Recombinant adenoviral vector and methods of use

• US 5,932,210 A
• Filed: 10/28/1997
• Issued: 08/03/1999
• Est. Priority Date: 10/25/1993
• Status: Expired due to Term

• Current Assignee: Canji Inc. (Merck & Co., Inc.)
• Original Assignee: Canji Inc. (Merck & Co., Inc.)
• Inventors: Maneval, Daniel C., Wills, Ken N., Gregory, Richard J.
• Primary Examiner(s): Guzo, David
• Application Number:
  US08/959,638
• Time in Patent Office: 644 Days
• Field of Search: 435/69.1, 435/172.1, 435/172.3, 435/320.1, 435/235.1, 435/455, 435/456, 435/157, 424/93.2, 424/93.6
• US Class Current: 424/93.2
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/4746 p53
• CPC Class Codes: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2710/10343 viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 2830/008 cell type or tissue specific enhancer/promoter combination

Abstract

This invention provides a recombinant adenovirus expression vector characterized by the partial or total deletion of the adenoviral protein IX DNA and having a gene encoding a foreign protein or a functional fragment or mutant thereof. Transformed host cells and a method of producing recombinant proteins and gene therapy also are included within the scope of this invention. Thus, for example, the adenoviral vector of this invention can contain a foreign gene for the expression of a protein effective in regulating the cell cycle, such as p53, Rb, or mitosin, or in inducing cell death, such as the conditional suicide gene thymidine kinase. (The latter must be used in conjunction with a thymidine kinase metabolite in order to be effective).

Claims

1. A composition comprising a recombinant adenovirus expression vector and a pharmaceutically acceptable carrier, the vector comprising:

(a) an insert of exogenous DNA comprising a gene encoding a foreign protein; and

(b) adenovirus DNA in which all of the coding sequences of E1a, E1b, and protein IX, and at least part of E3 have been deleted.

2. The composition of claim 1, wherein the protein IX polyadenylation site is deleted from the adenovirus vector.

3. The composition of claim 1, wherein the adenovirus is a group C adenovirus selected from a serotype 1, 2, 5, or 6.

4. The composition of claim 1, wherein the insert of exogenous DNA is up to 2.6 KB.

5. The composition of claim 1, wherein the insert of exogenous DNA is up to 4.5 KB.

6. The composition of claim 1, wherein the foreign protein is a functional protein or a biologically active fragment thereof.

7. The composition of claim 1, wherein the foreign protein is a tumor suppressor protein.

8. The composition of claim 1, wherein the foreign protein is a suicide protein or functional equivalent thereof.

9. The composition of claim 1, wherein the gene encoding the foreign protein is expressed under control of a cytomegalovirus (CMV) promoter.

10. The composition of claim 1, wherein the gene encoding the foreign protein is expressed under control of an adenovirus promoter.

11. The composition of claim 1, wherein the exogenous DNA further comprises a polyadenylation site.

12. The composition of claim 1, wherein the vector is A/C/N/53.

13. The composition of claim 1, wherein the vector is A/M/N/53.

14. The composition of claim 1, further comprising a host cell transformed with the adenovirus vector.

15. The composition of claim 1, wherein the pharmaceutically acceptable carrier comprises a physiologically acceptable compound.

16. The composition of claim 7, wherein the tumor suppressor protein is p53.

17. The composition of claim 7, wherein the tumor suppressor protein is RB56.

18. The composition of claim 9, wherein the CMV promoter is the CMV immediate early promoter.

19. The composition of claim 18, wherein the adenovirus promoter is the adenovirus 2 major late promoter.