# US 10,300,145 B2 · Synthetic nanoparticles for delivery of immunomodulatory compounds

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- Number: US 10,300,145 B2
- Document ID: US10300145B2
- Status: Granted
- Kind: B2
- Application number: 15/650,177
- Filed: 2017-07-14
- Published: 2018-01-18
- Granted: 2019-05-28
- Earliest claimed: 2016-07-15
- Assignees: Massachusetts Institute of Technology
- Applicants: Massachusetts Institute of Technology
- Inventors: Darrell J. Irvine; Eric Dane
- Web page: https://patentgrep.com/patent/US10300145B2

## CPC

- A61K 47/6425: {the peptide or protein in the drug conjugate being a receptor, e.g. CD4, a cell surface antigen, i.e. not a peptide ligand targeting the antigen, or a cell surface determinant, i.e. a part of the surface of a cell}
- A61K 9/5123: {Organic compounds, e.g. fats, sugars}
- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61K 47/543: {Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine}
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 47/645: {Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT}
- A61K 47/6807: {the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense}
- A61K 47/6911: {the form being a liposome}
- C07K 14/003: {Peptide-nucleic acids (PNAs)}
- C08G 69/10: Alpha-amino-carboxylic acids {(polysuccinimides C08G73/1092)}
- C07K 19/00: Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes}
- 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)
- 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)
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS

## Abstract

The present disclosure provides a synthetic nanoparticle comprising a peptide nucleic acid (PNA) oligomer conjugated to a lipid, wherein the PNA oligomer noncovalently complexes with an immunomodulatory compound, thereby forming a nanoparticle. The nanoparticles are useful to elicit immune responses and can be used to treat a broad range of cancers and infectious diseases.

## Claims

### Claim 1

A synthetic nanoparticle comprising a PNA-amphiphile conjugate and an immunomodulatory compound, wherein the PNA-amphiphile conjugate comprises (i) a peptide nucleic acid (PNA) oligomer comprising at least one guanine nucleoside, or an analog thereof, (ii) one or more lipids, and optionally, (iii) a polymer, wherein the immunomodulatory compound is a cyclic dinucleotide (CDN), and wherein the CDN is noncovalently complexed with the PNA oligomer, thereby forming a synthetic nanoparticle.

### Claim 2 (depends on 1)

The synthetic nanoparticle of claim 1, wherein the PNA oligomer comprises 3 guanine nucleosides, or analogs thereof, or at least one positively charged amino acid.

### Claim 3 (depends on 1)

The synthetic nanoparticle of claim 1, wherein the positively charged amino acid is lysine or arginine.

### Claim 4 (depends on 1)

The synthetic nanoparticle of claim 1, wherein the PNA oligomer is represented from N- to C- terminus by the formula: Xaa1-(G)n-Xaa2, wherein Xaa1 is selected from the group consisting of lysine and arginine, wherein G is guanine and n is 1 to 12, and wherein Xaa2 is selected from the group consisting of lysine and arginine.

### Claim 5 (depends on 4)

The synthetic nanoparticle of claim 4, wherein Xaa1 and Xaa2 are lysine and n is 3 to 6.

### Claim 6 (depends on 1)

The synthetic nanoparticle of claim 1, wherein the PNA oligomer is lysine-(G)3-lysine, wherein G is guanine.

### Claim 7 (depends on 1)

The synthetic nanoparticle of claim 1, wherein the one or more lipids is a diacyl lipid tail.

### Claim 8 (depends on 1)

The synthetic nanoparticle of claim 1, wherein the CDN is cyclic di-guanine mono phosphate (cdGMP), an agonist of STING (STimulator of Interferon Genes), cyclic di-inosine monophosphate, or cyclic d-AMP.

### Claim 9 (depends on 1)

The synthetic nanoparticle of claim 1, further comprising a polymer, wherein the polymer is polyethylene glycol, or another hydrophilic polymer.

### Claim 10 (depends on 1)

The synthetic nanoparticle of claim 1, wherein the nanoparticle has a diameter in the range of approximately 10 nm to approximately 100 nm.

### Claim 11 (depends on 1)

The synthetic nanoparticle of claim 1, wherein the nanoparticle comprises a structure selected from the group consisting of a worm-like micelle, a disc-like micelle, a nanofiber and a spherical micelle.

### Claim 12 (depends on 1)

A composition comprising a synthetic nanoparticle of claim 1, and a pharmaceutically acceptable carrier.

### Claim 13 (depends on 12)

A method of modulating an immune response in a subject, inducing or enhancing an immune response in a subject with cancer, or treating cancer, comprising administering to a subject in need thereof the composition of claim 12.

### Claim 14 (depends on 1)

A vaccine comprising the synthetic nanoparticle of claim 1, and an antigen, optionally wherein the antigen is conjugated to the synthetic nanoparticle.

### Claim 15 (depends on 14)

A method of immunizing a subject comprising administering the vaccine of claim 14.

### Claim 16

A complex comprising a peptide nucleic acid (PNA) oligomer comprising at least one guanine nucleoside, or an analog thereof, noncovalently bound to a cyclic dinucleotide (CDN).

### Claim 17

A PNA-amphiphile conjugate comprising a peptide nucleic acid (PNA) oligomer comprising at least one guanine nucleoside, or an analog thereof, and one or more lipids, and optionally, a polymer conjugated to the one or more lipids or the PNA.

### Claim 18 (depends on 17)

A method of making a synthetic nanoparticle comprising combining the PNA-amphiphile conjugate of claim 17 with a cyclic dinucleotide (CDN), thereby forming a synthetic nanoparticle.

### Claim 19 (depends on 14)

A method of inducing an antigen specific CD8+T cell response in a subject inducing an immune response to an antigen in a subject, or activating STING in a subject, the method comprising administering the vaccine of claim 14 to the subject.