Compositions and methods of monoclonal and polyclonal antibodies specific for T cell subpopulations

Abstract

The invention provides compounds and methods for the ex vivo or in vivo expansion of NK T cells, CD1d-reactive T cells, and JαQ + T cells, and the modulation of their activities. These compounds and methods have diagnostic and therapeutic applications.

What is claimed is:  
     
         1 . A purified antibody that preferentially binds a T cell antigen receptor (TCR), wherein said antibody preferentially binds a CDR3-loop or an α-β junction of said TCR; or preferentially binds or modulates the expansion or activation of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, and JαQ +  T cells.  
     
     
         2 . The purified antibody of  claim 1 , that preferentially binds and preferentially expands an invariant T cell.  
     
     
         3 . The purified antibody of  claim 1 , that preferentially binds the antigen binding site of the TCR of said T cell subpopulation.  
     
     
         4 . A combination of purified antibodies that preferentially binds a TCR, wherein said antibody combination preferentially binds a CDR3-loop or an α-β junction of said TCR; or preferentially binds or modulates the expansion or activation of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, and JαQ +  T cells; wherein said antibody combination is selected from the group consisting of: 
 (i) an anti-Vα24 antibody and an anti-CD161 antibody;  
 (ii) an anti-Vα24 antibody and an anti-CD94 antibody;  
 (iii) an anti-Vβ11 antibody and an anti-CD161 antibody; and  
 (iv) an anti-Vβ11 antibody and an anti-CD94 antibody.  
 
     
     
         5 . A fragment or derivative of an antibody, wherein said antibody preferentially binds a CDR3-loop or an α-β junction of a TCR; or preferentially binds or modulates the expansion or activation of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, and JαQ +  T cells.  
     
     
         6 . A bifunctional antibody comprising: 
 (a) a first antibody or fragment thereof that preferentially binds a CDR3-loop or an α-β junction of a TCR; or preferentially binds or modulates the expansion or activation of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, and JαQ +  T cells; wherein said first antibody or fragment binds a first epitope; and    (b) a second antibody or fragment thereof that binds a second epitope expressed on a T cell expressing said TCR or expressed on a NK T cell, CD1d-reactive T cell, or JαQ +  T cell that is bound by said first antibody or fragment thereof.    
     
     
         7 . A stable hybridoma that produces an antibody, wherein said antibody preferentially binds a CDR3-loop or an α-β junction of a TCR; or preferentially binds or modulates the expansion or activation of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, and JαQ +  T cells.  
     
     
         8 . A purified T cell subpopulation, wherein said T cells are specifically bound by an antibody or a combination of antibodies, wherein said antibody or said antibody combination preferentially binds a CDR3-loop or an α-β junction of a TCR; or wherein said antibody preferentially binds or modulates the expansion or activation of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, and JαQ +  T cells.  
     
     
         9 . A method of generating an antibody that preferentially binds a CDR3-loop or an α-β junction of a TCR; or preferentially binds or modulates the expansion or activation of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, and JαQ +  T cells; said method comprising: 
 (a) coupling a cyclic peptide to a carrier;  
 (b) immunizing a mammal with said coupled peptide; and  
 (c) isolating an antibody that preferentially binds a CDR3-loop or an α-β junction of a TCR; or preferentially binds or modulates the expansion or activation of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, and JαQ +  T cells.  
 
     
     
         10 . A method of generating an antibody that preferentially binds a CDR3-loop or an α-β junction of a TCR; or preferentially binds or modulates the expansion or activation of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, and JαQ +  T cells; said method comprising: 
 (a) immunizing a CD1 or invariant T cell deficient mammal with invariant T cells; and  
 (b) isolating an antibody that preferentially binds a CDR3-loop or an α-β junction of a TCR; or preferentially binds or modulates the expansion or activation of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, and JαQ +  T cells.  
 
     
     
         11 . The method of  claim 9  or  10 , wherein said mammal is a CD1d knockout mouse, a mammal tolerized to NK T cells, a mammal tolerized to CD1d-reactive T cells, a mammal tolerized to JαQ +  T cell, a mammal tolerized to the invariant TCR, a mammal in which invariant T cells have been removed, a mammal lacking part of the a chain of said TCR a chain, or a mammal lacking part of the β chain of said TCR.  
     
     
         12 . A method of measuring the amount of NK TCRs or the amount of NK T cells in a sample, said method comprising contacting said sample with an antibody that preferentially binds a CDR3-loop, an antigen binding site, or an α-β junction of said TCRs.  
     
     
         13 . A method of measuring the amount of CD1d-reactive TCRs or the amount of CD1d-reactive T cells in a sample, said method comprising contacting said sample with an antibody that preferentially binds a CDR3-loop, an antigen binding site, or an α-β junction of said TCRs.  
     
