Antibodies which bind human cxcr3

Abstract

Antibodies and antigen-binding fragments of antibodies that bind human CXCR3 are disclosed. In preferred embodiments, the antibodies are human. Nucleic acids and vectors encoding the antibodies or portions thereof, recombinant cells that contain the nucleic acids, and compositions comprising the antibodies or antigen-binding fragments are also disclosed. The invention also provides therapeutic and diagnostic methods which employ the antibodies and antigen-binding fragments.

1 . A method for treating a subject having a disorder selected from the group consisting of an inflammatory disorder, an autoimmune disease, an allograft rejection and cancer, comprising administering to said subject an effective amount of an antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof binds a CXCR3 protein, and
 a) said antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising the amino acid sequences:
 HCDR1: SEQ ID NO: 4; 
 HCDR2: SEQ ID NO: 6; and 
 HCDR3: SEQ ID NO: 8; and 
    three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) comprising the amino acid sequences:
 LCDR1: SEQ ID NO: 12; 
 LCDR2: SEQ ID NO: 14; and 
 LCDR3: SEQ ID NO: 16; or 
   b) said antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising the amino acid sequences:
 HCDR1: SEQ ID NO: 20; 
 HCDR2: SEQ ID NO: 22; and 
 HCDR3: SEQ ID NO: 24; and 
    three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) comprising an amino acid sequences:
 LCDR1: SEQ ID NO: 28; 
 LCDR2: SEQ ID NO: 30; and 
 LCDR3: SEQ ID NO: 32. 
   
     
     
         2 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof:
 inhibits binding of a ligand to said CXCR3 protein;   inhibits a function of a CXCR3 protein selected from the group consisting of CXCR3 ligand-induced intracellular calcium release, CXCR3 ligand-induced chemotaxis, CXCR3 ligand-induced cell differentiation, CXCR3 ligand-induced cell proliferation and CXCR3 ligand-induced cell activation;   competitively inhibits binding of human monoclonal antibody 5H7 or human monoclonal antibody 7H5 to said CXCR3 protein; or   has the epitopic specificity of human monoclonal antibody 5H7 or human monoclonal antibody 7H5.   
     
     
         3 . The method of  claim 2 , wherein said CXCR3 ligand is selected from the group consisting of IP-10, MIG and I-TAC. 
     
     
         4 . The method of  claim 1 , wherein said antibody or antigen-binding fragment thereof is selected from the group consisting of a human antibody, an antigen-binding fragment of a human antibody, a humanized antibody, an antigen-binding fragment of a humanized antibody, a chimeric antibody and an antigen-binding fragment of a chimeric antibody. 
     
     
         5 . The method of  claim 1 , wherein said antigen-binding fragment is selected from the group consisting of an Fab fragment, an Fab′ fragment, an F(ab′) 2  fragment and an Fv fragment. 
     
     
         6 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof comprises
 a) a heavy chain variable region encoded by SEQ ID NO:1 and a light chain variable region encoded by SEQ ID NO:9, or   b) a heavy chain variable region encoded by SEQ ID NO:17, and a light chain variable region encoded by SEQ ID NO:25.   
     
     
         7 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof comprises
 a) a heavy chain variable region comprising SEQ ID NO:2 and a light chain variable region comprising SEQ ID NO:10, or   b) a heavy chain variable region comprising SEQ ID NO:18, and a light chain variable region comprising SEQ ID NO:26.   
     
     
         8 . The method of  claim 1 , wherein the antibody or antigen-binding portion thereof is an immunoconjugate. 
     
     
         9 . The method of  claim 8 , wherein said immunoconjugate comprises a therapeutic agent. 
     
     
         10 . The method of  claim 1 , wherein the inflammatory disease is ulcerative colitis. 
     
     
         11 . The method of  claim 1 , wherein the inflammatory disease is graft rejection. 
     
     
         12 . The method of  claim 1 , wherein the inflammatory disease is a respiratory inflammatory disease. 
     
     
         13 . The method of  claim 1 , wherein the autoimmune disease is multiple sclerosis. 
     
     
         14 . The method of  claim 1 , wherein the autoimmune disease is rheumatoid arthritis. 
     
