Pseudotyped oncolytic viral delivery of therapeutic polypeptides

Abstract

Described herein are pseudotyped oncolytic viruses comprising nucleic acids encoding an engager molecule. In some embodiments, the pseudotyped oncolytic viruses comprises nucleic acids encoding an engager molecule and one or more therapeutic molecules. Pharmaceutical compositions containing the pseudotyped oncolytic virus and methods of treating cancer using the pseudotyped oncolytic viruses are further provided herein.

1 . A pseudotyped oncolytic virus comprising a recombinant nucleic acid comprising:
 i) a first nucleic acid sequence encoding a polypeptide comprising:
 an activation domain specific for an antigen expressed on an effector cell and a therapeutic molecule domain specific for an antigen selected from the group consisting of programmed death ligand 1 (PDL1), PDL2, CD80, CD86, herpesvirus entry mediator (HVEM), and CD47; and 
   ii) a second nucleic acid sequence complementary to a microRNA selected from miR-10b, miR-17, miR-21, miR-106a, miR-125b, miR-145, miR-146a, miR-146b, miR-155, miR-96, miR-182, miR-183, miR-221, miR-222, and miR-1247-5p.   
     
     
         2 . The pseudotyped oncolytic virus of  claim 1 , wherein the second nucleic acid sequence is complementary to a plurality of microRNAs selected from miR-10b, miR-17, miR-21, miR-106a, miR-125b, miR-145, miR-146a, miR-146b, miR-155, miR-96, miR-182, miR-183, miR-221, miR-222, and miR-1247-5p. 
     
     
         3 . The pseudotyped oncolytic virus of  claim 1 , wherein the antigen expressed on the effector cell is CD3. 
     
     
         4 . The pseudotyped oncolytic virus of  claim 1 , wherein the pseudotyped oncolytic virus possesses an altered tropism relative to a non-pseudotyped virus. 
     
     
         5 . The pseudotyped oncolytic virus of  claim 1 , wherein the pseudotyped oncolytic virus yields reduced toxicity and/or reduced entry of non-tumor cells or tissue relative to a non-pseudotyped virus. 
     
     
         6 . The pseudotyped oncolytic virus of  claim 1 , wherein the pseudotyped oncolytic virus is derived from herpes simplex virus-1 (HSV-1). 
     
     
         7 . A pseudotyped oncolytic virus capable of preferential replication in a tumor cell, comprising a recombinant nucleic acid comprising:
 i) a first nucleic acid sequence encoding a polypeptide comprising:
 (a) an activation domain specific for an antigen expressed on an effector cell and a therapeutic molecule domain that binds to an inhibitory antigen expressed on a cell surface; or 
 (b) an activation domain specific for an antigen expressed on an effector cell and an antigen recognition domain specific for a tumor cell antigen expressed on a target cell; and 
   ii) a second nucleic acid sequence encoding an immune modulator polypeptide selected from the group consisting of a cytokine, a costimulatory molecule, an immune checkpoint polypeptide, an anti-angiogenesis factor, and a matrix metalloprotease (MMP).   
     
     
         8 . The pseudotyped oncolytic virus of  claim 7 , wherein the first and second nucleic acid sequences are expressed from a single promoter sequence present in the recombinant nucleic acid. 
     
     
         9 . The pseudotyped oncolytic virus of  claim 7 , wherein the antigen expressed on the effector cell is CD3, and wherein the tumor cell antigen is CD19. 
     
     
         10 . The pseudotyped oncolytic virus of  claim 7 , wherein the first and second nucleic acids have a size of 7.2-38 kb. 
     
     
         11 . The pseudotyped oncolytic virus of  claim 7 , wherein the pseudotyped oncolytic virus may be administered to a subject in a repeated manner over time without being neutralized by the immune system 
     
     
         12 . A pseudotyped oncolytic virus comprising a recombinant nucleic acid comprising:
 i) a first nucleic acid sequence encoding a polypeptide comprising:
 an activation domain specific for an antigen expressed on an effector cell, and an antigen recognition domain specific for a tumor cell antigen expressed on a target cell, and wherein the tumor cell antigen is CD19; and 
   ii) a second nucleic acid sequence complementary to a microRNA selected from miR-10b, miR-17, miR-21, miR-106a, miR-125b, miR-145, miR-146a, miR-146b, miR-155, miR-96, miR-182, miR-183, miR-221, miR-222, and miR-1247-5p.