Cytomegalovirus vectors enabling control of t cell targeting

Patent metadata

Field	Value
Publication number	US-2016010112-A1
Application number	US-201414773130-A
Country	US
Kind code	A1
Filing date	Mar 5, 2014
Priority date	Mar 5, 2013
Publication date	Jan 14, 2016
Grant date	—

Abstract

Disclosed herein are CMV vectors that include a heterologous protein antigen, an active UL131 protein (or an ortholog thereof), an active UL128 protein (or an ortholog thereof), but wherein the CMV vector lacks an active UL130 protein (or an ortholog thereof). Also disclosed herein are CMV vectors comprising: a heterologous protein antigen, an active UL131 protein (or an ortholog thereof), an active UL130 protein (or an ortholog thereof), but wherein the CMV vector lacks an active UL128 protein. Further disclosed are 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.

First claim

1 . A human or animal cytomegalovirus vector comprising:
a first nucleic acid sequence that encodes a heterologous protein antigen; a second nucleic acid sequence that encodes UL128 or an ortholog thereof; and a third nucleic acid sequence that encodes UL131 or an ortholog thereof wherein the vector does not express an active UL130 protein.

2 . A human or animal cytomegalovirus vector comprising:
a first nucleic acid sequence that encodes an heterologous protein antigen; a second nucleic acid sequence that encodes UL130 or an ortholog thereof; and a third nucleic acid sequence that encodes UL131 or an ortholog thereof; wherein the vector does not express an active UL128 protein.

3 . The vector of claims 1 - 2 wherein the vector comprises a mutation in UL128 or UL130 selected from a point mutation, a frameshift mutation, or a deletion of all or less than all of UL128 or UL130.

4 . The vector of any of claims 1 - 2 further comprising a fourth nucleic acid sequence, wherein the third nucleic acid sequence comprises an antisense sequence or an RNAi sequence that inhibits the expression of UL128 or UL130.

5 . The vector of claims 1 - 4 wherein the heterologous antigen comprises a pathogen specific antigen.

6 . The vector of claim 5 wherein the pathogen specific antigen is derived from a human immunodeficiency virus, simian immunodeficiency virus, or Mycobacterium tuberculosis.

7 . A method of generating a CD8 + T cell response to a heterologous antigen in a subject, the method comprising:
administering an effective amount of a first cytomegalovirus (CMV) vector to the subject; the first CMV vector comprising a first nucleic acid sequence encoding a first heterologous antigen and a second nucleic acid sequence encoding an active UL131 protein;
wherein the first CMV vector does not encode an active UL128 protein or does not encode an active UL130 protein; and wherein at least 10% of the CD8+ T cell to the heterologous antigen is directed against epitopes presented by MHC Class II.

8 . The method of claim 7 wherein the first CMV vector does not encode an active UL128 protein and does not encode an active UL130 protein.

9 . The method of claim 7 wherein the response comprises at least 50% Class II restricted CD8+ epitopes.

10 . The method of any of claims 7 - 9 wherein the first heterologous antigen comprises a pathogen specific antigen.

11 . The method of claim 10 wherein the pathogen specific antigen is derived from human immunodeficiency virus, simian immunodeficiency virus, or Mycobacterium tuberculosis.

12 . The method of any of claims 7 - 11 wherein the subject has been previously exposed to CMV.

13 . The method of any of claims 7 - 12 wherein the subject is a human or nonhuman primate.

14 . The method of any of claims 7 - 13 wherein administering comprises intravenous, intramuscular, intraperitoneal, or oral administration of the CMV vector.

15 . The method of claim 7 further comprising administering a second CMV vector comprising a third nucleic acid sequence encoding a second heterologous antigen to the subject.

16 . The method of claim 15 where in the second CMV vector encodes an active UL128 protein and an active UL130 protein.

17 . The method of claim 15 or 16 wherein the first heterologous antigen and the second heterologous antigen are the same antigen.

18 . The method of claims 15 - 17 wherein the second CMV vector is administered before, concurrently with or after the first CMV vector.

Assignees

• Univ Oregon Health & Science

Inventors

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

Classifications

• C12N15/86 Primary

  Viral vectors · CPC title

• A61K2039/5256

  expressing foreign proteins · CPC title

• A61K48/00

  Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy · CPC title

• C12N7/00

  Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00) · CPC title

• C12N2710/16011

  Herpesviridae · CPC title