# US 11,440,945 B2 · Systems and methods to improve vaccine efficacy

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- Number: US 11,440,945 B2
- Document ID: US11440945B2
- Status: Granted
- Kind: B2
- Application number: 16/474,503
- Filed: 2018-01-05
- Published: 2020-04-23
- Granted: 2022-09-13
- Earliest claimed: 2017-01-05
- Assignees: Fred Hutchinson Cancer Center
- Applicants: Fred Hutchinson Cancer Research Center
- Inventors: Matthias Stephan
- Web page: https://patentgrep.com/patent/US11440945B2

## CPC

- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 39/001168: {Mesothelin [MSLN]}
- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6931: {the material constituting the nanoparticle being a polymer}
- A61P 35/00: Antineoplastic agents
- A61K 2039/555: {characterised by a specific combination antigen/adjuvant}
- A61K 2039/852: {Pancreas}
- 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)
- 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

## Abstract

Systems and methods to increase the efficacy of vaccines that require or are rendered more effective with T cell mediated immunity are described. The systems and methods utilize polynucleotides that genetically modify T cells to express a T cell receptor specific for an administered vaccine antigen.

## Claims

### Claim 1

A method, comprising
administering a vaccine antigen to a subject; and
administering an effective amount of a nanoparticle to the subject; wherein the nanoparticle comprises
(i) a polynucleotide encoding a T cell receptor (TCR) that specifically binds the vaccine antigen; and
(ii) a binding fragment of an anti-CD4 or anti-CD8 antibody exposed on the surface of the nanoparticle.

### Claim 2 (depends on 1)

The method of claim 1, wherein the vaccine antigen comprises a cancer antigen selected from prostate-specific membrane antigen (PSMA), prostate stem cell antigen (PSCA), mesothelin, CD19, CD20, receptor tyrosine kinase-like orphan receptor 1 (ROR1), and Wilms' tumor protein 1 (WT1) or a fragment of PSMA, PSCA, mesothelin, CD19, CD20, ROR1, and WT1 or a viral antigen selected from Nef (66-97), Nef (116-145), Gag p17 (17-35), Gag p17-p24 (253-284), Pol 325-355 (RT 158-188), circumsporozoite protein (CSP) central repeat region, and E protein Domain III.

### Claim 3 (depends on 1)

The method of claim 1, wherein the vaccine antigen comprises a cancer antigen selected from SEQ ID NOs. 135-141 or a viral antigen selected from SEQ ID NOs: 128-134.

### Claim 4 (depends on 1)

The method of claim 1, wherein the encoded TCR comprises an α chain selected from SEQ ID NOs: 1, 4, 18, 21, 23, 25, 27, 29-32, 34, and 36.

### Claim 5 (depends on 1)

The method of claim 1, wherein the encoded TCR comprises a β chain selected from SEQ ID NOs: 2, 3, 19, 22, 24, 26, 28, 33, 35, and 37.

### Claim 6 (depends on 1)

The method of claim 1, wherein the encoded TCR comprises a sequence selected from SEQ ID NOs: 5-12, 15, 16, and 39.

### Claim 7 (depends on 1)

The method of claim 1, comprising administering an adjuvant.

### Claim 8 (depends on 7)

The method of claim 7, wherein the vaccine adjuvant is selected from CpG, Cpg-28, Polyriboinosinic polyribocytidylic acid (Poly(I:C)), α-galactoceramide, monophosphoryl lipid A (MPLA), a toll-like receptor agonist, Amino-1-isobutyl-1H-imidazo(4,5-c)quinoline, polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin, and/or a stimulator of interferon genes (STING) agonist selected from c-diGMP, c-diAMP, c-GAMP, c-AIMP, (3′,2′)c-AIMP, (2′,2′)c-AIMP, (2′,3′)c-AIMP, c-AIMP(S), c-(dAMP-dIMP), c-(dAMP-2′FdIMP), c-(2′FdAMP-2′FdIMP), (2′,3′)c-(AMP-2′FdIMP), c-[2′FdAMP(S)-2′FdIMP(S)], c-[2′FdAMP(S)-2′FdIMP(S)](POM)2, and/or dimethylxanthone acetic acid (DMXAA).

### Claim 9 (depends on 1)

The method of claim 1, wherein the polynucleotide is encapsulated within a positively-charged polymer matrix.

### Claim 10 (depends on 9)

The method of claim 9, wherein the positively-charged polymer matrix comprises poly-β-amino ester (PBAE).

### Claim 11 (depends on 9)

The method of claim 9, wherein the positively-charged polymer matrix is surrounded by a negatively-charged coating.

### Claim 12 (depends on 11)

The method of claim 11, wherein the negatively-charged coating comprises polyglutamic acid (PGA).