     
         14 . A method of measuring the amount of JαQ +  TCRs or the amount of JαQ +  T cells in a sample, said method comprising contacting said sample with an antibody or a combination of antibodies that preferentially binds a CDR3-loop, an antigen binding site, or an α-β junction of said TCRs.  
     
     
         15 . A method of visualizing the NK TCRs or the NK T cells in a sample, said method comprising contacting said sample with an antibody that preferentially binds a CDR3-loop, an antigen binding site, or an α-β junction of said TCRs.  
     
     
         16 . A method of visualizing the CD1d-reactive TCRs or the CD1d-reactive T cells in a sample, said method comprising contacting said sample with an antibody that preferentially binds a CDR3-loop, an antigen binding site, or an α-β junction of said TCRs.  
     
     
         17 . A method of visualizing the JαQ +  TCRs or the JαQ +  T cells in a sample, said method comprising contacting said sample with an antibody or a combination of antibodies that preferentially binds a CDR3-loop, an antigen binding site, or an α-β junction of said TCRs.  
     
     
         18 . A method of diagnosing a subject with a condition or an increased risk for a condition selected from the group consisting of autoimmune disease, viral infection, bacterial infection, parasitic infection, infection by a eukaryotic pathogen, allergy, asthma, inflammatory condition, graft versus host disease, graft rejection, immunodeficiency disease, spontaneous abortion, pregnancy, and cancer; said method comprising the following: 
 (a) contacting a sample from said subject with an antibody or a combination of antibodies that preferentially binds a CDR3-loop or an α-β junction of a TCR; or an antibody that preferentially binds or modulates the expansion or activation of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, and JαQ +  T cells;    (b) quantitating the amount of said antibody or said antibody combination bound to said TCR or said T cells; thereby determining the amount of T cells of interest in said sample; and    (c) comparing the amount of said T cells of interest in said sample to the amount of said T cells of interest found in subjects diagnosed with said condition or subjects not diagnosed with said condition.    
     
     
         19 . The method of  claim 18 , further comprising comparing the amount of another T cell type in said sample with the amount of said another T cell type found in subjects diagnosed with said condition or subjects not diagnosed with said condition.  
     
     
         20 . A method of treating or preventing an autoimmune disease, viral infection, bacterial infection, parasitic infection, infection by a eukaryotic pathogen, allergy, asthma, inflammatory condition, graft versus host disease, graft rejection, immunodeficiency disease, spontaneous abortion, pregnancy, or cancer in a mammal, said method comprising administering to said mammal an antibody or a combination of antibodies that preferentially binds a CDR3-loop or an α-β junction of a TCR; or preferentially binds or modulates the expansion or activation of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, and JαQ +  T cells.  
     
     
         21 . A method of inhibiting T cell pathogenesis in a mammal, said method comprising administering to said mammal an antibody or a combination of antibodies that preferentially binds a CDR3-loop, an antigen binding site, or an α-β junction of said TCRs; or inhibits the expansion of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, and JαQ +  T cells; said administering sufficient to inhibit a T cell expressing said TCR, a NIK T cell, a CD1d-reactive T cell, or a JαQ +  T cell.  
     
     
         22 . The method of  claim 21 , wherein said antibody is covalently linked to a toxin or a radiolabel.  
     
     
         23 . A method of increasing the size of a subpopulation of T cells, said method comprising contacting a sample comprising said T cells with an antibody that preferentially binds or modulates the expansion or activation of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, JαQ +  T cells, and T cells expressing a CDR3-loop or an α-β junction of a TCR that is preferentially bound by said antibody, wherein said contacting occurs under conditions that result in an increase in the number of said T cells.  
     
     
         24 . The method of  claim 23 , further comprising contacting said sample with an antigen and antigen presenting cells under conditions that allow said contacting to increase the number of said T cells; wherein said antigen is not α-galactosylceramide.  
     
     
         25 . The method of  claim 24 , wherein said antigen is a lipid or glycosyl-phosphatidylinositol antigen from an infectious pathogen, an antigen from a cancerous cell, or a self-lipid.  
     
     
         26 . The method of  claim 23 , further comprising contacting said sample with an antigen and antigen presenting cells under conditions that allow said contacting to increase the number of said T cells; wherein said antigen is α-galactosylceramide.  
     
     
         27 . A method of increasing the size of a subpopulation of T cells, said method comprising: 
 (a) contacting a sample comprising said T cells with an antibody or a combination of antibodies that preferentially binds a CDR3-loop or an α-β junction of a TCR; or an antibody that preferentially binds or modulates the expansion or activation of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, and JαQ +  T cells; said contacting conducted under conditions that allow complex formation between said T cells and said antibody or said combination of antibodies;    (b) isolating said complex; and    (c) contacting said T cells in said complex or recovered from said complex with an antigen and antigen presenting cells under conditions that allow said contacting to increase the number of said T cells; wherein said antigen is not α-galactosylceramide.    
     
