Synthetic nanoparticles for delivery of immunomodulatory compounds

Patent metadata

Field	Value
Publication number	US-11207418-B2
Application number	US-201916380886-A
Country	US
Kind code	B2
Filing date	Apr 10, 2019
Priority date	Jul 15, 2016
Publication date	Dec 28, 2021
Grant date	Dec 28, 2021

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 composition comprising a synthetic nanoparticle and a pharmaceutically acceptable carrier, wherein the synthetic nanoparticle comprises a PNA-amphiphile conjugate and an immunomodulatory compound, wherein the PNA-amphiphile conjugate comprises:
(i) a peptide nucleic acid (PNA) oligomer, represented from N- to C-terminus by the formula: Xaa1-(G)n-Xaa2, wherein Xaa1 and Xaa2 are a positively charged amino acid, wherein G is a guanine nucleoside or an analog thereof, and n is 1 to 12;
(ii) one or more lipids;
(iii) and optionally 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 composition of claim 1 , wherein the positively charged amino acid is lysine or arginine.

3. The composition of claim 1 , wherein Xaa1 and Xaa2 are lysine and n is 3 to 6.

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

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

6. The composition 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.

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

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

9. The composition 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.

10. 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 1 .

11. The method of claim 10 , wherein the immune response is an antigen specific immune response or an antigen specific CD8+ T cell immune response, and wherein the antigen is a cancer antigen.

12. A method of inhibiting a bacterial infection, or disrupting biofilm production, comprising administering to a subject in need thereof the composition of claim 1 .

13. A vaccine comprising the composition of claim 1 , and an antigen.

14. A method of immunizing a subject, of inducing an antigen specific CD8+ T cell response in a subject, of inducing an immune response to an antigen in a subject, or of activating STING in a subject, the method comprising administering the vaccine of claim 13 .

15. A complex comprising a PNA oligomer noncovalently bound to a cyclic dinucleotide (CDN), wherein the PNA oligomer is represented from N- to C-terminus by the formula: Xaa1-(G)n-Xaa2, wherein Xaa1 and Xaa2 are a positively charged amino acid, wherein G is a guanine nucleoside or an analog thereof, and n is 1 to 12.

16. The complex of claim 15 , wherein the positively charged amino acid is lysine or arginine.

17. The complex of claim 15 , wherein Xaa1 and Xaa2 are lysine and n is 3 to 6, or wherein the PNA oligomer is lysine-(G)3-lysine, and wherein G is guanine.

18. The complex of claim 15 , 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.

19. A PNA-amphiphile conjugate comprising a PNA oligomer, and one or more lipids, and optionally, a polymer conjugated to the one or more lipids, wherein the PNA oligomer is represented from N- to C-terminus by the formula: Xaa1-(G)n-Xaa2, wherein Xaa1 and Xaa2 are a positively charged amino acid selected from the group consisting of lysine and arginine, wherein G is a guanine nucleoside or an analog thereof, and n is 1 to 12.

20. The PNA-amphiphile conjugate of claim 19 , wherein Xaa1 and Xaa2 are lysine and n is 3 to 6, or wherein the PNA oligomer is lysine-(G)3-lysine, wherein G is guanine.

21. The PNA-amphiphile conjugate of claim 19 , wherein the one or more lipids is a diacyl lipid tail.

22. The PNA-amphiphile conjugate of claim 19 , comprising a cysteine chemically linked to either the N- or C-terminus of the PNA oligomer, and further comprising a polymer, wherein the polymer is chemically linked to the cysteine of the PNA oligomer.

23. The PNA-amphiphile conjugate of claim 19 , wherein the polymer is polyethylene glycol.

24. A method of making a synthetic nanoparticle comprising combining the PNA-amphiphile conjugate of claim 19 with a cyclic dinucleotide (CDN), thereby forming a synthetic nanoparticle.

25. The method of claim 24 , wherein the synthetic nanoparticle has a diameter in the range of approximately 10 nm to approximately 100 nm, and wherein the synthetic nanoparticle comprises a structure selected from the group consisting of a worm-like micelle, a disc-like micelle, a nanofiber and a spherical micelle.

26. The vaccine of claim 13 , wherein the antigen is conjugated to the synthetic nanoparticle.

27. The method of claim 14 , wherein the vaccine is administered by inhalation, mucosal administration, oral administration, or parenteral administration.

28. The method of claim 27 , wherein the parenteral administration is subcutaneous, intramuscular, or intradermal administration.

29. The composition of claim 1 , wherein said pharmaceutically acceptable carrier comprises an aqueous solution.

30. The composition of claim 1 , wherein said pharmaceutically acceptable carrier is non-aqueous.

31. The composition of claim 1 , wherein said composition is lyophilized.

32. The composition of claim 1 , wherein said composition is pyrogen free.

33. The composition of claim 1 , wherein said composition comprises any of injectable microspheres, bio-erodible particles, polymeric compounds, beads, and liposomes.

Assignees

• Massachusetts Inst Technology

Inventors

• Irvine Darrell J
• Dane Eric

Classifications

• C07K14/003 Primary

  Peptide-nucleic acids (PNAs) · CPC title

• A61K47/543

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

• A61K47/64

  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) · CPC title

• A61K47/6911

  the form being a liposome · CPC title

• A61K47/542

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