Cytomegalovirus vectors enabling control of T cell targeting

Patent metadata

Field	Value
Publication number	US-9783823-B2
Application number	US-201414773130-A
Country	US
Kind code	B2
Filing date	Mar 5, 2014
Priority date	Mar 5, 2013
Publication date	Oct 10, 2017
Grant date	Oct 10, 2017

Abstract

CMV vectors comprising a heterologous protein antigen, an active UL131 protein (or an ortholog thereof), and an active UL128 protein (or an ortholog thereof) but lacking an active UL130 protein (or an ortholog thereof) are provided. CMV vectors comprising a heterologous protein antigen, an active UL131 protein (or an ortholog thereof), and an active UL130 protein (or an ortholog thereof) but lacking an active UL128 protein are also provided. In addition, methods of using CMV vectors to generate an immune response characterized as having at least 10% of the CD8+ T cells directed against epitopes presented by MHC Class II are provided.

First claim

The invention claimed is:

1. A method of generating a CD8 + T cell response to a heterologous antigen in a subject, the method comprising administering to the subject an effective amount of a first recombinant cytomegalovirus (CMV) vector before, concurrently with, or after administering an effective amount of a second recombinant CMV vector;
wherein the first CMV vector comprises a nucleic acid sequence encoding a heterologous antigen and an active UL131 protein, or an ortholog thereof; wherein the first CMV vector does not encode an active UL128 protein, or an ortholog thereof, or does not encode an active UL130 protein, or an ortholog thereof;
wherein the second CMV vector comprises a nucleic acid sequence encoding the heterologous antigen and active UL128, UL130, and UL131 proteins, or orthologs thereof;
wherein at least 10% of the CD8 + T cells to the heterologous antigen are directed against epitopes presented by Major Histocompatibility Complexes (MHC) Class II; and
wherein:
(i.) the first and second CMV vectors are attenuated human CMV (HCMV) vectors, and the subject is a human; or
(ii.) the first and second CMV vectors are attenuated rhesus CMV (RhCMV) vectors, and the subject is a rhesus macaque.

2. The method of claim 1 , wherein the first CMV vector does not encode an active UL128 protein, or an ortholog thereof, and does not encode an active UL130 protein, or an ortholog thereof.

3. The method of claim 1 , wherein at least 50% of the CD8 + T cells to the heterologous antigen are directed against epitopes presented by MHC Class II.

4. The method of claim 1 , wherein the heterologous antigen comprises a pathogen specific antigen.

5. The method of claim 4 , wherein the pathogen specific antigen is derived from human immunodeficiency virus, simian immunodeficiency virus, herpes simplex type 1, herpes simplex type 2, hepatitis B virus, human papillomavirus, or Mycobacterium tuberculosis.

6. The method of claim 1 , wherein the first and second CMV vectors are attenuated RhCMV vectors, and wherein the subject is a rhesus macaque that has been previously exposed to RhCMV.

7. The method of claim 1 , wherein the first and second CMV vectors are attenuated HCMV vectors, and wherein the subject is a human that has been previously exposed to HCMV.

8. The method of claim 1 , wherein administering comprises intravenous, intramuscular, intraperitoneal, or oral administration.

9. The method of claim 1 , wherein the heterologous antigen comprises a cancer antigen.

10. The method of claim 9 , wherein the cancer antigen is a prostate cancer antigen.

11. The method of claim 7 , wherein the first HCMV vector and the second HCMV vector are administered concurrently.

12. The method of claim 6 , wherein the first RhCMV vector and the second RhCMV vector are administered concurrently.

13. A method of generating a CD8 + T cell response to a heterologous antigen in a subject, the method comprising administering to the subject an effective amount of a first recombinant CMV vector before, concurrently with, or after administering an effective amount of a second recombinant CMV vector;
wherein the first CMV vector comprises a nucleic acid sequence encoding a first heterologous antigen and an active UL131 protein, or an ortholog thereof; wherein the first CMV vector does not encode an active UL128 protein, or an ortholog thereof, or does not encode an active UL130 protein, or an ortholog thereof;
wherein the second CMV vector comprises a nucleic acid sequence encoding a second heterologous antigen and active UL128, UL130, and UL131 proteins, or orthologs thereof;
wherein at least 10% of the CD8 + T cells to the first heterologous antigen are directed against epitopes presented by MHC Class II; and
wherein:
(i.) the first and second CMV vectors are attenuated HCMV vectors, and the subject is human that has been previously exposed to HCMV; or
(ii.) the first and second CMV vectors are attenuated RhCMV vectors, and the subject is a rhesus macaque that has been previously exposed to RhCMV.

14. The method of claim 13 , wherein the first CMV vector does not encode an active UL128 protein, or an ortholog thereof, and does not encode an active UL130 protein, or an ortholog thereof.

15. The method of claim 13 , wherein at least 50% of the CD8 + T cells to the first heterologous antigen are directed against epitopes presented by MHC Class II.

16. The method of claim 13 , wherein the first heterologous antigen comprises a pathogen specific antigen.

17. The method of claim 16 , wherein the pathogen specific antigen is derived from human immunodeficiency virus, simian immunodeficiency virus, herpes simplex type 1, herpes simplex type 2, hepatitis B virus, human papillomavirus, or Mycobacterium tuberculosis.

18. The method of claim 13 , wherein the first heterologous antigen comprises a cancer antigen.

19. The method of claim 18 , wherein the cancer antigen is a prostate cancer antigen.

20. The method of claim 13 , wherein the second heterologous antigen comprises a pathogen specific antigen.

21. The method of claim 20 , wherein the pathogen specific antigen is derived from human immunodeficiency virus, simian immunodeficiency virus, herpes simplex type 1, herpes simplex type 2, hepatitis B virus, human papillomavirus, or Mycobacterium tuberculosis.

22. The method of claim 13 , wherein the second heterologous antigen comprises a cancer antigen.

23. The method of claim 22 , wherein the cancer antigen is a prostate cancer antigen.

24. The method of claim 13 , wherein the first and second CMV vectors are attenuated HCMV vectors, and wherein the subject is a human that has been previously exposed to HCMV.

25. The method of claim 13 , wherein the first and second CMV vectors are attenuated RhCMV vectors, and wherein the subject is a rhesus macaque that has been previously exposed to RhCMV.

26. The method of claim 24 , wherein the first HCMV vector and the second HCMV vector are administered concurrently.

27. The method of claim 25 , wherein the first RhCMV vector and the second RhCMV vector are administered concurrently.

28. The method of claim 13 , wherein administering comprises intravenous, intramuscular, intraperitoneal, or oral administration.

Assignees

• Univ Oregon Health & Science

Inventors

• Picker Louis
• Hansen Scott
• Frueh Klaus
• Malouli Daniel

Classifications

• C12N2740/15034

  Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein · CPC title

• C12N2710/16143

  viral genome or elements thereof as genetic vector · CPC title

• A61K2039/572

  cytotoxic response · CPC title

• A61K2039/5256

  expressing foreign proteins · CPC title

• A61K39/04

  Mycobacterium, e.g. Mycobacterium tuberculosis · CPC title