPNDKYEPFWEDEEKNESGLTE (SEQ ID NO:38), and wherein the antibody or antigen binding molecule is a PAR1 antagonist. 
     
     
         17 . The method of  claim 16 , comprising administering an antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences, SEQ ID NO:21, SEQ ID NO:22 and SEQ ID NO:23, respectively; and light chain CDR1, CDR2, and CDR3 sequences, SEQ ID NO:24, SEQ ID NO:25, and SEQ ID NO:26, respectively. 
     
     
         18 . The method of  claim 16 , comprising administering an antibody comprising an antibody comprising heavy chain CDR1, CDR2, and CDR3 sequences, SEQ ID NO:27, SEQ ID NO:28 and SEQ ID NO:29, respectively; and light chain CDR1, CDR2, and CDR3 sequences, SEQ ID NO:30, SEQ ID NO:31, and SEQ ID NO:32, respectively. 
     
     
         19 . The method of  claim 16 , wherein the disease condition mediated by aberrant intracellular signaling through PAR1 is a chronic intestinal inflammatory disorder, a fibrotic disorder, a cancer that overexpresses PAR1, or ischemia-reperfusion injury.