IP Library › Granted Patent US 9,982,241
Granted Patent B2
US 9,982,241 · App. 14/872,756 · Granted May 29, 2018

Recombinant HCMV and RHCMV vectors and uses thereof

Inventors: Louis Picker (Portland, OR); Jay A. Nelson (Lake Oswego, OR); Klaus Frueh (Portland, OR); Michael A. Jarvis (Portland, OR); Scott G. Hansen (Portland, OR)
Assignee: Oregon Health & Science University
C12N7/00A61K39/0011A61K39/08A61K39/12A61K39/13A61K39/145A61K39/275C12N15/86C12N15/869A61K2039/5254A61K2039/5256A61K2039/552A61K2039/572A61K2039/58C07K14/005C07K14/045C07K14/16C07K14/161C07K14/162C07K14/163C12N2710/16111C12N2710/16134C12N2710/16141C12N2710/16143C12N2710/16162C12N2710/16171C12N2710/24134C12N2740/15022C12N2740/15034C12N2760/14134C12N2760/16134C12N2770/32634
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Quick Facts
Patent No.
US 9,982,241
App. No.
14/872,756
Granted
May 29, 2018
Kind
B2
Abstract

The recombinant rhesus cytomegalovirus (RhCMV) and human cytomegalovirus (HCMV) vectors of this invention encode heterologous antigens, such as pathogen-specific antigens or tumor antigens, which may be used, for example, for the treatment or prevention of infectious disease or cancer. The recombinant RhCMV or HCMV vectors elicit and maintain high level cellular immune responses specific for the heterologous antigen while including deletions in one or more genes essential or augmenting for CMV replication, dissemination or spread.

Claims (60)

1. A method of treating a subject with an infectious disease or cancer comprising administering to the subject in need thereof a recombinant viral vector comprising a nucleic acid sequence encoding a human cytomegalovirus (HCMV) or rhesus cytomegalovirus (RhCMV) backbone vector and at least one heterologous antigen,

wherein the at least one heterologous antigen is a pathogen-specific antigen or a tumor antigen, and

wherein the recombinant viral vector: (a) comprises a deletion in the HCMV UL82 or RhCMV Rh110 gene that eliminates expression of a functional pp71 protein, (b) is deficient in host to host spread, (c) infects a HCMV or RhCMV seropositive host upon administration of said recombinant viral vector, and (d) induces and maintains a long-term effector memory T cell response to the at least one heterologous antigen in the seropositive host.

2. The method of claim 1 , wherein the recombinant viral vector further comprises a deletion in a HCMV or RhCMV gene or gene region non-essential for growth in vivo.

3. The method of claim 2 , wherein the non-essential HCMV or RhCMV gene region is selected from the group consisting of: the RL11 family, the pp65 family, the US12 family, and the US28 family.

4. The method of claim 1 , wherein the recombinant viral vector further comprises at least one deletion in a HCMV or RhCMV gene required for optimal growth in certain cell types.

5. The method of claim 4 , wherein the at least one deletion in a HCMV gene required for optimal growth in certain cell types comprises a deletion in UL64 or US29, or a combination thereof.

6. The method of claim 4 , wherein the recombinant viral vector has a deficient tropism for epithelial cells, the central nervous system (CNS), macrophages, or a combination thereof.

7. The method of claim 1 , wherein the recombinant viral vector further comprises a deletion in at least one immune modulatory HCMV gene selected from the group consisting of: US2, US3, US4, US5, US6, US7, US8, US9, US10, US11, UL118, UL119, UL36, UL37, UL111a, UL146, and UL147.

8. The method of claim 1 , wherein the recombinant viral vector further comprises a deletion in at least one immune modulatory RhCMV gene selected from the group consisting of: Rh158, Rh159, Rh160, Rh161, Rh162, Rh163, Rh164, Rh165, Rh166, Rh182, Rh183, Rh184, Rh185, Rh186, Rh187, Rh188, and Rh189.

