Methods and compositions for enhanced cellular selectivity using nanocarrier-associated ligands
The presently disclosed subject matter provides methods and compositions for activation of clustered receptors on a target cell using nanocarrier-associated ligands, particularly methods and compositions for targeted activation of clustered receptors on antigen-experienced T cells using nanocarrier-associated antibodies.
1. A method for selectively enhancing activation of antigen-experienced T cells, the method comprising:
a) administering a selected antigen to T cells in an amount sufficient to produce microclustering of ligand-binding receptors on the surface of the T cells, thereby producing antigen-experienced T cells comprising microclustered ligand-binding receptors; and
b) administering nanocarrier-associated ligands and the selected antigen to the antigen-experienced T cells, wherein the ligand-binding receptors bind ligands selected from the group consisting of anti-CD3 antibodies, anti-PD-1 antibodies, and functional variants thereof;
wherein the nanocarrier-associated ligands bind the microclustered ligand-binding receptors of the antigen-experienced T cells, thereby selectively enhancing activation of the antigen-experienced T cells as compared to:
i) the binding of free ligands to the microclustered ligand-binding receptors of the antigen-experienced T cells; and
ii) the binding of nanocarrier-associated ligands to ligand-binding receptors of nave T cells, wherein the nave T cells are non-specifically activated.
2. The method of claim 1 , wherein the T cells are selected from the group consisting of CD4 + T cells or CD8 + T cells.
3. The method of claim 1 , wherein selectively enhancing activation of the antigen-experienced T cells as compared to the naïve T cells comprises selectively enhancing an antigen-specific T cell response in the antigen-experienced T cells as compared to the naïve T cells.
4. The method of claim 3 , wherein the antigen-specific T cell response comprises enhanced proliferation of the antigen-experienced T cells as compared to the naïve T cells.
5. The method of claim 3 , wherein the antigen-specific T cell response comprises promoting the generation and function of specific effector cells from the antigen-experienced T cells as compared to the naïve T cells.
6. The method of claim 5 , wherein promoting the generation and function of specific effector cells from the antigen-experienced T cells comprises increasing the number of antigen-experienced T cells producing one or more proteins.
7. The method of claim 6 , wherein the one or more proteins comprise interleukins.
8. The method of claim 7 , wherein the interleukins comprise IL-12 or IL-4.
9. The method of claim 3 , wherein the enhanced response of the antigen-experienced T cells as compared to the naïve T cells comprises vaccine-induced proliferation of antigen-experienced T cells and generation of functional memory cells.
10. The method of claim 1 , wherein the antigen is a protein or peptide.
11. The method of claim 1 , wherein the ligand-binding receptors are T cell receptors.
12. The method of claim 1 , wherein the nanocarrier-associated ligands are associated with nanocarriers selected from the group consisting of lipid nanoparticles, polymeric nanoparticles, metallic nanoparticles, carbon nanoparticles, surfactant-based emulsions, dendrimers, and nanoparticles developed using a combination of nanomaterials.
13. The method of claim 1 , wherein the nanocarrier-associated ligands are associated with nanocarriers with a mean geometric diameter that is less than 100 nm.
14. A method for treating infectious disease or cancer in a subject in need thereof, the method comprising administering to the subject:
a) a selected antigen in an amount sufficient to produce microclustering of ligand-binding receptors on the surface of T cells in the subject, thereby producing antigen-experienced T cells comprising microclustered ligand-binding receptors; and
b) nanocarrier-associated ligands in an amount sufficient for the nanocarrier-associated ligands to bind microclustered ligand-binding receptors of the antigen-experienced T cells, wherein the ligand-binding receptors bind ligands selected from the group consisting of anti-CD3 antibodies, anti-PD-1 antibodies, and functional variants thereof, thereby selectively enhancing activation of the antigen-experienced T cells as compared to:
i) the binding of free ligands to the microclustered ligand-binding receptors; and
ii) the binding of nanocarrier-associated ligands to ligand-binding receptors of naïve T cells, wherein the naïve T cells are non-specifically activated.
15. The method of claim 14 , wherein the selected antigen and the nanocarrier-associated ligands are administered to the subject concurrently.
16. The method of claim 14 , wherein the selected antigen and the nanocarrier-associated ligands are administered to the subject sequentially.
17. The method of claim 14 , wherein the T cells are selected from the group consisting of CD4 + T cells or CD8 + T cells.
18. The method of claim 14 , wherein selectively enhancing activation of the antigen-experienced T cells as compared to the naïve T cells comprises selectively enhancing an antigen-specific T cell response in the antigen-experienced T cells as compared to the naïve T cells.
