Adjuvant incorporation in immunonanotherapeutics
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.
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).