     
         15 . A method for treating a subject having a disorder selected from the group consisting of an inflammatory disorder, an autoimmune disease, an allograft rejection and cancer an inflammatory disorder, comprising administering to said subject an effective amount of an antibody or antigen-binding fragment of an antibody selected from the group consisting of the antibody produced by hybridoma 5H7 (ATCC® Accession No. PTA-5388) and the antibody produced by hybridoma 7H5 (ATCC® Accession No. PTA-5389). 
     
     
         16 . The method of  claim 1 , wherein the heavy chain of the antibody comprises the immunoglobulin heavy chain or an antigen-binding portion thereof of the antibody produced by the hybridoma 5H7(ATCC® Accession No. PTA-5388) or of the antibody produced by hybridoma 7H5 (ATCC® Accession No. PTA-5389). 
     
     
         17 . The method of  claim 1 , wherein the light chain of the antibody comprises the immunoglobulin light chain or an antigen-binding portion thereof of the antibody produced by the hybridoma 5H7 (ATCC® Accession No. PTA-5388) or of the antibody produced by hybridoma 7H5 (ATCC® Accession No. PTA-5389). 
     
     
         18 . An isolated cell which produces an antibody or antigen-binding fragment, wherein the antibody or antigen-binding fragment thereof binds a CXCR3 protein, and
 a) said antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising the amino acid sequences:
 HCDR1: SEQ ID NO: 4; 
 HCDR2: SEQ ID NO: 6; and 
 HCDR3: SEQ ID NO: 8; and 
    three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) comprising the amino acid sequences:
 LCDR1: SEQ ID NO: 12; 
 LCDR2: SEQ ID NO: 14; and 
 LCDR3: SEQ ID NO: 16; or 
   b) said antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) comprising the amino acid sequences:
 HCDR1: SEQ ID NO: 20; 
 HCDR2: SEQ ID NO: 22; and 
 HCDR3: SEQ ID NO: 24; and 
    three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) comprising an amino acid sequences:
 LCDR1: SEQ ID NO: 28; 
 LCDR2: SEQ ID NO: 30; and 
 LCDR3: SEQ ID NO: 32. 
   
     
     
         19 . The isolated cell of  claim 18 , wherein the antibody or antigen-binding fragment thereof comprises
 a) a heavy chain variable region encoded by SEQ ID NO:1 and a light chain variable region encoded by SEQ ID NO:9, or   b) a heavy chain variable region encoded by SEQ ID NO:17, and a light chain variable region encoded by SEQ ID NO:25.   
     
     
         20 . The isolated cell of  claim 18 , wherein the antibody or antigen-binding fragment thereof comprises
 a) a heavy chain variable region comprising SEQ ID NO:2 and a light chain variable region comprising SEQ ID NO:10, or   b) a heavy chain variable region comprising SEQ ID NO:18, and a light chain variable region comprising SEQ ID NO:26.   
     
     
         21 . An isolated and/or recombinant nucleic acid comprising a nucleotide sequence that encodes an immunoglobulin heavy chain or antigen-binding portion thereof comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), wherein HCDR3 comprises an amino acid sequence selected from the group consisting of the amino acid sequence of SEQ ID NO: 8, the amino acid sequence of SEQ ID NO: 8 wherein one, two or three amino acid residues are conservatively substituted, the amino acid sequence of SEQ ID NO:24 and the amino acid sequence of SEQ ID NO: 24 wherein one, two or three amino acid residues are conservatively substituted, and
 wherein an antibody comprising said heavy chain or antigen-binding portion thereof and a complementary light chain or antigen-binding portion of a complementary light chain binds a CXCR3 protein.   
     
     
         22 . An expression construct comprising a recombinant nucleic acid that encodes an immunoglobulin heavy chain or antigen-binding portion thereof comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), wherein HCDR3 comprises an amino acid sequence selected from the group consisting of the amino acid sequence of SEQ ID NO: 8, the amino acid sequence of SEQ ID NO: 8 wherein one, two or three amino acid residues are conservatively substituted, the amino acid sequence of SEQ ID NO:24 and the amino acid sequence of SEQ ID NO: 24 wherein one, two or three amino acid residues are conservatively substituted, and
 wherein an antibody comprising said heavy chain or antigen-binding portion thereof and a complementary light chain or antigen-binding portion of a complementary light chain binds a CXCR3 protein.   
     
