Selective cell targeting using adenovirus and chemical dimers

Abstract

Compositions and methods for retargeting adenovirus to a cell using chemical dimers are described. In particular, a recombinant adenovirus comprising a nucleic acid comprising a capsid-dimerizing agent binder conjugate and a ligand-dimerizing agent binder conjugate is provided.

1 . A recombinant nucleic acid encoding a capsid-dimerizing agent binder conjugate and a ligand-dimerizing agent binder conjugate, wherein the capsid-dimerizing agent binder conjugate comprises an adenoviral fiber protein and a FRB protein inserted into the H1 loop of the adenoviral fiber protein, and the ligand-dimerizing agent binder conjugate comprises a ligand and a FKBP protein. 
     
     
         2 . The recombinant nucleic acid of  claim 1 , wherein the ligand is capable of binding a tumor cell. 
     
     
         3 . The recombinant nucleic acid of  claim 2 , wherein the ligand is an antibody. 
     
     
         4 . The recombinant nucleic acid of  claim 3 , wherein the antibody is a single domain antibody. 
     
     
         5 . The recombinant nucleic acid of  claim 1 , wherein the FRB protein is 90 amino acids in length. 
     
     
         6 . The recombinant nucleic acid of  claim 1 , wherein the FRB protein comprises a wild-type mTOR FRB domain. 
     
     
         7 . The recombinant nucleic acid of  claim 1 , wherein the FRB protein is encoded by the nucleotide sequence of SEQ ID NO: 69. 
     
     
         8 . The recombinant nucleic acid of  claim 1 , wherein the FRB protein comprises a mutant mTOR FRB domain. 
     
     
         9 . The recombinant nucleic acid of  claim 8 , comprising SEQ ID NO: 110. 
     
     
         10 . The recombinant nucleic acid of  claim 1 , wherein the FKBP protein is a human FKBP protein. 
     
     
         11 . The recombinant nucleic acid of  claim 10 , wherein the human FKBP protein is FKBP12. 
     
     
         12 . A recombinant adenovirus comprising the recombinant nucleic acid of  claim 1 . 
     
     
         13 . A recombinant adenovirus comprising a capsid-dimerizing agent binder conjugate, wherein the capsid-dimerizing agent binder conjugate comprises an adenoviral fiber protein and a FRB protein inserted into the H1 loop of the adenoviral fiber protein. 
     
     
         14 . The recombinant adenovirus of  claim 13 , wherein the capsid-dimerizing agent binder conjugate is bound to a dimerizing agent. 
     
     
         15 . The recombinant adenovirus of  claim 14 , wherein the dimerizing agent is further bound to a ligand-dimerizing agent binder conjugate. 
     
     
         16 . The recombinant adenovirus of  claim 14 , wherein the dimerizing agent is rapamycin or a rapalog. 
     
     
         17 . The recombinant adenovirus of  claim 13 , wherein the FRB protein is 90 amino acids in length. 
     
     
         18 . The recombinant adenovirus of  claim 13 , wherein the FRB protein comprises a wild-type mTOR FRB domain. 
     
     
         19 . The recombinant adenovirus of  claim 18 , wherein the FRB protein is encoded by the nucleotide sequence of SEQ ID NO: 69. 
     
     
         20 . The recombinant adenovirus of  claim 13 , wherein the FRB protein comprises a mutant mTOR FRB domain.