     
         28 . The method of  claim 27 , wherein said antigen is a lipid or glycosyl-phosphatidylinositol antigen from an infectious pathogen, an antigen from a cancerous cell, or a self-lipid.  
     
     
         29 . A method of increasing the size of a subpopulation of T cells, said method comprising: 
 (a) contacting a sample comprising said T cells with an antibody or a combination of antibodies that preferentially binds a CDR3-loop or an α-β junction of a TCR; or an antibody that preferentially binds or modulates the expansion or activation of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, and JαQ +  T cells; said contacting conducted under conditions that allow complex formation between said T cells and said antibody or said combination of antibodies;    (b) isolating said complex; and    (c) contacting said T cells in said complex or recovered from said complex with an antigen and antigen presenting cells under conditions that allow said contacting to increase the number of said T cells; wherein said antigen is wherein said antigen is α-galactosylceramide.    
     
     
         30 . The method of  claim 27  or  29 , further comprising contacting said sample or said complex with one or more cytokines.  
     
     
         31 . A method of increasing the size of a subpopulation of T cells in a mammal, said method comprising: 
 (a) obtaining a sample comprising said T cells from said mammal;    (b) contacting said T cells with an antibody or a combination of antibodies that preferentially binds or modulates the expansion or activation of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, JαQ +  T cells, and T cells expressing a CDR3-loop or an α-β junction of a TCR that is preferentially bound by said antibody or said antibody combination; said contacting conducted under conditions that allow said contacting to increase the number of said T cells; and    (c) administering said contacted T cells to said mammal.    
     
     
         32 . The method of  claim 31 , further comprising purifying said T cells prior to said contacting step or after said contacting step.  
     
     
         33 . A method of increasing the size of a subpopulation of T cells in a mammal, said method comprising: 
 (a) obtaining a sample comprising said T cells from said mammal;    (b) contacting said T cells with an antibody or a combination of antibodies that preferentially binds a CDR3-loop or an α-β junction of a TCR; or an antibody that preferentially binds or modulates the expansion or activation of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, and JαQ +  T cells; said contacting conducted under conditions that allow complex formation between said T cells and said antibody or said combination of antibodies;    (c) isolating said complex; and    (d) contacting said T cells in said complex or recovered from said complex with an antigen and antigen presenting cells under conditions that allow said contacting to increase the number of said T cells; wherein said antigen is not α-galactosylceramide; and    (e) administering said contacted T cells to said mammal.    
     
     
         34 . The method of  claim 33 , wherein said antigen is a lipid or glycosyl-phosphatidylinositol antigen from an infectious pathogen, an antigen from a cancerous cell, or a self-lipid.  
     
     
         35 . A method of increasing the size of a subpopulation of T cells in a mammal, said method comprising: 
 (a) obtaining a sample comprising said T cells from said mammal;    (b) contacting said T cells with an antibody or a combination of antibodies that preferentially binds a CDR3-loop or an α-β junction of a TCR; or an antibody that preferentially binds or modulates the expansion or activation of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, and JαQ +  T cells; said contacting conducted under conditions that allow complex formation between said T cells and said antibody or said combination of antibodies;    (c) isolating said complex; and    (d) contacting said T cells in said complex or recovered from said complex with an antigen and antigen presenting cells under conditions that allow said contacting to increase the number of said T cells; wherein said antigen is α-galactosylceramide; and    (e) administering said contacted T cells to said mammal.    
     
     
         36 . The method of  claim 33  or  35 , further comprising administering one or more cytokines to said mammal.  
     
     
         37 . The method of  claim 33  or  35 , further comprising contacting said sample or said T cells with one or more cytokines, wherein said contacting alters the ratio of Th1/Th2/immune deviation response by said contacted T cells  
     
     
         38 . The method of  claim 33  or  35 , wherein said method is used in the treatment or prevention of an autoimmune disease, viral infection, bacterial infection, parasitic infection, infection by a eukaryotic pathogen, allergy, asthma, inflammatory condition, graft versus host disease, graft rejection, immunodeficiency disease, spontaneous abortion, pregnancy, or cancer in said mammal.  
     
     
         39 . A method of purifying a subpopulation of T cells from a sample, said method comprising contacting said sample with an antibody or a combination of antibodies that preferentially binds a CDR3-loop or an α-β junction of a TCR; or an antibody that preferentially binds or modulates the expansion or activation of at least one T cell subpopulation selected from the group of NK T cells, CD1d-reactive T cells, and JαQ +  T cells.  
     
     
         40 . The method of  claim 39 , further comprising contacting said sample with an anti-Vα24, CD4, CD8, CD56, CD161, or Vβ11 antibody.  
     
     
         41 . The method of  claim 39 , wherein said antibody is covalently linked to a fluorescent label, wherein said complex is isolated based on the fluorescence signal of said complex.  
     
     
         42 . The method of  claim 39 , wherein said antibody is covalently linked to a magnetic label, wherein said complex is isolated based on the magnetism of said complex.