Use of tam receptor inhibitors as immunoenhancers and tam activators as immunosuppressors

Abstract

This disclosure concerns compositions and methods for immunoenhancement and/or immunosuppression. In certain embodiments, the disclosure concerns methods of using a TAM receptor inhibitor for immunoenhancement, for example as a vaccine adjuvant, for the treatment of sepsis, or for treating an immunocompromised subject. Also disclosed are methods of screening for immunoenhancing agents. In other embodiments, the disclosure concerns methods of using a TAM receptor agonist for immunosuppression, for example as a treatment for an autoimmune disorder, for the treatment of an allergy, or for treating graft-versus-host disease in a subject. Also disclosed are methods of screening for immunosuppressive agents.

1 . A method of enhancing an immune response in a subject, comprising: administering to a subject in need of immunoenhancement a therapeutically effective amount of a TAM receptor inhibitor, thereby enhancing the immune response in the subject. 
     
     
         2 . A method of suppressing an immune response in a subject, comprising: administering to a subject in need of immunosuppression a therapeutically effective amount of a TAM receptor agonist, thereby suppressing the immune response in the subject. 
     
     
         3 . The method of  claim 1 , wherein the TAM receptor is Tyro3, Axl, or Mer. 
     
     
         4 . The method of  claim 1 , wherein the TAM receptor inhibitor has an IC 50  of less than about 50 μM. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the TAM receptor inhibitor;
 binds to an intracellular ATP binding site of Tyro3, Axl, or Mer,   binds to an extracellular domain of the TAM receptor or a TAM receptor ligand, or   binds to Gas6 or Protein S and interferes with the binding of Gas6 or Protein S to the extracellular domain of the TAM receptor and/or activation of the TAM receptor.   
     
     
         7 . The method of  claim 1 , wherein the TAM receptor inhibitor is MP470, SGI- AXL-277, AXL-1, AXL-2, AXL-3, AXL-4, AXL-5, AXL-6, AXL-7, AXL-8, AXL-9, or a derivatives thereof. 
     
     
         8 . The method of  claim 1 , wherein the TAM receptor inhibitor has a chemical structure of: 
       
         
           
           
               
               
           
         
       
       wherein R is a hydrogen or methyl group. 
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein the TAM receptor inhibitor is a small molecule inhibitor, a monoclonal antibody, or an siRNA. 
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the method further comprises:
 administering to the subject a therapeutically effective amount of a vaccine, thereby enhancing the immune response to the vaccine.   
     
     
         13 . The method of  claim 12 , wherein the TAM receptor inhibitor is administered to the subject substantially concurrently with the vaccine. 
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein the method is a method of treating a tumor in the subject, a method of treating a disease of immunosuppression, or a method of treating sepsis. 
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 1 , wherein the method is a method of treating an infection in a subject in need thereof. 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 2 , wherein the TAM receptor agonist is GAS6, Protein S, an amino-terminally truncated GAS6, an amino-terminally-truncated Protein S, a Gas6-Fc fusion protein, a Gas6 protein having at least 95% sequence identify to a native Gas6-Fc fusion protein and can activate a TAM receptor, an antibody that binds to an extracellular domain of the TAM receptor and can cross-link and activate the TAM receptor in a TAM receptor dimer, or a small molecule that binds to an extracellular domain of the TAM receptor and can activate the TAM receptor. 
     
     
         20 . The method of  claim 2 , wherein the TAM receptor agonist is a GAS6 or Protein S protein that does not have one or more Gla or EGF domains and can activate the TAM receptor. 
     
     
         21 . The method of  claim 2 , wherein the method further comprises:
 administering to the subject a therapeutically effective amount of an immunosuppressive agent, thereby suppressing the immune response in the subject.   
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 2 , wherein the method is a method of treating or preventing an autoimmune disease, an allergy, graft-versus-host (GVH) disease, AIDS, or transplant rejection. 
     
     
         24 . The method of  claim 23 , wherein the autoimmune disease is rheumatoid arthritis, Hashimoto's thyroiditis, pernicious anemia, Crohn's disease, ulcerative colitis, psoriasis, renal fibrosis, pulmonary fibrosis, hepatic fibrosis, Addison's disease, type I diabetes, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, multiple sclerosis, myasthenia gravis, Reiter's syndrome, or Grave's disease. 
     
     
         25 . A method of screening for an immunomodulator agent, comprising: contacting a cell expressing a TAM receptor with a test agent; and determining if
 (a) the test agent alters TAM receptor activity; or   (b) the test agent inhibits binding of a ligand to the TAM receptor, wherein test agents that increase TAM receptor activity or enhance binding of a ligand to the TAM receptor are identified as immunosuppressive agents and wherein test agents that inhibit TAM receptor activity or reduce or inhibit binding of a ligand to the TAM receptor are identified as immunoenhancing agents.   
     
     
         26 - 35 . (canceled) 
     
     
         36 . The method of  claim 2 , wherein the TAM receptor is Tyro3, Axl, or Mer.