Anti-CCR4 antibodies and methods of use therefor

Abstract

The present invention relates to an antibody or functional fragment thereof which binds to a mammalian (e.g., human) CC-chemokine receptor 4 (CCR4) or a portion of the receptor and blocks binding of a ligand to the receptor. The invention further relates to a method of inhibiting the interaction of a cell bearing mammalian CCR4 with a ligand thereof, and to use of the antibodies and fragments in research, therapeutic, prophylactic and diagnostic methods.

1 - 45 . (canceled)  
     
     
         46 . An antibody or antigen-binding fragment thereof which binds to a mammalian CC-chemokine receptor 4 (CCR4) or a portion of said receptor, wherein said antibody or antigen-binding fragment thereof comprises one or more antigen-binding regions of monoclonal antibody 10E4, and wherein said antibody or antigen-binding fragment thereof is selected from the group consisting of: 
 a) a human antibody;    b) a humanized antibody;    c) a chimeric antibody; and    d) a recombinant antibody.    
     
     
         47 . The antibody or antigen-binding fragment thereof according to  claim 46 , wherein said antibody or antigen-binding fragment thereof inhibits one or more functions associated with binding of a ligand to the mammalian CCR4.  
     
     
         48 . The antibody or antigen-binding fragment thereof according to  claim 47 , wherein said one or more functions associated with binding of a ligand to the mammalian CCR4 is selected from the group consisting of a signaling activity and stimulation of at least one cellular response.  
     
     
         49 . The antibody or antigen-binding fragment thereof according to  claim 48 , wherein the signaling activity is selected from the group consisting of: 
 a) activation of a G protein; and    b) induction of an increase in the concentration of cytosolic free calcium.    
     
     
         50 . The antibody or antigen-binding fragment thereof according to  claim 48 , wherein the at least one cellular response is selected from the group consisting of: 
 a) stimulation of chemotaxis;    b) exocytosis;    c) release of at least one inflammatory mediator;    d) activation of an integrin; and    e) T cell activation.    
     
     
         51 . The antibody or antigen-binding fragment thereof according to  claim 47 , wherein said ligand is a chemokine.  
     
     
         52 . The antibody or antigen-binding fragment thereof according to  claim 51 , wherein said chemokine is TARC or MDC.  
     
     
         53 . The antibody or antigen-binding fragment thereof according to  claim 46 , wherein the antigen-binding fragment is selected from the group consisting of an Fv fragment, an Fab fragment, an Fab′ fragment and an F(ab′) 2  fragment.  
     
     
         54 . The antibody or antigen-binding fragment thereof according to  claim 46 , wherein said mammalian CCR4 is a human CCR4.  
     
     
         55 . A test kit for use in detecting the presence of a mammalian CC-chemokine receptor 4 (CCR4) or a portion thereof in a biological sample comprising: 
 a) at least one antibody or antigen-binding fragment thereof which binds to a mammalian CC-chemokine receptor 4 (CCR4) or a portion of said receptor, wherein said antibody or antigen-binding fragment thereof comprises one or more antigen-binding regions of monoclonal antibody 10E4, and wherein said antibody is selected from the group consisting of: 
 i) a human antibody;  
 ii) a humanized antibody;  
 iii) a chimeric antibody; and  
 iv) a recombinant antibody; and  
   b) one or more ancillary reagents suitable for detecting the presence of a complex between said antibody or antigen-binding fragment thereof and said mammalian CCR4 or a portion thereof.    
     
     
         56 . A composition comprising at least one antibody or antigen-binding fragment thereof and optionally a physiologically acceptable carrier, wherein said antibody or antigen-binding fragment thereof binds to a mammalian CC-cbemokine receptor 4 (CCR4) or a portion of said receptor, and wherein said antibody or antigen-binding fragment thereof comprises one or more antigen-binding regions of monoclonal antibody 10E4, and wherein said antibody is selected from the group consisting of: 
 a) a human antibody;    b) a humanized antibody;    c) a chimeric antibody; and    d) a recombinant antibody.    
     
