C-C chemokine receptor 3 proteins

Abstract

The present invention relates to methods of inhibiting a mammalian C-C chemokine receptor 3 protein (CCR3). The invention further relates to methods of treating an inflammatory disease or condition. Administration of a compound which inhibits or promotes CCR3 function to an individual in need of therapy provides a new approach to selective modulation of leukocyte function, which is useful in a variety of inflammatory and autoimmune diseases, or in the treatment of infections. As a major leukocyte chemokine receptor present in leukocytes such as eosinophils and lymphocytes, the receptor provides a key target for drug screening and design.

1 . A method of inhibiting a mammalian C-C chemokine receptor 3 protein (CCR3), comprising the step of contacting said CCR3 with an inhibitor of said CCR3 in an amount sufficient to inhibit at least one function of said CCR3. 
     
     
         2 . The method of  claim 1 , wherein said CCR3 has at least about 95% amino acid sequence identity with SEQ ID NO:2 or SEQ ID NO:6. 
     
     
         3 . The method of  claim 2 , wherein the amino acid sequence of said CCR3 is SEQ ID NO:2. 
     
     
         4 . The method of  claim 2 , wherein the amino acid sequence of said CCR3 is SEQ ID NO:6. 
     
     
         5 . The method of  claim 1 , wherein said CCR3 binds a natural ligand selected from the group consisting of eotaxin, RANTES and MCP-3. 
     
     
         6 . The method of  claim 1 , wherein said inhibitor is an antibody or antigen-binding fragment thereof that has binding specificity for said CCR3 and inhibits binding of a ligand to said CCR3. 
     
     
         7 . The method of  claim 6 , wherein said antibody or antigen-binding fragment competes with monoclonal antibody 7B11 for binding to said CCR3 or a portion thereof. 
     
     
         8 . The method of  claim 6 , wherein said antibody or antigen-binding fragment is monoclonal antibody 7B11 or an antigen-binding fragment thereof. 
     
     
         9 . The method of  claim 1 , wherein said at least one function of said CCR3 is selected from the group consisting of binding to a natural ligand, signaling upon binding to a natural ligand and stimulation of a cellular response upon binding to a natural ligand. 
     
     
         10 . The method of  claim 9 , wherein said signaling is activation of a G protein or induction of a rapid and transient increase in the concentration of cytosolic free calcium ([Ca 2+ ] i ), and said cellular response is chemotaxis, exocytosis, inflammatory mediator release or integrin activation. 
     
     
         11 . A method of treating an inflammatory disease or condition, comprising the step of administering to a mammal in need thereof an effective amount of an inhibitor of a mammalian C-C chemokine receptor 3 protein (CCR3). 
     
     
         12 . The method of  claim 11 , wherein said CCR3 has at least about 95% amino acid sequence identity with SEQ ID NO:2 or SEQ ID NO:6. 
     
     
         13 . The method of  claim 11 , wherein said CCR3 binds a natural ligand selected from the group consisting of eotaxin, RANTES and MCP-3. 
     
     
         14 . The method of  claim 11 , wherein said inhibitor is an antibody or antigen-binding fragment thereof that has binding specificity for said CCR3 and inhibits binding of a ligand to said CCR3. 
     
     
         15 . The method of  claim 14 , wherein said antibody or antigen-binding fragment competes with monoclonal antibody 7B11 for binding to said CCR3 or a portion thereof. 
     
     
         16 . The method of  claim 14 , wherein said antibody or antigen-binding fragment is monoclonal antibody 7B11 or an antigen-binding fragment thereof. 
     
     
         17 . The method of  claim 11 , wherein an inflammatory response selected from the group consisting of leukocyte emigration, chemotaxis, exocytosis, inflammatory mediator release and integrin activation is inhibited. 
     
     
         18 . The method of  claim 11 , wherein said inflammatory disease or condition is selected from the group consisting of an allergic disease or condition, an autoimmune disease, and graft rejection. 
     
     
         19 . The method of  claim 11 , wherein said inflammatory disease or condition is asthma or allergic hypersensitivity. 
     
     
         20 . The method of  claim 11 , wherein said mammal is a human.