SELECTIVE CELL TARGETING USING ADENOVIRUS AND CHEMICAL DIMERS
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 capsid protein and a dimerizing agent binder, and the ligand-dimerizing agent binder conjugate comprises a ligand and a dimerizing agent binder.
2 . The recombinant nucleic acid of claim 1 , wherein the adenoviral capsid protein is operably linked to the dimerizing agent binder, the ligand is operably linked to the dimerizing agent binder, or both.
3 . The recombinant nucleic acid of claim 2 , wherein the adenoviral capsid protein is a fiber protein.
4 . The recombinant nucleic acid of claim 2 , wherein the ligand is capable of binding a tumor cell.
5 . The recombinant nucleic acid of claim 2 , wherein the ligand is an antibody.
6 . The recombinant nucleic acid of claim 5 , wherein the antibody is a single domain antibody.
7 . The recombinant nucleic acid of claim 1 , wherein the dimerizing agent binder of the capsid-dimerizing agent binder conjugate is a FRB protein.
8 . The recombinant nucleic acid of claim 1 , wherein the dimerizing agent binder of the ligand-dimerizing agent binder conjugate is an immunophilin protein.
9 . The recombinant nucleic acid of claim 8 , wherein the immunophilin protein is a FKBP protein.
10 . A recombinant adenovirus comprising the recombinant nucleic acid of claim 1 .
11 . A recombinant adenovirus comprising a capsid-dimerizing agent binder conjugate, wherein the capsid-dimerizing agent binder conjugate comprises an adenoviral capsid protein and a dimerizing agent binder.
12 . The recombinant adenovirus of claim 11 , wherein the capsid-dimerizing agent binder conjugate is bound to a dimerizing agent.
13 . The recombinant adenovirus of claim 12 , wherein the dimerizing agent is further bound to a ligand-dimerizing agent binder conjugate.
14 . The recombinant adenovirus of claim 12 , wherein the dimerizing agent is rapamycin.
15 . A cell comprising the recombinant adenovirus of claim 11 .
16 . A method of forming an adenoviral cancer cell targeting construct, comprising:
infecting a cell with the recombinant adenovirus of claim 10 , thereby forming an adenoviral infected cell;
allowing the adenoviral infected cell to express the recombinant nucleic acid, thereby forming a ligand-dimerizing agent binder conjugate and a recombinant adenovirus comprising a capsid-dimerizing agent binder conjugate;
contacting the recombinant adenovirus and the ligand-dimerizing agent binder conjugate with a dimerizing agent; and
allowing the recombinant adenovirus and the ligand-dimerizing agent binder conjugate to bind to the dimerizing agent, thereby forming the adenoviral cancer cell targeting construct.
17 . A method of targeting a cell, comprising contacting a cell with a recombinant adenovirus of claim 11 .
18 . A method of targeting a cancer cell in a cancer patient, comprising:
administering to the cancer patient the recombinant adenovirus of claim 10 ;
allowing the recombinant adenovirus to infect a cell in the cancer patient, thereby forming an adenoviral infected cell;
allowing the adenoviral infected cell to express the recombinant nucleic acid, thereby forming a ligand-dimerizing agent binder conjugate and a recombinant adenovirus comprising a capsid-dimerizing agent binder conjugate;
administering to the cancer patient a dimerizing agent;
allowing the recombinant adenovirus and the ligand-dimerizing agent binder conjugate to bind to the dimerizing agent, thereby forming an adenoviral cancer cell targeting construct; and
allowing the adenoviral cancer cell targeting construct to bind to a cancer cell, thereby targeting the cancer cell in the cancer patient.
19 . A method of targeting a cell, comprising:
contacting a first cell with the recombinant adenovirus of claim 10 ;
allowing the recombinant adenovirus to infect the first cell, thereby forming an adenoviral infected cell;
allowing the adenoviral infected cell to express the recombinant nucleic acid, thereby forming a ligand-dimerizing agent binder conjugate and a recombinant adenovirus comprising a capsid-dimerizing agent binder conjugate;
contacting the ligand-dimerizing agent binder conjugate and the recombinant adenovirus with a dimerizing agent;
allowing the recombinant adenovirus and the ligand-dimerizing agent binder conjugate to bind to the dimerizing agent, thereby forming an adenoviral cell targeting construct; and
allowing the adenoviral cell targeting construct to bind to a second cell, thereby targeting the cell.
20 . The method of claim 19 , wherein the first cell and the second cell form part of an organism, or the first cell and the second cell form part of a tissue culture vessel.