Compositions and methods for therapeutic delivery
Described herein are compositions comprising a recombinant retroviral vector for delivering a therapeutic comprising a nucleic acid construct comprising a polynucleotide sequence encoding an interleukin or a subunit thereof. Also described herein are methods of using the composition comprising a recombinant retroviral vector described herein for delivering a therapeutic comprising a nucleic acid construct comprising a polynucleotide sequence encoding an interleukin or a subunit thereof to a subject.
1. A method of treating cancer in a subject, comprising administering to the subject a first murine leukemia virus recombinant retroviral vector comprising a nucleic acid construct comprising a viral promoter operatively linked to a first polynucleotide sequence encoding a P40 subunit of Interleukin-12 (IL-12), a second polynucleotide sequence encoding a P35 subunit of IL-12, and a third polynucleotide sequence between the first and second polynucleotide sequences, wherein the third polynucleotide sequence encodes a cleavage site that facilitates cleavage between P40 subunit and P35 subunit, wherein route of the administering to the subject is selected from the group consisting of intravenous and intra-arterial routes, and wherein the recombinant retroviral vector induces a cell kill activity in the subject, thereby treating cancer in said subject.
2. The method of claim 1 , wherein the cleavage site comprises a furin cleavage site.
3. The method of claim 2 , wherein the furin cleavage site comprises an amino acid sequence of SEQ ID NO:3 or SEQ ID NO:12.
4. The method of claim 1 , wherein the nucleic acid construct further comprises a fourth polynucleotide sequence between the first and second polynucleotide sequences, wherein the fourth polynucleotide sequence encodes a self-cleaving peptide.
5. The method of claim 4 , wherein the self-cleaving peptide comprises an amino acid sequence selected from any one of SEQ ID Nos: 4-11 or a combination thereof.
6. The method of claim 1 , further comprising:
a. administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a second recombinant retroviral vector comprising a nucleic acid construct comprising a polynucleotide sequence encoding a thymidine kinase; and
b. co-administering a nucleoside agent, wherein the nucleoside agent is at least one of ganciclovir, valganciclovir, acyclovir, valacyclovir, or penciclovir.
7. The method of claim 6 , wherein the polynucleotide sequence encoding the thymidine kinase and the polynucleotide sequence encoding the P40 subunit of IL-12 and the P35 subunit of IL-12 are in the same recombinant retroviral vector.
8. The method of claim 6 , wherein the polynucleotide sequence encoding a thymidine kinase and the polynucleotide sequence encoding the P40 subunit of IL-12 and the P35 subunit of IL-12 are in different recombinant retroviral vectors.
9. The method of claim 8 , wherein the recombinant retroviral vector encoding the thymidine kinase and the recombinant retroviral vector encoding IL-12 are administered at different time points to the subject.
10. The method of claim 6 , wherein the nucleoside agent is administered between 1 day and 2 days after administration of the second recombinant retroviral vector to said subject.
11. The method of claim 1 , further comprising monitoring IL-12 level in the subject and inhibiting IL-12 expression in the subject when IL-12 level in the subject reaches a predetermined threshold.
12. The method of claim 1 , wherein at least 1×10 5 total viral particles of the recombinant retroviral vector is administered cumulatively to said subject.
13. The method of claim 1 , further comprising modulating an expression of IL-12 in said subject.
14. The method of claim 1 , wherein administration of the first recombinant retroviral vector elicits reduced toxicity in the subject by at least 0.1 fold compared to toxicity induced by direct administration of IL-12 protein in said subject.
15. The method of claim 1 , wherein administration of the first recombinant retroviral vector increases the efficacy of the treatment of the cancer in the subject by at least 0.1 fold compared to efficacy of the treatment of the cancer by direct administration of IL-12 protein in said subject.
16. The method of claim 1 , further comprising delivering the retroviral vector to a cell or microenvironment associated with the cancer in said subject.
17. The method of claim 1 , wherein the administration of the first recombinant retroviral vector decreases toxicity associated with administration of IL-12 protein in the subject without decreasing the efficacy of the treatment of the cancer by administration of the IL-12 protein in said subject.