# US 11,305,015 B2 · Cytomegalovirus vectors eliciting T cells restricted by major histocompatibility complex E molecules

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- Number: US 11,305,015 B2
- Document ID: US11305015B2
- Status: Granted
- Kind: B2
- Application number: 16/696,403
- Filed: 2019-11-26
- Published: 2020-07-30
- Granted: 2022-04-19
- Earliest claimed: 2016-10-18
- Assignees: Oregon Health & Science University
- Applicants: Oregon Health & Science University
- Inventors: Louis Picker; Scott Hansen; Klaus Frueh; Daniel Malouli; Jay Nelson; Jonah Sacha; Meaghan Hancock
- Web page: https://patentgrep.com/patent/US11305015B2

## CPC

- A61K 45/00: Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K 39/12: Viral antigens
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/32: T-cell receptors [TCR]
- A61K 40/42: Cancer antigens
- A61K 40/46: Viral antigens
- A61P 31/14: for RNA viruses
- C07K 14/005: from viruses
- C12N 7/045: {Pseudoviral particles; Non infectious pseudovirions, e.g. genetically engineered}
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C12N 15/86: Viral vectors
- A61K 2039/5256: {expressing foreign proteins}
- A61K 2039/53: {DNA (RNA) vaccination}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- A61K 2039/55: {characterised by the host/recipient, e.g. newborn with maternal antibodies}
- A61K 2039/572: {cytotoxic response}
- C12N 2310/141: MicroRNAs, miRNAs
- C12N 2710/16134: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- C12N 2710/16143: viral genome or elements thereof as genetic vector
- C12N 2710/16171: Demonstrated in vivo effect
- C12N 2740/15034: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

CMV vectors that lack active UL128, UL130, UL146 and UL147 proteins that may also comprise one or more microRNA regulatory elements (MRE) that restrict expression of the CMV are provided. Immunization with CMV vectors having the described features allows selection of different CD8+ T cell responses—CD8+ T cells restricted by MHC-Ia, MHC-II, or by MHC-E.

## Claims

### Claim 1

A cytomegalovirus (CMV) vector comprising:
(a) a first nucleic acid sequence that encodes at least one heterologous antigen; and
(b) a second nucleic acid sequence comprising a first heterologous microRNA recognition element (MRE) operably linked to a UL122 (IE2) or UL79 CMV gene, wherein the MRE is complementary to a microRNA that is expressed by a cell of endothelial lineage, wherein the microRNA is miR-126-3p, miR-130a, miR-210, miR-221/222, miR-378, miR-296, or miR-328.

### Claim 2 (depends on 1)

The CMV vector of claim 1, wherein the microRNA is miR-126-3p.

### Claim 3 (depends on 1)

The CMV vector of claim 1, wherein the at least one heterologous antigen comprises a pathogen-specific antigen, a tumor antigen, a tissue-specific antigen, or a host self-antigen.

### Claim 4 (depends on 3)

The CMV vector of claim 3, wherein the host self-antigen is an antigen derived from the variable region of a T cell receptor (TCR) or an antigen derived from the variable region of a B cell receptor.

### Claim 5 (depends on 3)

The CMV vector of claim 3, wherein the pathogen specific antigen is derived from a pathogen selected from the group consisting of: human immunodeficiency virus, simian immunodeficiency virus, herpes simplex virus type 1, herpes simplex virus type 2, hepatitis B virus, hepatitis C virus, papillomavirus, Plasmodium parasites, and Mycobacterium tuberculosis.

### Claim 6 (depends on 3)

The CMV vector of claim 3, wherein the tumor antigen is related to a cancer selected from the group consisting of: acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, non-Hodgkin's lymphoma, multiple myeloma, malignant melanoma, breast cancer, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, colon cancer, renal cell carcinoma (RCC), and germ cell tumors.

### Claim 7 (depends on 1)

The CMV vector of claim 1, wherein the CMV vector does not express an active UL82 (pp71) protein, or an ortholog thereof.

### Claim 8 (depends on 1)

The CMV vector of claim 1, wherein the CMV vector does not express an active US11 protein, or an ortholog thereof.

### Claim 9 (depends on 1)

The CMV vector of claim 1, wherein the CMV vector does not express an active UL82 (pp71) protein or an active US11 protein, or orthologs thereof.

### Claim 10 (depends on 1)

The CMV vector of claim 1, wherein the CMV vector is a human CMV vector (HCMV), a cynomolgus CMV (CyCMV) vector, or a rhesus CMV (RhCMV) vector.

### Claim 11 (depends on 1)

A method of generating an immune response in a subject to at least one heterologous antigen, the method comprising:
administering to the subject the CMV vector of claim 1 in an amount effective to elicit a CD8+ T cell response to the at least one heterologous antigen.

### Claim 12 (depends on 11)

The method of claim 11, further comprising administering to the subject a second CMV vector comprising a nucleic acid sequence that encodes at least one heterologous antigen.

### Claim 13 (depends on 12)

The method of claim 12, wherein the at least one heterologous antigen of the first CMV vector and the second CMV vector are the same antigen.

### Claim 14 (depends on 12)

The method of claim 12, wherein the second CMV vector is administered before, concurrently with, or after the first CMV vector.

### Claim 15 (depends on 11)

The method of claim 11, wherein the subject has been previously exposed to CMV.

### Claim 16 (depends on 11)

The method of claim 11, wherein the subject is a human or nonhuman primate.

### Claim 17 (depends on 11)

The method of claim 11, wherein administering the CMV vector comprises subcutaneous, intravenous, intramuscular, intraperitoneal, or oral administration of the CMV vector.

### Claim 18

A cytomegalovirus (CMV) vector comprising:
(a) a first nucleic acid sequence that encodes at least one heterologous antigen;
(b) a second nucleic acid sequence comprising a first heterologous microRNA recognition element (MRE) operably linked to a UL122 (IE2) or UL79 CMV gene, wherein the MRE is complementary to a microRNA that is expressed by a cell of endothelial lineage; and
(c) a third nucleic acid sequence comprising a second heterologous MRE operably linked to a UL122 (IE2) or UL29-UL79 CMV gene, wherein the MRE is complementary to a microRNA that is expressed by a cell of myeloid lineage, wherein the first microRNA is miR-126-3p, miR-130a, miR-210, miR-221/222, miR-378, miR-296, or miR-328 and the second microRNA is miR-142-3p, miR-223, miR-27a, miR-652, miR-155, miR-146a, miR-132, miR-21, or miR-125.

### Claim 19 (depends on 18)

The CMV vector of claim 18, wherein the first microRNA is miR-126-3p.