Controlled delivery of TLR3 agonists in structural polymeric devices

• US 9,821,045 B2
• Filed: 04/21/2016
• Issued: 11/21/2017
• Est. Priority Date: 02/13/2008
• Status: Active Grant

• Current Assignee: Dana-Farber Cancer Institute, President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: Dana-Farber Cancer Institute, President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Ali, Omar Abdel-Rahman, Dranoff, Glenn, Mooney, David J.
• Primary Examiner(s): STOICA, ELLY GERALD
• Application Number:
  US15/135,216
• Publication Number:
  US 20160296611A1
• Time in Patent Office: 579 Days
• Field of Search: None
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/55516 Proteins; Peptides
• CPC Class Codes: A61K 2039/55522 Cytokines; Lymphokines; Interferons
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• CPC Class Codes: A61K 2039/55588 Adjuvants of undefined constitution
• CPC Class Codes: A61K 2039/6093 Synthetic polymers, e.g. polyethyleneglycol [PEG], Polymers or copolymers of (D) glutamate and (D) lysine
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/708 having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants

Abstract

The present invention comprises compositions, methods, and devices for creating an stimulating an antigen-specific dendritic cell immune response. Devices and methods provide prophylactic and therapeutic immunity to subjects against cancer and infectious agents.

Claims

1. A device comprising a polymeric structure composition, a tumor antigen, and a TLR3 agonist, wherein said TLR3 agonist comprises condensed polyinosine-polycytidylic acid (poly I:

C) cationic nanoparticles, said condensed poly I;

C cationic nanoparticles being formed by mixing said poly I;

C with a polycation comprising positively charged amine groups at a charge ratio resulting in positively charged condensates and an average particle size of 98-545 nm.

2. The device of claim 1, further comprising a TLR9 agonist.

3. The device of claim 1, wherein said TLR3 agonist is present at a concentration effective to induce production of interleukin-12 (IL-12) by dendritic cells.

4. The device of claim 1, wherein when the device is implanted in a subject, 200-400 ng/mL of IL-12 is produced at the site of implantation.

5. The device of claim 1, wherein the condensed poly (I:

C) cationic nanoparticle comprises PEI-poly(I;

C).

6. The device of claim 2, wherein the TLR9 agonist comprises a cytosine-guanosine oligonucleotide (CpG-ODN) or condensed CpG-ODN.

7. The device of claim 1, wherein the polymeric structure composition comprises poly-lactide-co-glycolide (PLG).

8. The device of claim 2, wherein the polymeric structure composition comprises poly-lactide-co-glycolide (PLG).

9. The device of claim 1, further comprising pathogen associated molecular patterns (PAMPs).

10. The device of claim 2, wherein the TLR9 agonist comprises a nucleic acid.

11. The device of claim 10, wherein the nucleic acid comprises a cytosine-guanosine oligonucleotide (CpG-ODN) or a PEI-CpG-ODN.

12. The device of claim 1, further comprising a recruitment composition.

13. The device of claim 12, wherein the recruitment composition comprises granulocyte macrophage colony stimulating factor (GM-CSF), Flt3L, or CCL20.

14. The device of claim 13, wherein the device comprises 0.5 μ

g to 500 μ

g of GM-CSF.

15. The device of claim 13, wherein the recruitment composition comprises encapsulated GM-CSF.

16. The device of claim 1, wherein the tumor antigen comprises a tumor lysate, purified protein tumor antigen, or synthesized tumor antigen.

17. The device of claim 1, comprising 100 μ

g-10,000 μ

g of tumor antigen.

18. The device of claim 1, wherein the tumor antigen is a lung cancer tumor antigen.

19. The device of claim 1, wherein the tumor antigen comprises an antigen from a cancer selected from the group consisting of a central nervous system (CNS) cancer, CNS Germ Cell tumor, Leukemia, Multiple Myeloma, Renal Cancer, Malignant Glioma, breast cancer, squamous cell carcinoma, ovarian carcinoma, prostate cancer, Kaposi'"'"'s sarcoma, colon cancer, adenocarcinoma, testicular cancer, hepatocellular carcinoma, Synovial sarcoma, and Medulloblastoma.

20. The device of claim 2, wherein the tumor antigen comprises an antigen from a cancer selected from the group consisting of a central nervous system (CNS) cancer, CNS Germ Cell tumor, Leukemia, Multiple Myeloma, Renal Cancer, Malignant Glioma, breast cancer, squamous cell carcinoma, ovarian carcinoma, prostate cancer, Kaposi'"'"'s sarcoma, colon cancer, adenocarcinoma, testicular cancer, hepatocellular carcinoma, Synovial sarcoma, and Medulloblastoma.

21. The device of claim 2, further comprising a recruitment composition.

22. The device of claim 21, wherein the recruitment composition comprises granulocyte macrophage colony stimulating factor (GM-CSF), Flt3L, or CCL20.

23. The device of claim 2, wherein the tumor antigen comprises a tumor lysate, purified protein tumor antigen, or synthesized tumor antigen.

24. The device of claim 1, wherein said polymeric structure composition is anionic and said condensed poly I:

C cationic nanoparticles are electrostatically immobilized on said anionic polymeric structure composition of said device.

25. The device of claim 2, wherein said polymeric structure composition is anionic and said condensed poly I:

C cationic nanoparticles are electrostatically immobilized on said anionic polymeric structure composition of said device.

26. The device of claim 1, wherein said charge ratio comprises an amino-phosphate charge ratio of 3, 4, 7, or 15.

27. The device of claim 2, wherein said charge ratio comprises an amino-phosphate charge ratio of 3, 4, 7, or 15.