Modified vaccinia virus strains for use in diagnostic and therapeutic methods
Modified viruses and methods for preparing the modified viruses are provided. Vaccines that contain the viruses are provided. The viruses can be used in methods of treatment of diseases, such as proliferative and inflammatory disorders, including cancer, and as anti-tumor and/or antiangiogenic agents. The viruses also can be used in diagnostic methods.
1. A method of treatment of cancer, comprising administering a recombinant vaccinia virus to a subject for the treatment of a tumor or metastasis, wherein:
the recombinant vaccinia virus encodes a diagnostic or therapeutic protein selected from among a ferritin, click beetle green 99 luciferase-monomeric red fluorescent protein fusion (CBG99-mRFP1), plasminogen kringle 5 domain, a soluble IL-6 receptor-IL-6 fusion protein (sIL-6R/IL-6), interleukin-24 (IL-24), a truncated human tissue factor protein fused to an RGD peptide (tTF-RGD), and an anti-VEGF single chain antibody or fragment thereof; and
the nucleic acid encoding the diagnostic or therapeutic protein is inserted into a non-essential locus in the virus.
2. The method of claim 1 , wherein the recombinant vaccinia virus comprises replacement of the A34R gene with the A34R gene from another vaccinia virus strain.
3. The method of claim 1 , wherein the recombinant vaccinia virus comprises replacement of the A34R gene with the A34R gene from vaccinia IHD-J strain.
4. The method of claim 2 , wherein the replacement increases the extracellular enveloped virus (EEV) form of vaccinia virus and/or increases the resistance of the virus to virus neutralizing antibodies.
5. The method of claim 1 , wherein the recombinant vaccinia virus comprises deletion of the A35R gene.
6. The method of claim 1 , wherein the virus comprises one or more additional heterologous nucleic acid molecule(s) that encode(s) another diagnostic and/or therapeutic gene product.
7. The method of claim 6 , wherein the heterologous nucleic acid encodes a diagnostic protein that is a detectable protein or a protein that induces a detectable signal.
8. The method of claim 7 , wherein the heterologous nucleic acid encodes a diagnostic protein that is selected from among a luciferase, a fluorescent protein, an iron storage molecule, an iron transporter, an iron receptor or a protein that binds a contrasting agent, a chromophore or a compound or a detectable ligand that can be detected.
9. The method of claim 6 , wherein the heterologous nucleic acid encodes a therapeutic gene product that is selected from among a cytokine, a chemokine, an immunomodulatory molecule, an antigen, a single chain antibody, an antisense RNA, a prodrug converting enzyme, an siRNA, an angiogenesis inhibitor, a toxin, an antitumor oligopeptide, a mitosis inhibitor protein, an antimitotic oligopeptide, an anti-cancer polypeptide antibiotic and a tissue factor.
10. The method of claim 1 , wherein the virus is administered systemically.
11. The method of claim 1 , wherein the virus is administered locally.
12. The method of claim 1 , wherein the diagnostic or therapeutic protein is an anti-VEGF single chain antibody.
13. The method of claim 1 , further comprising administering another chemotherapeutic compound.
14. The method of claim 13 , wherein the chemotherapeutic compound is a chemotherapeutic antibiotic.
15. The method of claim 14 , wherein the chemotherapeutic antibiotic is selected from among doxorubicin hydrochloride, idarubicin hydrochloride, daunorubicin hydrochloride, aclarubicin hydrochloride, epirubicin hydrochloride, pirarubicin hydrochloride, pleomycins, a mitomycin, an actinomycin, zinostatinstimalamer and ncocarzinostatin.
16. The method of claim 1 , wherein the recombinant replication competent vaccinia virus encodes a diagnostic or therapeutic protein that comprises a soluble IL-6 receptor-IL-6 fusion protein (sIL-6R/IL-6) and that comprises an inactivated hemagglutinin (HA) gene, thymidine kinase (TK) gene or F14.5L gene.
17. The method of claim 1 , wherein:
the recombinant vaccinia virus comprises an inactivated hemagglutinin (HA) gene, thymidine kinase (TK) gene, and F14.5L gene or locus, wherein nucleic acid encoding the diagnostic or therapeutic protein is inserted into one or more gene locus selected from among the HA gene locus, the TK gene locus and the F14.5L gene locus in the vaccinia virus.