Adjuvant incorporation in immunoanotherapeutics

• US 9,439,859 B2
• Filed: 11/19/2013
• Issued: 09/13/2016
• 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): Hines, Ja'na
• Application Number:
  US14/084,424
• Publication Number:
  US 20140127301A1
• Time in Patent Office: 1,029 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2239/31 characterized by the route of administration
• CPC Class Codes: A61K 2239/38 characterised by the dose, timing or administration schedule
• 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 39/4611 T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
• CPC Class Codes: A61K 39/4612 B-cells
• CPC Class Codes: A61K 39/4622 Antigen presenting cells
• CPC Class Codes: A61K 39/4632 T-cell receptors [TCR]; antibody T-cell receptor constructs
• CPC Class Codes: A61K 39/4644 Cancer antigens
• CPC Class Codes: A61K 39/464838 Viral antigens
• 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 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 polymeric particulate composition comprising:

nanocarriers formed by self-assembly of a mixture of amphiphilic polymers having a hydrophobic polymer selected from the group consisting of polyanhydrides, polyhydroxy acids, and polyesters at one end and a hydrophilic polymer comprising a polyalkylene oxide at the other end and amphiphilic polymers having at least one moiety bound to the hydrophilic ends of the amphiphilic polymers; and

an immunostimulatory agent or MHC Class I, MHC Class II or CD1 presentable polypeptide antigen associated with the surface of the nanocarrier;

as the moiety bound to the hydrophilic end of the polymer, or encapsulated within the nanocarrier.

2. The composition of claim 1, comprising MHC Class I, MHC Class II or CD-1 presentable polypeptide antigen as the moiety bound to the hydrophilic end of the amphiphilic polymer.

3. The composition of claim 1, comprising a Toll-Like Receptor (TLR) agonist as an immunostimulatory agent.

4. The composition of claim 3, 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.

5. The composition of claim 1, comprising a cytokine as an immunostimulant.

6. The composition of claim 1, wherein the composition enhances T-cell proliferation in a human subject.

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

8. The composition of claim 2, wherein the nanocarriers comprise two or more different MHC Class I, MHC Class II or CD 1 presentable polypeptide antigens.

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

10. The composition of claim 9, wherein the composition comprises two or more Toll-Like Receptor (TLR) agonists.

11. The composition of claim 9, wherein the composition comprises one Toll-Like Receptor (TLR) agonist and one non-TLR agonist.

12. The composition of claim 11, wherein the non-TLR agonist is a moiety that induces signaling through the inflammasome, CD40, or a cytokine receptor.

13. The composition of claim 1, further comprising an agent selected from the group consisting of proteins, peptides, carbohydrates, glycoproteins, glycopeptides, and proteoglycans obtained from inactivated, dead or genetically engineered organisms selected from the group consisting of viruses, fungal, protozoan, and parasitic organisms, and cell extracts.

14. 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 to deliver a therapeutically effective amount.

15. The method of claim 14, wherein the time period is an interval ranging from 1 day to 1 year.

16. The method of claim 14, wherein the first dose of the composition elicits T-cell proliferation in the subject.

17. The method of claim 14, 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.

18. The method of claim 14, 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.

19. The composition of claim 1, wherein the moiety is present in an amount effective to provide a humoral response to the moieties.

20. The composition of claim 1, wherein the diameter of the nanocarriers is greater than 100 nm.

21. The composition of claim 1, comprising one or more pharmaceutically acceptable excipients selected from the group consisting of solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, and lubricants.

22. The composition of claim 19, wherein the composition targets a dendritic cell.

23. The composition of claim 19, wherein the composition does not activate complement.

24. The composition of claim 1, wherein the amphiphilic polymers are the same or different.