Adjuvant incorporation in immunoanotherapeutics
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.
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.