Monoclonal Antibodies Against NKG2A

Abstract

The present invention relates to methods of treating immune disorders, particularly autoimmune or inflammatory disorders, and methods of producing antibodies and other compounds for use in therapeutic strategies for treating such disorders. Generally, the present methods involve the use of antibodies or other compounds that prevent the stimulation of NKG2A receptors on NK cells, leading to the lysis of dendritic cells that contribute to the pathology of the disorders.

1 . A monoclonal antibody or a fragment thereof that:
 a) specifically binds to NKG2A;   b) does not specifically binding to an F c  receptor; and   c) when bound to NKG2A on a human NK cell, causes said NK cell to lyse a target human cell bearing HLA-E or Qa1 b  on the target cell surface when said target cell comes into contact with said NK cell.   
     
     
         2 . The monoclonal antibody or a fragment thereof according to  claim 1  , wherein said monoclonal antibody or fragment thereof does not specifically bind to NKG2C or NKG2E. 
     
     
         3 . The monoclonal antibody or fragment thereof according to  claim 2 , wherein said monoclonal antibody or fragment thereof competes with Z199 or Z270 for binding to NKG2A. 
     
     
         4 . The monoclonal antibody or fragment thereof according to  claim 1 , wherein said monoclonal antibody or fragment thereof specifically binds to a non-human primate NKG2A. 
     
     
         5 . The monoclonal antibody or fragment thereof according to  claim 4 , wherein upon binding to NKG2A on a non-human primate NK cell, said antibody causes said NK cell to lyse a target non-human primate cell bearing HLA-E on the target cell surface when said target cell comes into contact with said NK cell. 
     
     
         6 . The monoclonal antibody or fragment thereof according to  claim 3 , comprising the amino acid sequence of SEQ ID NO:2. 
     
     
         7 . The monoclonal antibody or fragment thereof according to  claim 3 , comprising an amino acid sequence of SEQ ID NO:6. 
     
     
         8 . The monoclonal antibody or fragment thereof according to  claim 1 , wherein said antibody comprises a mouse or human IgG 1  region that has been modified to prevent binding to an F c  receptor. 
     
     
         9 . The monoclonal antibody or fragment thereof according to  claim 1 , wherein said antibody or fragment thereof is chimeric or humanized. 
     
     
         10 . The monoclonal antibody or fragment thereof according to  claim 9 , wherein said antibody comprises a human IgG 4  constant region. 
     
     
         11 . The monoclonal antibody or fragment thereof according to  claim 9 , wherein said antibody or fragment thereof is produced from a nucleic acid sequence comprising SEQ ID NO: 3. 
     
     
         12 . The monoclonal antibody or fragment thereof according to  claim 9 , wherein said antibody or fragment thereof is produced from a nucleic acid sequence comprising SEQ ID NO:7. 
     
     
         13 . The monoclonal antibody or fragment thereof according to  claim 1 , further comprising a cytotoxic agent. 
     
     
         14 . The monoclonal antibody or fragment thereof according to  claim 1 , further comprising a detectable marker. 
     
     
         15 . The monoclonal antibody or fragment thereof according to  claim 14 , wherein said detectable marker is selected from a radioisotope, a fluorescent dye, a member of an antigen-antibody pair, other than an antibody to NKG2A, a member of a lectin-carbohydrate pair; avidin; biotin; a member of a receptor-ligand pair; or a member of a molecularly imprinted polymer-print molecule system. 
     
     
         16 . A composition comprising:
 a) an effective amount of a monoclonal antibody or a fragment thereof that:
 i) specifically binds to NKG2A; 
 ii) does not specifically binding to an F c  receptor; and 
 iii) when bound to NKG2A on a human NK cell, causes said NK cell to lyse a target human cell bearing HLA-E or Qa1 b  on the target cell surface when said target cell comes into contact with said NK cell; and 
   b) a pharmaceutically acceptable carrier or excipient.   
     
     
         17 . The composition according to  claim 16 , wherein said monoclonal antibody or a fragment thereof does not specifically bind to NKG2C or NKG2E. 
     
     
         18 . The composition according to  claim 16 , additionally comprising a second therapeutic agent selected from: a therapeutic agent used in the treatment of cancers, including a chemotherapeutic compound, a hormone, an angiogenesis inhibitor, or an apoptotic agent; a therapeutic agents used to treat infectious disease, including an antiviral compound; a therapeutic agent used in other immunotherapies selected from the treatment of autoimmune disease, inflammatory disorders, or transplant rejection; a cytokine; a cytokine inhibitor; an immunomodulatory agent; an adjunct compound; a hematopoietic growth factor; an agonist of an activating NK cell receptor, or an antagonist of an inhibitory NK cell receptor. 
     
     
         19 . The composition according to  claim 17 , additionally comprising a second therapeutic agent selected from: a therapeutic agent used in the treatment of cancers, including a chemotherapeutic compound, a hormone, an angiogenesis inhibitor, or an apoptotic agent; a therapeutic agents used to treat infectious disease, including an antiviral compound; a therapeutic agent used in other immunotherapies, selected from the treatment of autoimmune disease, inflammatory disorders, or transplant rejection; a cytokine; a cytokine inhibitor; an immunomodulatory agent; an adjunct compound; a hematopoietic growth factor; an agonist of an activating NK cell receptor, or an antagonist of an inhibitory NK cell receptor.