Recombinant adenoviruses for gene therapy in cancers
View Patent ↗The invention concerns recombinant viruses comprising a heterologous DNA sequence under the control of expression signals specifically active in tumor cells, and their preparation and use in the treatment and prevention of cancers.
1. A replication defective recombinant adenovirus comprising a heterologous DNA sequence under the control of an expression signal which is inducible by the an Epstein-Barr virus (EBV) antigen, or by a papilloma virus antigen, wherein the EBV antigen is EBNA 1 or EBNA 2 , and wherein the papilloma virus antigen is E 6 .
2. An The adenovirus according to claim 1 , wherein the expression signal is activated by the EBNA1 antigen, or the EBNA 2 antigen.
3. An The adenovirus according to claim 2 , wherein the expression signal consists of a chimeric promoter comprising a sequence which is activated by the EBNA1 antigen fused upstream of a viral promoter.
4. An The adenovirus according to claim 1 2 , lacking regions of its genome which are required for replication in a target cell.
5. An The adenovirus according to claim 4 , wherein said adenovirus is a type Ad5 human adenovirus or a type CAV-2 canine adenovirus.
6. An The adenovirus according to claim 1 2 , wherein the heterologous DNA sequence comprises a gene which encodes a product toxic in a cell infected by said adenovirus.
7. An The adenovirus according to claim 6 , wherein said product renders said cell sensitive to a therapeutic agent.
8. An The adenovirus according to claim 7 , wherein the gene is the thymidine kinase gene and the therapeutic agent is ganciclovir or acyclovir.
9. An The adenovirus according to claim 1 2 , wherein the heterologous DNA sequence comprises a gene which encodes a product effective to inhibit cell division.
10. An The adenovirus according to claim 9 , wherein the gene is selected from the group consisting of tumour suppressor genes, antisense sequences and ribozymes.
11. An The adenovirus according to claim 6 , wherein the heterologous DNA sequence comprises a gene whose expression product induces apoptosis of a cell infected by said adenovirus.
12. A composition comprising a the replication defective recombinant adenovirus according to claim 1 2 and an acceptable carrier.
13. A The composition according to claim 12 , in injectable form.
14. The adenovirus of claim 4 3 , wherein the viral promoter is the terminal protein 1 (TP1) gene promoter.
15. An isolated cell comprising the adenovirus of claim 1 2 .
16. The composition of claim 12 comprising from 10 6 to 10 10 pfu/ml of replication defective recombinant adenoviruses.
17. The adenovirus according to claim 2 , wherein the expression signal is the EBNA 1 responsive element ( EBNA 1 - RE ).
18. The adenovirus according to claim 14 , wherein the sequence which is activated by the EBNA 1 antigen is the EBNA 1 responsive element ( EBNA 1 - RE ).
19. The adenovirus according to claim 17 , wherein said adenovirus is a type Ad 5 human adenovirus or a type CAV- 2 canine adenovirus.
20. The adenovirus of claim 2 , wherein the expression signal comprises a promoter sequence from an Epstein- Barr virus.
21. The adenovirus according to claim 20 , wherein said adenovirus is a type Ad 5 human adenovirus or a type CAV- 2 canine adenovirus.
22. The adenovirus according to claim 20 , wherein the promoter sequence is inducible by the EBNA 1 antigen.
23. The adenovirus according to claim 1 , wherein the expression signal is inducible by the papilloma virus E 6 antigen.
24. The adenovirus according to claim 2 , wherein the expression signal comprises a BCR 2 viral promoter.