Adjuvant incorporation in immunonanotherapeutics

• US 9,233,072 B2
• Filed: 10/12/2012
• Issued: 01/12/2016
• Est. Priority Date: 10/12/2008
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated, President and Fellows of Harvard College (Harvard Corporation), Massachusetts Institute of Technology
• Original Assignee: Brigham and Women's Hospital Incorporated, President and Fellows of Harvard College (Harvard Corporation), Massachusetts Institute of Technology
• Inventors: Alexis, Frank, Iannacone, Matteo, Shi, Jinjun, Basto, Pamela, Moseman, Elliott Ashley, von Andrian, Ulrich, Langer, Robert S., Farokhzad, Omid C., Tonti, Elena
• Primary Examiner(s): Navarro, Albert
• Application Number:
  US13/651,124
• Publication Number:
  US 20130129790A1
• Time in Patent Office: 1,187 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 38/20 Interleukins [IL]
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/0002 Fungal antigens, e.g. Trichophyton, Aspergillus, Candida
• CPC Class Codes: A61K 39/002 Protozoa antigens
• CPC Class Codes: A61K 39/05 Actinobacteria, e.g. Actinomyces, Streptomyces, Nocardia, Bifidobacterium, Gardnerella, Corynebacterium; Propionibacterium Mycobacterium A61K39/04
• CPC Class Codes: A61K 39/08 Clostridium, e.g. Clostridium tetani
• CPC Class Codes: A61K 39/12 Viral 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: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention provides compositions and systems for delivery of nanocarriers to cells of the immune system. The invention provides nanocarriers capable of stimulating an immune response in T cells and/or in B cells. The invention provides nanocarriers that comprise an immunofeature surface and an immunostimulatory moiety. In some embodiments, the immunostimulatory moiety is an adjuvant. The invention provides pharmaceutical compositions comprising inventive nanocarriers. The present invention provides methods of designing, manufacturing, and using inventive nanocarriers and pharmaceutical compositions thereof.

Claims

1. A composition comprising:

(1) polymeric synthetic nanocarriers formed from the self-assembly of a mixture of amphiphilic polymers comprising a hydrophilic and a hydrophobic polymer, and amphiphilic polymers having a moiety attached thereto prior to self-assembly into nanocarriers

wherein the moiety is a targeting moiety that binds markers on dendritic cells or subcapsular sinus macrophages or is an immunostimulatory agent for dendritic cells or subcapsular sinus macrophages; and

(2) a pharmaceutically acceptable excipient.

2. The composition of claim 1, wherein the immunostimulatory agent:

(i) is associated with the surface of the nanocarrier;

or (ii) is encapsulated within the nanocarrier.

3. The composition of claim 1 further comprising an MHC Class 1, MHC Class II or CD1 presentable polypeptide antigen, wherein the MHC Class I, MHC Class II or CD-1 presentable polypeptide antigen:

(i) is associated with the surface of the nanocarrier;

or (ii) is encapsulated within a core region of the nanocarrier.

4. The composition of claim 1, wherein the immunostimulatory agent is a Toll-Like Receptor (TLR) agonist.

5. The composition of claim 4, wherein the TLR agonist is a TLR-1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, or TLR-10 agonist.

6. The composition of claim 1, wherein the immunostimulatory agent is selected from the group consisting of an interleukin, an interferon, a cytokine, and an adjuvant.

7. The composition of claim 1, wherein the composition is capable of providing enhanced T-cell proliferation in a human subject.

8. The composition of claim 1, wherein the composition elicits dendritic cell maturation when administered to a human subject.

9. The composition of claim 1, wherein the nanocarrier comprises two or more different MHC Class I, MHC Class II or CD1 presentable polypeptide antigens.

10. The composition of claim 1, wherein the composition comprises two or more immunostimulatory agents.

11. The composition of claim 10, wherein the composition comprises two or more Toll-Like Receptor (TLR) agonists.

12. The composition of claim 10, wherein the composition comprises one Toll-Like Receptor (TLR) agonist and one non-TLR agonist.

13. The composition of claim 12, wherein the non-TLR agonist is a moiety that induces signaling through the inflammasome, CD40, or a cytokine receptor.

14. The composition of claim 1, wherein the nanocarrier further comprises antigens selected from the group consisting of B-cell antigens and T-cell antigens.

15. A method comprising:

administering to a subject an initial dose of the composition of claim 1; and

administering to the subject a first subsequent dose of the composition of claim 1 at a time period after the administration of the initial dose.

16. The method of claim 15, wherein the time period is an interval ranging from 1 day to 1 year.

17. The method of claim 15, wherein the first dose of the composition elicits T-cell proliferation in the subject.

18. The method of claim 15, wherein one week after administration of the initial dose the blood concentration of antigen-specific T cells in the subject is at least 10-fold higher than the concentration of T cells recognizing an irrelevant antigen to which the subject has no immunological memory.

19. The method of claim 18, wherein the irrelevant anitigen is serum albumin.

20. The method of claim 15, wherein one week after administration of the first subsequent dose the blood concentration of antigen-specific T cells in the subject is at least 10-fold higher than the concentration of T cells recognizing an irrelevant antigen to which the subject has no immunological memory.

21. The method of claim 20, wherein the irrelevant antigen is serum albumin.

22. The composition of claim 1 wherein the hydrophobic polymer is selected from the group consisting of polyanhydrides and polyhydroxy acids, and the hydrophilic polymer comprises a polyalkylene oxide.

23. The composition of claim 22, wherein the amphiphilic polymer comprises polyethylene glycol-polylactic acid (PEG-PLA).