9. The method of claim 1 , wherein the subject is a human.

10. The method of claim 1 , wherein the subject is a non-human primate.

11. A method of treating a subject infected with human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) comprising administering to the subject in need thereof a recombinant viral vector comprising a nucleic acid sequence encoding a HCMV or RhCMV backbone vector and at least one HIV-derived or SIV-derived antigen,

wherein the recombinant viral vector: (a) comprises a deletion in the HCMV UL82 or RhCMV Rh110 gene that eliminates expression of a functional pp71 protein, (b) is deficient in host to host spread, (c) infects a HCMV or RhCMV seropositive host upon administration of said recombinant viral vector, and (d) induces and maintains a long-term effector memory T cell response to the at least one HIV-derived or SIV-derived antigen in the seropositive host.

12. The method of claim 11 , wherein the HIV-derived or SIV-derived antigen is selected from the group consisting of: Gag, Pol, Env, Rev, Tat, and Nef, or an epitope or antigenic fragment thereof.

13. The method of claim 11 , wherein the subject is a human.

14. The method of claim 11 , wherein the subject is a non-human primate.

15. A method of inducing a tumor-specific or pathogen-specific immune response in a subject at risk of developing cancer or becoming infected with an infectious disease comprising administering to the subject in need thereof a recombinant viral vector comprising a nucleic acid sequence encoding a HCMV or RhCMV backbone vector and at least one heterologous antigen,

wherein the at least one heterologous antigen is a tumor antigen or a pathogen-specific antigen, and

wherein the recombinant viral vector: (a) comprises a deletion in the HCMV UL82 or RhCMV Rh110 gene that eliminates expression of a functional pp71 protein, (b) is deficient in host to host spread, (c) infects a HCMV or RhCMV seropositive host upon administration of said recombinant viral vector, and (d) induces and maintains a long-term effector memory T cell response to the at least one heterologous antigen in the seropositive host.

16. The method of claim 15 , wherein the recombinant viral vector further comprises a deletion in a HCMV or RhCMV gene or gene region non-essential for growth in vivo.

17. The method of claim 16 , wherein the non-essential HCMV or RhCMV gene region is selected from the group consisting of: the RL11 family, the pp65 family, the US12 family, and the US28 family.

18. The method of claim 15 , wherein the recombinant viral vector further comprises at least one deletion in a HCMV or RhCMV gene required for optimal growth in certain cell types.

19. The method of claim 18 , wherein the at least one deletion in a HCMV gene required for optimal growth in certain cell types comprises a deletion in UL64 or US29, or a combination thereof.

20. The method of claim 18 , wherein the recombinant viral vector has a deficient tropism for epithelial cells, the CNS, macrophages, or a combination thereof.

21. The method of claim 15 , wherein the recombinant viral vector further comprises a deletion in at least one immune modulatory HCMV gene selected from the group consisting of: US2, US3, US4, US5, US6, US7, US8, US9, US10, US11, UL118, UL119, UL36, UL37, UL111a, UL146, and UL147.

22. The method of claim 15 , wherein the recombinant viral vector further comprises a deletion in at least one immune modulatory RhCMV gene selected from the group consisting of: Rh158, Rh159, Rh160, Rh161, Rh162, Rh163, Rh164, Rh165, Rh166, Rh182, Rh183, Rh184, Rh185, Rh186, Rh187, Rh188, and Rh189.

23. The method of claim 15 , wherein the subject is a human.

24. The method of claim 15 , wherein the subject is a non-human primate.

25. A method of inducing an HIV-specific or SIV-specific immune response in a subject at risk of becoming infected with HIV or SIV comprising administering to the subject in need thereof a recombinant viral vector comprising a nucleic acid sequence encoding a HCMV or RhCMV backbone vector and at least one HIV-derived or SIV-derived antigen,

wherein the recombinant viral vector: (a) comprises a deletion in the HCMV UL82 or RhCMV Rh110 gene that eliminates expression of a functional pp71 protein, (b) is deficient in host to host spread, (c) infects a HCMV or RhCMV seropositive host upon administration of the recombinant viral vector, and (d) induces and maintains a long-term effector memory T cell response to the at least one HIV-derived or SIV-derived antigen in the seropositive host.

26. The method of claim 25 , wherein the HIV-derived or SIV-derived antigen is selected from the group consisting of: Gag, Pol, Env, Rev, Tat, and Nef, or an epitope or antigenic fragment thereof.

