Pd-l1 and pd-l2-based fusion proteins and uses thereof

Abstract

Provided are fusion proteins comprising a first domain and a second domain, wherein the first domain comprises a polypeptide that binds to and triggers PD-1 and the second domain comprises a polypeptide that binds to and triggers a TRAIL receptor or Fas. In some embodiments, the polypeptide that binds to and triggers PD-1 comprises at least a portion of the extracellular domain of PD-L1 or PD-L2 and the second domain comprises at least a portion of the extracellular domain of TRAIL or Fas ligand. Also provided are methods for treating autoimmune, alloimmune or inflammatory diseases, and methods for treating cancer, using the fusion proteins.

1 . A fusion protein comprising a first domain and a second domain, wherein the first domain comprises a polypeptide that binds to and triggers PD-1 and the second domain comprises a polypeptide that binds to and triggers a TRAIL receptor or Fas,
 wherein the polypeptide that binds to and triggers PD-1 comprises at least a portion of the extracellular domain of PD-L1 and the second domain comprises at least a portion of the extracellular domain of TRAIL or Fas ligand, or   wherein the polypeptide that binds to and triggers PD-1 comprises at least a portion of the extracellular domain of PD-L2 and the second domain comprises at least a portion of the extracellular domain of Fas ligand.   
     
     
         2 . (canceled) 
     
     
         3 . The fusion protein according to  claim 1 , wherein the fusion protein comprises at least a portion of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO:11 or SEQ ID NO: 12. 
     
     
         4 . The fusion protein according to  claim 1  comprising a first domain and a second domain, wherein the first domain comprises a portion of the extracellular domain of PD-L1 comprising at least 20 contiguous amino acids of said extracellular domain, and the second domain comprises a portion of the extracellular domain of TRAIL or Fas ligand comprising at least 20 contiguous amino acids of said extracellular domain. 
     
     
         5 . The fusion protein according to  claim 1 , wherein the first domain comprises human PD-L1 or human PD-L2, or a fragment thereof capable of binding to and triggering PD-1, and the second domain comprises human TRAIL or human Fas ligand, or a fragment thereof. 
     
     
         6 . The fusion protein according to  claim 1 , wherein the first domain and the second domain are connected via a linker. 
     
     
         7 . The fusion protein according to  claim 6 , wherein the linker is a protein linker. 
     
     
         8 . The fusion protein according to according to  claim 1 , further comprising a trimerization domain. 
     
     
         9 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a fusion protein according to  claim 1 . 
     
     
         10 . A method of treating an autoimmune or alloimmune disease comprising administering a therapeutically effective amount of a fusion protein according to  claim 1  to a patient in need of such treatment. 
     
     
         11 . The method of  claim 10 , wherein the autoimmune disease is multiple sclerosis. 
     
     
         12 . A method of treating an inflammatory disease comprising administering a therapeutically effective amount of a fusion protein according to  claim 1  to a patient in need of such treatment. 
     
     
         13 . A method of inhibiting proliferation and differentiation of T cells, B cells, mast cells, antigen presenting cells, dendritic cells or NK cells in a patient in need thereof, the method comprising the step of administering to said patient a therapeutically effective amount of a fusion protein according to  claim 1 . 
     
     
         14 . A method of treating cancer comprising administering to a patient in need of such treatment a therapeutically effective amount of a fusion protein according to  claim 1 . 
     
     
         15 . A method of treating autoimmune disease or alloimmune disease comprising administering to a patient in need of such treatment an effective amount of a genetic sequence encoding a fusion protein according to  claim 1 . 
     
     
         16 . A method of treating inflammatory disease comprising administering to a patient in need of such treatment an effective amount of a genetic sequence encoding a fusion protein according to  claim 1 . 
     
     
         17 . A method of treating cancer comprising administering to a patient in need of such treatment an effective amount of a genetic sequence encoding the fusion protein according to  claim 1 . 
     
     
         18 . The method of  claim 10 , wherein administration of said fusion protein is parenteral. 
     
     
         19 . The method of  claim 12 , wherein administration of said fusion protein is parenteral. 
     
     
         20 . The method of  claim 13 , wherein administration of said fusion protein is parenteral. 
     
     
         21 . The method of  claim 14 , wherein administration of said fusion protein is parenteral. 
     
     
         22 . A pharmaceutical composition comprising a fusion protein according to  claim 1 , for treating an autoimmune or alloimmune disease. 
     
     
         23 . A pharmaceutical composition comprising a fusion protein according to  claim 1 , for treating an inflammatory disease. 
     
     
         24 . A pharmaceutical composition comprising a fusion protein according to  claim 1 , for treating cancer. 
     
     
         25 . A pharmaceutical composition comprising a genetic sequence encoding a fusion protein according to  claim 1 , for treating autoimmune disease or alloimmune disease. 
     
     
         26 . A pharmaceutical composition comprising a genetic sequence encoding a fusion protein according to  claim 1 , for treating an inflammatory disease. 
     
     
         27 . A pharmaceutical composition comprising a genetic sequence encoding a fusion protein according to  claim 1 , for treating cancer. 
     
     
         28 . The fusion protein according to  claim 1  comprising a first domain and a second domain, wherein the first domain comprises a portion of the extracellular domain of PD-L2 comprising at least 20 contiguous amino acids of said extracellular domain, and the second domain comprises a portion of the extracellular domain of Fas ligand comprising at least 20 contiguous amino acids of said extracellular domain.