     
         57 . The composition according to  claim 56 , wherein the antigen-binding fragment is selected from the group consisting of an Fv fragment, an Fab fragment, an Fab′ fragment and an F(ab′) 2  fragment.  
     
     
         58 . The composition according to  claim 56 , wherein said antibody or antigen-binding fragment thereof inhibits one or more functions associated with binding of a ligand to the mammalian CCR4.  
     
     
         59 . A method of inhibiting a function associated with binding of a chemokine to a mammalian CC-chemokine receptor 4 (CCR4) or a functional portion of said receptor, comprising contacting a composition comprising the receptor or portion of said receptor with an effective amount of an antibody or antigen-binding fragment thereof which binds to a mammalian CCR4 or portion of said receptor, wherein said antibody or antigen-binding fragment thereof inhibits binding of said chemokine to the mammalian CCR4 and inhibits one or more functions associated with binding of the chemokine to the receptor, and wherein said antibody or antigen-binding fragment thereof comprises one or more antigen-binding regions of monoclonal antibody 10E4, monoclonal antibody 1G1 or monoclonal antibody 2B10, and wherein said antibody is selected from the group consisting of: 
 a) a human antibody;    b) a humanized antibody;    c) a chimeric antibody; and    d) a recombinant antibody.    
     
     
         60 . The method according to  claim 59 , wherein said chemokine is TARC or MDC.  
     
     
         61 . The method according to  claim 59 , wherein said one or more functions associated with binding of the chemokine to the mammalian CCR4 is selected from the group consisting of a signaling activity and stimulation of at least one cellular response.  
     
     
         62 . The method according to  claim 59 , wherein said mammalian CCR4 is a human CCR4.  
     
     
         63 . A method of inhibiting leukocyte trafficking in a patient, comprising administering to the patient a composition comprising an effective amount of an antibody or antigen-binding fragment thereof which binds to a mammalian CC-chemokine receptor 4 (CCR4) or portion of said receptor and inhibits binding of a ligand to the receptor, wherein said antibody or antigen-binding fragment thereof comprises one or more antigen-binding regions of monoclonal antibody 10E4, monoclonal antibody 1G1 or monoclonal antibody 2B10, and wherein said antibody is selected from the group consisting of: 
 a) a human antibody;    b) a humanized antibody;    c) a chimeric antibody; and    d) a recombinant antibody.    
     
     
         64 . The method according to  claim 63 , wherein said ligand is a chemokine.  
     
     
         65 . The method according to  claim 64 , wherein said chemokine is TARC or MDC.  
     
     
         66 . A method of inhibiting the interaction of a cell bearing mammalian CC-chemokine receptor 4 (CCR4) with a ligand thereof, comprising contacting said cell with an effective amount of an antibody or antigen-binding fragment thereof which binds to mammalian CCR4 or portion of said receptor and inhibits binding of said ligand to the receptor, wherein said antibody or antigen-binding fragment thereof comprises one or more antigen-binding regions of monoclonal antibody 10E4, monoclonal antibody 1G1 or monoclonal antibody 2B10, and wherein said antibody is selected from the group consisting of: 
 a) a human antibody;    b) a humanized antibody;    c) a chimeric antibody; and    d) a recombinant antibody.    
     
     
         67 . The method according to  claim 66 , wherein said ligand is a chemokine.  
     
     
         68 . The method according to  claim 67 , wherein said chemokine is TARC or MDC.  
     
     
         69 . The method according to  claim 66 , wherein the method of inhibiting the interaction of a cell bearing mammalian CCR4 with a ligand thereof comprises administering to a patient a composition comprising said antibody or antigen-binding fragment thereof and, optionally, a physiologically acceptable carrier, and wherein said method treats a disease or condition selected from the group consisting of inflammatory disease, allergic disease, autoimmune disease, graft rejection, atherosclerosis, human immunodeficiency virus (HIV) infection, lymphomas, cancers involving leukocyte infiltration, and inflammatory responses.