Method of inhibiting leukocytes with human cxc chemokine receptor 3 antibody

Abstract

The present invention relates to proteins or polypeptides, referred to herein as isolated and/Or recombinant mammalian (e.g., human) IP-10/Mig receptor proteins designated CXC Chemokine Receptor 3 (CXCR3) and variants thereof, including those characterized by selective binding of one or more chemokines (e.g., IP-10 and/or Mig), and/or the ability to induce a cellular response (e.g., chemotaxis, exocytosis). Antibodies reactive with CXCR3 receptors can be produced using the proteins or variants thereof or host cells comprising same as immunogen.

1 . A method of inhibiting receptor function in an individual, comprising administering to said individual an effective amount of an antibody or antigen-binding fragment thereof which binds a human CXC Chemokine Receptor 3 (CXCR3) protein having the amino acid sequence of SEQ ID NO:2, wherein said antibody or antigen-binding fragment desensitizes CXCR3. 
     
     
         2 . The method of  claim 1 , wherein said antibody or antigen-binding fragment inhibits T cell activation. 
     
     
         3 . The method of  claim 1 , wherein an antigen-binding fragment is administered, and said antigen-binding fragment is selected from the group consisting of a Fab fragment, a Fab′ fragment, a F(ab′) 2  fragment and a Fv fragment. 
     
     
         4 . The method of  claim 1 , wherein said antibody or antigen-binding fragment is selected from the group consisting of a human antibody or antigen-binding fragment thereof, a humanized antibody or antigen-binding fragment thereof, and a chimeric antibody or antigen-binding fragment thereof. 
     
     
         5 . The method of  claim 1 , wherein binding of said antibody or antigen-binding fragment to human CXCR3 is inhibited by a portion of a human CXCR3 corresponding to the N-terminal extracellular segment of SEQ ID NO:2. 
     
     
         6 . The method of  claim 1 , wherein binding of said antibody or antigen-binding fragment to human CXCR3 protein is inhibited by a polypeptide having a sequence which is the same as that of residues 1-15 of SEQ ID NO:2. 
     
     
         7 . The method of  claim 1 , wherein binding of said antibody or antigen-binding fragment to human CXCR3 protein is inhibited by a polypeptide having a sequence which is the same as that of residues 16-30 of SEQ ID NO:2. 
     
     
         8 . The method of  claim 1 , wherein binding of said antibody or antigen-binding fragment to human CXCR3 protein is inhibited by a polypeptide having a sequence which is the same as that of residues 45-58 of SEQ ID NO:2. 
     
     
         9 . The method of  claim 1 , wherein said antibody or antigen-binding fragment also inhibits binding of a ligand to said human CXCR3 protein. 
     
     
         10 . The method of  claim 9 , wherein said ligand is selected from the group consisting of IP-10 and Mig. 
     
     
         11 . A method of inhibiting T cell activation in an individual, comprising administering to said individual an effective amount of an antibody or antigen-binding fragment thereof which binds human CXC Chemokine Receptor 3 (CXCR3) protein having the amino acid sequence of SEQ ID NO:2. 
     
     
         12 . The method of  claim 11 , wherein an antigen-binding fragment is administered, and said antigen-binding fragment is selected from the group consisting of a Fab fragment, a Fab′ fragment, a F(ab′) 2  fragment and a Fv fragment. 
     
     
         13 . The method of  claim 11 , wherein said antibody or antigen-binding fragment is selected from the group consisting of a human antibody or antigen-binding fragment thereof, a humanized antibody or antigen-binding fragment thereof, and a chimeric antibody or antigen-binding fragment thereof. 
     
     
         14 . The method of  claim 11 , wherein binding of said antibody or antigen-binding fragment to human CXCR3 is inhibited by a portion of a human CXCR3 corresponding to the N-terminal extracellular segment of SEQ ID NO:2 or a portion thereof having at least one immunological property of a human CXCR3 protein. 
     
     
         15 . The method of  claim 11 , wherein binding of said antibody or antigen-binding fragment to human CXCR3 protein is inhibited by a polypeptide having a sequence which is the same as that of residues 1-15 of SEQ ID NO:2. 
     
     
         16 . The method of  claim 11 , wherein binding of said antibody or antigen-binding fragment to human CXCR3 protein is inhibited by a polypeptide having a sequence which is the same as that of residues 16-30 of SEQ ID NO:2. 
     
     
         17 . The method of  claim 11 , wherein binding of said antibody or antigen-binding fragment to human CXCR3 protein is inhibited by a polypeptide having a sequence which is the same as that of residues 45-58 of SEQ ID NO:2. 
     
     
         18 . A method of inhibiting a function associated with T-cell activation, selected from the group consisting of cytokine production, cytotoxic T cell killing, and provision of T cell help, comprising administering to said individual an effective amount of an antibody or antigen-binding fragment thereof which binds CXC Chemokine Receptor 3 (CXCR3) protein having the amino acid sequence of SEQ ID NO:2. 
     
     
         19 . A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof which binds human CXC Chemokine Receptor 3 (CXCR3) protein having the amino acid sequence of SEQ ID NO:2 and a parenteral or intravenous vehicle. 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein said parenteral vehicle is selected from the group consisting of sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. 
     
     
         21 . A method of antitumor therapy, comprising administering to a mammal a therapeutically effective amount of a promoter of a mammalian CXCR3 protein, other than a natural ligand of said protein. 
     
     
         22 . A method of antiviral therapy, comprising administering to a mammal a therapeutically effective amount of a promoter of a mammalian CXCR3 protein, other than a natural ligand of said protein. 
     
     
         23 . An antisense nucleic acid comprising a nucleic acid having a sequence that hybridizes to a nucleic acid having the sequence:
 a) SEQ ID NO:1,   b) a portion thereof comprising the coding sequence,   c) or an RNA counterpart of any one of (a) and (b).   
     
     
         24 . A method for diagnosing a condition characterized by an increased level of activated T cells comprising providing a sample obtained from an individual;
 combining the sample and an antibody that binds human CXCR3 and quantifying cells that express CXCR3,   wherein an increased level of cells that express CXCR3 relative to a suitable control is indicative of said condition.   
     
     
         25 . The method of  claim 24 , wherein said condition is selected from the group consisting of delayed type hypersensitivity reaction, allograft rejection, and a pathological condition. 
     
     
         26 . The method of  claim 24 , wherein said quantifying comprises the method of flow cytometry.