27. The method of claim 25 , wherein the subject is a human.

28. The method of claim 25 , wherein the subject is a non-human primate.

29. The method of claim 1 , wherein the nucleic acid sequence of the recombinant viral vector further encodes at least one cellular microRNA (miRNA) target sequence.

30. The method of claim 29 , wherein the at least one miRNA target sequence is complimentary to an miRNA expressed in tissue selected from myeloid lineage cells, central nervous system tissue, and liver tissue.

31. The method of claim 29 , wherein the at least one miRNA target sequence is complimentary to an miRNA selected from miR-124, miR-142-3p, and miR-122.

32. The method of claim 11 , wherein the recombinant viral vector further comprises a deletion in a HCMV or RhCMV gene or gene region non-essential for growth in vivo.

33. The method of claim 32 , wherein the non-essential HCMV or RhCMV gene region is selected from the group consisting of: the RL11 family, the pp65 family, the US12 family, and the US28 family.

34. The method of claim 11 , wherein the nucleic acid sequence of the recombinant viral vector further encodes at least one cellular microRNA (miRNA) target sequence.

35. The method of claim 34 , wherein the at least one miRNA target sequence is complimentary to an miRNA expressed in tissue selected from myeloid lineage cells, central nervous system tissue, and liver tissue.

36. The method of claim 34 , wherein the at least one miRNA target sequence is complimentary to an miRNA selected from miR-124, miR-142-3p, and miR-122.

37. The method of claim 15 , wherein the nucleic acid sequence of the recombinant viral vector further encodes at least one cellular microRNA (miRNA) target sequence.

38. The method of claim 37 , wherein the at least one miRNA target sequence is complimentary to an miRNA expressed in tissue selected from myeloid lineage cells, central nervous system tissue, and liver tissue.

39. The method of claim 37 , wherein the at least one miRNA target sequence is complimentary to an miRNA selected from miR-124, miR-142-3p, and miR-122.

40. The method of claim 25 , wherein the recombinant viral vector further comprises a deletion in a HCMV or RhCMV gene or gene region non-essential for growth in vivo.

41. The method of claim 40 , wherein the non-essential HCMV or RhCMV gene region is selected from the group consisting of: the RL11 family, the pp65 family, the US12 family, and the US28 family.

42. The method of claim 25 , wherein the nucleic acid sequence of the recombinant viral vector further encodes at least one cellular microRNA (miRNA) target sequence.

43. The method of claim 42 , wherein the at least one miRNA target sequence is complimentary to an miRNA expressed in tissue selected from myeloid lineage cells, central nervous system tissue, and liver tissue.

44. The method of claim 42 , wherein the at least one miRNA target sequence is complimentary to an miRNA selected from miR-124, miR-142-3p, and miR-122.

45. The method of claim 1 , wherein the pathogen-specific antigen is a herpes simplex virus (HSV)-1 antigen or a HSV-2 antigen.

46. The method of claim 1 , wherein the pathogen-specific antigen is a human papilloma virus (HPV) antigen.

47. The method of claim 1 , wherein the pathogen-specific antigen is a hepatitis B virus antigen.

48. The method of claim 1 , wherein the tumor antigen is a prostate cancer antigen.

49. The method of claim 48 , wherein the prostate cancer antigen is prostate-specific antigen (PSA).

50. The method of claim 15 , wherein the pathogen-specific antigen is a HSV-1 antigen or a HSV-2 antigen.

51. The method of claim 15 , wherein the pathogen-specific antigen is a HPV antigen.

52. The method of claim 15 , wherein the pathogen-specific antigen is a hepatitis B virus antigen.

53. The method of claim 15 , wherein the tumor antigen is a prostate cancer antigen.

54. The method of claim 53 , wherein the tumor antigen is PSA.

Continuity (6)
Division 13694280 · Nov 14, 2012
Continuation In Part PCTUS2011036657 · May 16, 2011
Continuation In Part PCTUS2011029930 · Mar 25, 2011
Provisional Application 61334976 · May 14, 2010
Provisional Application 61376911 · Aug 25, 2010
Related Publication 20160114027A1 · Apr 28, 2016