### Claim 13 (depends on 1)

The method of claim 1, wherein the binding fragment comprises a sequence selected from SEQ ID NOs: 41-58.

### Claim 14 (depends on 1)

The method of claim 1, wherein the nanoparticle comprises an iPB7 transposase comprising SEQ ID NO: 142.

### Claim 15 (depends on 1)

The method of claim 1, wherein the subject has a low T cell count.

### Claim 16 (depends on 1)

The method of claim 1, wherein the method improves the efficacy of the vaccination as compared to administration of the vaccine antigen alone.

### Claim 17 (depends on 1)

A kit for practicing the method of claim 1 comprising:
a vaccine antigen;
a positively-charged polymer;
a negatively-charged polymer covalently linked to a binding fragment of an anti-CD4 or anti-CD8 antibody; and
a polynucleotide encoding a T cell receptor (TCR) that specifically binds the vaccine antigen.

### Claim 18 (depends on 17)

The kit of claim 17, wherein the vaccine antigen comprises a cancer antigen selected from prostate-specific membrane antigen (PSMA), prostate stem cell antigen (PSCA), mesothelin, CD19, CD20), receptor tyrosine kinase-like orphan receptor 1 (ROR1), and Wilms' tumor gene 1 (WT1) or a fragment of PSMA, PSCA, mesothelin, CD19, CD20, ROR1, and WT1 or a viral antigen selected from Nef (66-97), Nef (116-145), Gag p17 (17-35), Gag p17-p24 (253-284), Pol 325-355 (RT 158-188), circumsporozoite protein (CSP) central repeat region, and E protein Domain III.

### Claim 19

A composition, comprising:
a vaccine antigen; and
an effective amount of a nanoparticle,
wherein the nanoparticle comprises
(i) a polynucleotide encoding a T cell receptor (TCR) that specifically binds the vaccine antigen; and
(ii) a binding fragment of an anti-CD4 or anti-CD8 antibody exposed on the surface of the nanoparticle.

### Claim 20 (depends on 19)

The composition of claim 19, wherein the vaccine antigen comprises a cancer antigen selected from prostate-specific membrane antigen (PSMA), prostate stem cell antigen (PSCA), mesothelin, CD19, CD20, receptor tyrosine kinase-like orphan receptor 1 (ROR1), and Wilms' tumor gene 1 (WT1) or a fragment of PSMA, PSCA, mesothelin, CD19, CD20, ROR1, and WT1 or a viral antigen selected from Nef (66-97), Nef (116-145), Gag p17 (17-35), Gag p17-p24 (253-284), Pol 325-355 (RT 158-188), circumsporozoite protein (CSP) central repeat region, and E protein Domain III.

### Claim 21 (depends on 19)

The composition of claim 19, comprising an adjuvant.

### Claim 22 (depends on 19)

The composition of claim 19, wherein the polynucleotide is encapsulated within a positively-charged polymer matrix.

### Claim 23 (depends on 22)

The composition of claim 22, wherein the positively-charged polymer matrix comprises poly-β-amino ester (PBAE).

### Claim 24 (depends on 22)

The composition of claim 22, wherein the positively-charged polymer matrix is surrounded by a negatively-charged coating.

### Claim 25 (depends on 24)

The composition of claim 24, wherein the negatively-charged coating comprises polyglutamic acid (PGA).

### Claim 26

A method, comprising:
administering an effective amount of a nanoparticle to a subject vaccinated with a vaccine antigen; wherein the nanoparticle comprises:
(i) a polynucleotide encoding a T cell receptor (TCR) that specifically binds the vaccine antigen; and
(ii) a binding fragment of an anti-CD4 or anti-CD8 antibody exposed on the surface of the nanoparticle.

### Claim 27 (depends on 7)

The method of claim 7, wherein the vaccine adjuvant is selected from CpG, Cpg-28, Polyriboinosinic polyribocytidylic acid (Poly(I:C)), α-galactoceramide, monophosphoryl lipid A (MPLA), 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine, polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin, and/or a stimulator of interferon genes (STING) agonist selected from c-diGMP, c-diAMP, c-GAMP, c-AIMP, (3′,2′)c-AIMP, (2′,2′)c-AIMP, (2′,3′)c-AIMP, c-AIMP(S), c-(dAMP-dIMP), c-(dAMP-2′FdIMP), c-(2′FdAMP-2′FdIMP), (2′,3′)c-(AMP-2′FdIMP), c-[2′FdAMP(S)-2′FdIMP(S)], c-[2′FdAMP(S)-2′FdIMP(S)](POM)2, and/or dimethylxanthenone acetic acid (DMXAA).

### Claim 28 (depends on 1)

The method of claim 1, wherein the vaccine antigen comprises mesothelin.