Tolerogenic artificial antigen-presenting cells
The disclosure is directed to a biodegradable particle comprising a polyester or polyester blend, a first protein that binds to an immune cell, and a second protein that promotes proliferation and/or activation of immune cells, and a third soluble protein or small molecule encapsulated within the particle. The second protein is a fusion protein comprising at least a portion of an antibody and at least a portion of a cytokine (i.e., an immunocytokine). The disclosure also is directed to methods for treating a disease or condition in a subject (e.g., an autoimmune disease) comprising administering the aforementioned biodegradable particle to the subject.
1. A biodegradable particle comprising:
a polyester or polyester blend;
a first protein that binds to an immune cell;
a second protein that promotes proliferation and/or activation of immune cells; and
a third soluble protein or small molecule encapsulated within the particle,
wherein:
(i) the first protein is a MHC II tetramer peptide complex attached to a surface of the particle or to a coating on the surface thereof; and
(ii) the second protein is an immunocytokine that binds to a polypeptide complex comprising an IL-2 receptor, wherein said immunocytokine comprises at least a portion of an antibody and at least a portion of a cytokine and is either attached to a surface of the particle or to a coating on the surface thereof or encapsulated within the particle.
2. The biodegradable particle of claim 1 , wherein the polyester or polyester blend is selected from the group consisting of poly (lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polyglycolide (PGA), poly(lactic acid) (PLA), polyhydroxyalkanoate (PHA), poly-3-hydroxybutyrate (P3HB), poly(acrylic acid) (PAA), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), poly(beta-amino ester) (PBAE), and combinations or blends thereof.
3. The biodegradable particle of claim 1 , wherein the immune cell to which the first protein binds comprises a T cell.
4. The biodegradable particle of claim 1 , wherein the immunocytokine comprises the amino acid sequences of SEQ ID NO: 5 and SEQ ID NO: 11.
5. The biodegradable particle of claim 1 , wherein the third soluble protein is an interleukin and/or a cytokine.
6. The biodegradable particle of claim 1 , wherein the small molecule is an immunosuppressive drug.
7. The biodegradable particle of claim 1 , wherein the small molecule is rapamycin, cyclosporine A, or analogs thereof.
8. The biodegradable particle of claim 1 , wherein said particle is a microparticle having an average diameter of from about 1 micron to about 5 microns.
9. The biodegradable particle of claim 1 , wherein said particle is a nanoparticle having an average diameter of from about 50 nm to about 1000 nm.
10. The biodegradable particle of claim 1 , wherein said particle is anisotropic and has a non-spherical shape.
11. The biodegradable particle of claim 1 , wherein said particle has a prolate ellipsoidal shape.
12. The biodegradable particle of claim 1 , wherein said coating comprises one or more synthetic and/or natural lipids and/or lipid membranes.
13. The biodegradable particle of claim 1 , wherein the first and second proteins are attached to the coating, and said coating comprises one or more synthetic and/or natural lipids and/or lipid membranes.
14. The biodegradable particle of claim 1 , wherein the first protein and the second protein are present on the particle in a 1:1 molar ratio.
15. The biodegradable particle of claim 1 , wherein said particle comprises a combination of poly(lactic-co-glycolic acid) (PLGA) and poly(beta-amino ester) (PBAE).
16. A method for treating a disease or condition in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a biodegradable particle of claim 1 .