SPHERICAL NUCLEIC ACID-BASED CONSTRUCTS AS IMMUNOSTIMULATORY AGENTS FOR PROPHYLACTIC AND THERAPEUTIC USE

• US 20160186178A1
• Filed: 07/25/2014
• Published: 06/30/2016
• Est. Priority Date: 07/25/2013
• Status: Active Grant

• Current Assignee: Exicure Inc.
• Original Assignee: Exicure Inc.
• Inventors: Radovic-Moreno, Aleksandar Filip, Mader, Christopher C., Nallagatla, Subbarao, Hasan, Warefta, Love, Aaron, Gryaznov, Sergei
• Granted Patent: US 10,894,963 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C12N 15/117 Nucleic acids having immunomodulatory properties, e.g. containing CpG-motifs
• CPC Class Codes: C12N 2310/17 Immunomodulatory nucleic acids
• CPC Class Codes: C12N 2320/30 Special therapeutic applications
• CPC Class Codes: C12N 2320/32 Special delivery means, e.g. tissue-specific
• CPC Class Codes: 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

Abstract

Aspects of the invention relate to spherical nucleic acid-based constructs and related methods and compositions thereof. The compositions of the invention are useful for activating agonists of nucleic acid interacting complexes, such as TLRs, stimulating an immune response, and treating diseases such as infectious disease, cancer, allergies, allergic diseases, and autoimmune disease

Claims

1. A nanoscale construct comprising:

a corona of an agonist of nucleic acid-interacting complexes wherein the surface density of the agonist of nucleic acid-interacting complexes is at least 0.3 pmol/cm².

5. The nanoscale construct of any one of claims 1-4, wherein the agonist of nucleic acid-interacting complexes contains a spacer.

6. The nanoscale construct of any one of claims 1-5, wherein the agonist of nucleic acid-interacting complexes is RNA or DNA.

7. The nanoscale construct of claim 6, wherein the agonists of nucleic acid-interacting complexes is a double stranded RNA.

8. The nanoscale construct of claim 7, wherein the double stranded RNA is poly(I:

C).

9. The nanoscale construct of claim 6, wherein the agonist of nucleic acid-interacting complexes is a single stranded RNA.

10. The nanoscale construct of claim 9, wherein the single stranded RNA contains UUG-motifs.

11. The nanoscale construct of claim 6, wherein the agonist of nucleic acid-interacting complexes is an unmethylated deoxyribonucleic acid.

12. The nanoscale construct of claim 11, wherein the unmethylated deoxyribonucleic acid is a CpG oligonucleotide.

13. The nanoscale construct of any one of claims 1-12, wherein the nanoscale construct contains a nanoparticle core at the center of the corona which is metallic.

14. The nanoscale construct of claim 13, wherein the metallic core is selected from the group consisting of gold, silver, platinum, aluminum, palladium, copper, cobalt, indium, nickel and mixtures thereof.

15. The nanoscale construct of claim 13, wherein the nanoparticle core comprises gold.

16. The nanoscale construct of any one of claims 1-16, wherein the nanoscale construct is degradable.

17. The nanoscale construct of any one of claims 1-16, wherein the diameter of the nanoscale is from 1 nm to about 250 nm in mean diameter, about 1 nm to about 240 nm in mean diameter, about 1 nm to about 230 nm in mean diameter, about 1 nm to about 220 nm in mean diameter, about 1 nm to about 210 nm in mean diameter, about 1 nm to about 200 nm in mean diameter, about 1 nm to about 190 nm in mean diameter, about 1 nm to about 180 nm in mean diameter, about 1 nm to about 170 ran in mean diameter, about 1 nm to about 160 nm in mean diameter, about 1 nm to about 150 nm in mean diameter, about 1 nm to about 140 nm in mean diameter, about 1 nm to about 130 nm in mean diameter, about 1 nm to about 120 nm in mean diameter, about 1 nm to about 110 nm in mean diameter, about 1 nm to about 100 nm in mean diameter, about 1 nm to about 90 nm in mean diameter, about 1 nm to about 80 nm in mean diameter, about 1 nm to about 70 nm in mean diameter, about 1 nm to about 60 nm in mean diameter, about 1 nm to about 50 nm in mean diameter, about 1 nm to about 40 nm in mean diameter, about 1 nm to about 30 nm in mean diameter, or about 1 nm to about 20 nm in mean diameter, or about 1 nm to about 10 nm in mean diameter.

21. The nanoscale construct of any one of claims 1-20, wherein the corona is a spherical corona.

22. A vaccine comprising a nanoscale construct of any of claims 1-21 and a carrier.

23. A method for delivering a therapeutic agent to a cell comprising delivering the nanoscale construct of any one of claims 1-21 to the cell.

24. A method for regulating expression of a target molecule comprising delivering the nanoscale construct of any one of claims 1-21 to the cell.

25. The method of claim 24, wherein the target molecule is a TLR selected from the group consisting of TLR3, 7, 8, and 9.

26. A method for activating a TLR comprising delivering the nanoscale construct of any one of claims 1-21 to the cell.

27. A method of treating a subject, comprising

administering to the subject the nanoscale construct of any one of claims 1-21 in an effective amount to stimulate an immune response.

28. The method of claim 27, wherein the subject has an infectious disease.

29. The method of claim 27, wherein the subject has cancer.

30. The method of claim 27, wherein the subject has an autoimmune disease.

31. The method of claim 27, wherein the subject has an allergy.

32. The method of claim 27, wherein the subject has an allergic disease.

2. A nanoscale construct comprising:

a corona of an agonist of nucleic acid-interacting complexes, and an antigen incorporated into the corona, wherein the surface density of the antigen is at least 0.3 pmol/cm².

3. The nanoscale construct of claim 2, wherein the antigen includes at least two different types of antigen.

4. A nanoscale construct comprising:

a corona with at least two agonists of nucleic acid-interacting complexes incorporated, wherein the agonists are selected from the group consisting of TLR 3, 7/8, and/or 9 agonists.

18. A nanoscale construct comprising;

a corona of an agonist of nucleic acid-interacting complexes, wherein the agonist is nucleic acid having at least one phosphodiester internucleotide linkage.

19. The nanoscale construct of claim 18, wherein the agonist is a CpG oligonucleotide.

20. The nanoscale construct of any one of claims 18-19, wherein each internucleotide linkage of the nucleic acid is a phosphodiester linkage.

33. A method of inducing an immune response in a subject, comprising

administering to the subject the nanoscale construct of any one of claims 18-21 in an effective amount to stimulate an immune response.