19. The method of claim 18 , wherein the antigen-specific T cell response comprises enhanced proliferation of the antigen-experienced T cells as compared to the naïve T cells.
20. The method of claim 18 , wherein the antigen-specific T cell response comprises promoting the generation and function of specific effector cells from the antigen-experienced T cells as compared to the naïve T cells.
21. The method of claim 20 , wherein promoting the generation and function of specific effector cells from the antigen-experienced T cells comprises increasing the number of antigen-experienced T cells producing one or more proteins.
22. The method of claim 21 , wherein the one or more proteins comprise interleukins.
23. The method of claim 22 , wherein the interleukins comprise IL-12 or IL-4.
24. The method of claim 18 , wherein the enhanced response of the antigen-experienced T cells to a vaccine as compared to the naïve T cells comprises vaccine-induced proliferation of antigen-experienced T cells and generation of functional memory cells.
25. The method of claim 14 , wherein the antigen is a protein or peptide.
26. The method of claim 14 , wherein the ligand-binding receptors are T cell receptors.
27. The method of claim 14 , wherein the nanocarrier-associated ligands are associated with nanocarriers selected from the group consisting of lipid nanoparticles, polymeric nanoparticles, metallic nanoparticles, carbon nanoparticles, surfactant-based emulsions, dendrimers, and nanoparticles developed using a combination of nanomaterials.
28. The method of claim 14 , wherein the nanocarrier-associated ligands are associated with nanocarriers with a mean geometric diameter that is less than 100 nm.
29. A method for selectively enhancing activation of cancer cells comprising microclustered ligand-binding receptors, the method comprising administering nanocarrier-associated ligands to a plurality of cells, wherein the plurality of cells comprises:
a) cancer cells comprising microclustered ligand-binding receptors; and
b) cells comprising non-microclustered ligand-binding receptors;
wherein the nanocarrier-associated ligands selectively bind microclustered ligand-binding receptors, thereby selectively enhancing activation of cancer cells comprising microclustered ligand-binding receptors as compared to cells comprising non-microclustered ligand-binding receptors, and wherein the ligand-binding receptors bind ligands selected from the group consisting of anti-CD3 antibodies, anti-PD-1 antibodies, and functional variants thereof.
30. The method of claim 29 , wherein the nanocarrier-associated ligands are anti-cancer agents, and wherein selectively enhancing activation of cancer cells comprising microclustered ligand-binding receptors comprises destroying the cancer cells.
31. The method of claim 29 , wherein the nanocarrier-associated ligands are associated with nanocarriers selected from the group consisting of lipid nanoparticles, polymeric nanoparticles, metallic nanoparticles, carbon nanoparticles, surfactant-based emulsions, dendrimers, and nanoparticles developed using a combination of nanomaterials.
32. The method of claim 29 , wherein the nanocarrier-associated ligands are associated with nanocarriers with a mean geometric diameter that is less than 100 nm.
33. A composition for selectively enhancing activation of antigen-experienced T cells, the composition comprising:
a) a selected antigen in an amount sufficient to produce microclustering of ligand-binding receptors on the surface of T cells, thereby producing antigen-experienced T cells comprising microclustered ligand-binding receptors; and
b) nanocarrier-associated ligands in an amount sufficient for the nanocarrier-associated ligands to bind microclustered ligand-binding receptors of the antigen-experienced T cells, wherein the ligand-binding receptors bind ligands selected from the group consisting of anti-CD3 antibodies, anti-PD-1 antibodies, and functional variants thereof, thereby selectively enhancing activation of the antigen-experienced T cells as compared to:
i) the binding of free ligands to the microclustered ligand-binding receptors; and
ii) the binding of nanocarrier-associated ligands to ligand-binding receptors of naïve T cells, wherein the naïve T cells are non-specifically activated.
34. The composition of claim 33 , wherein the T cells are selected from the group consisting of CD4 + T cells or CD8 + T cells.
35. The composition of claim 33 , wherein the antigen is a protein or peptide.
36. The composition of claim 33 , wherein the ligand-binding receptors are T cell receptors.
37. The composition of claim 33 , wherein the nanocarrier-associated ligands are associated with nanocarriers selected from the group consisting of lipid nanoparticles, polymeric nanoparticles, metallic nanoparticles, carbon nanoparticles, surfactant-based emulsions, dendrimers, and nanoparticles developed using a combination of nanomaterials.
38. The composition of claim 33 , wherein the nanocarrier-associated ligands are associated with nanocarriers with a mean geometric diameter that is less than 100 nm.