     
         23 . A host cell comprising a recombinant nucleic acid that encodes an immunoglobulin heavy chain or antigen-binding portion thereof comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), wherein HCDR3 comprises an amino acid sequence selected from the group consisting of the amino acid sequence of SEQ ID NO: 8, the amino acid sequence of SEQ ID NO: 8 wherein one, two or three amino acid residues are conservatively substituted, the amino acid sequence of SEQ ID NO:24 and the amino acid sequence of SEQ ID NO: 24 wherein one, two or three amino acid residues are conservatively substituted, and
 wherein an antibody comprising said heavy chain or antigen-binding portion thereof and a complementary light chain or antigen-binding portion of a complementary light chain binds a CXCR3 protein.   
     
     
         24 . An isolated cell that produces an immunoglobulin heavy chain or antigen-binding portion thereof comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), wherein HCDR3 comprises an amino acid sequence selected from the group consisting of the amino acid sequence of SEQ ID NO: 8, the amino acid sequence of SEQ ID NO: 8 wherein one, two or three amino acid residues are conservatively substituted, the amino acid sequence of SEQ ID NO:24 and the amino acid sequence of SEQ ID NO: 24 wherein one, two or three amino acid residues are conservatively substituted, and
 wherein an antibody comprising said heavy chain or antigen-binding portion thereof and a complementary light chain or antigen-binding portion of a complementary light chain binds a CXCR3 protein.   
     
     
         25 . An isolated and/or recombinant nucleic acid comprising a nucleotide sequence that encodes an immunoglobulin light chain or antigen-binding portion thereof comprising three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), wherein LCDR3 comprises an amino acid sequence selected from the group consisting of the amino acid sequence of SEQ ID NO: 16, the amino acid sequence of SEQ ID NO: 16 wherein one or two amino acid residues are conservatively substituted, the amino acid sequence of SEQ ID NO:32 and the amino acid sequence of SEQ ID NO: 32 wherein one or two amino acid residues are conservatively substituted, and
 wherein an antibody comprising said light chain or antigen-binding portion thereof and a complementary heavy chain or antigen-binding portion of a complementary light chain binds a CXCR3 protein.   
     
     
         26 . An expression construct comprising a recombinant nucleic acid that encodes an immunoglobulin light chain or antigen-binding portion thereof comprising three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), wherein LCDR3 comprises an amino acid sequence selected from the group consisting of the amino acid sequence of SEQ ID NO: 16, the amino acid sequence of SEQ ID NO: 16 wherein one or two amino acid residues are conservatively substituted, the amino acid sequence of SEQ ID NO:32 and the amino acid sequence of SEQ ID NO: 32 wherein one or two amino acid residues are conservatively substituted, and
 wherein an antibody comprising said light chain or antigen-binding portion thereof and a complementary heavy chain or antigen-binding portion of a complementary light chain binds a CXCR3 protein.   
     
     
         27 . A host cell comprising a recombinant nucleic acid that encodes an immunoglobulin light chain or antigen-binding portion thereof comprising three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), wherein LCDR3 comprises an amino acid sequence selected from the group consisting of the amino acid sequence of SEQ ID NO: 16, the amino acid sequence of SEQ ID NO: 16 wherein one or two amino acid residues are conservatively substituted, the amino acid sequence of SEQ ID NO:32 and the amino acid sequence of SEQ ID NO: 32 wherein one or two amino acid residues are conservatively substituted, and
 wherein an antibody comprising said light chain or antigen-binding portion thereof and a complementary heavy chain or antigen-binding portion of a complementary light chain binds a CXCR3 protein.   
     
     
         28 . An isolated cell that produces an immunoglobulin light chain or antigen-binding portion thereof comprising three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), wherein LCDR3 comprises an amino acid sequence selected from the group consisting of the amino acid sequence of SEQ ID NO: 16, the amino acid sequence of SEQ ID NO: 16 wherein one or two amino acid residues are conservatively substituted, the amino acid sequence of SEQ ID NO:32 and the amino acid sequence of SEQ ID NO: 32 wherein one or two amino acid residues are conservatively substituted, and
 wherein an antibody comprising said light chain or antigen-binding portion thereof and a complementary heavy chain or antigen-binding portion of a complementary light chain binds a CXCR3 protein.