Synthetic nanoparticles for delivery of immunomodulatory compounds

Patent metadata

Field	Value
Publication number	US-10300145-B2
Application number	US-201715650177-A
Country	US
Kind code	B2
Filing date	Jul 14, 2017
Priority date	Jul 15, 2016
Publication date	May 28, 2019
Grant date	May 28, 2019

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.

First claim

We 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.

2. 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.

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

4. The synthetic nanoparticle of claim 1 , wherein the PNA oligomer is represented from N- to C- terminus by the formula: Xaa 1 -(G) n -Xaa 2 , wherein Xaa 1 is selected from the group consisting of lysine and arginine, wherein G is guanine and n is 1 to 12, and wherein Xaa 2 is selected from the group consisting of lysine and arginine.

5. The synthetic nanoparticle of claim 4 , wherein Xaa 1 and Xaa 2 are lysine and n is 3 to 6.

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

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

8. 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.

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

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

11. 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.

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

13. 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 .

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

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

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).

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.

18. 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.

19. 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.

Assignees

• Massachusetts Inst Technology

Inventors

• Irvine Darrell J
• Dane Eric

Classifications

• C07K19/00

  Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes} · CPC title

• A61K47/6425 Primary

  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 · CPC title

• A61K47/542

  Carboxylic acids, e.g. a fatty acid or an amino acid · CPC title

• C08G69/10

  Alpha-amino-carboxylic acids {(polysuccinimides C08G73/1092)} · CPC title

• A61K47/543

  Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine · CPC title