Compositions and methods for enhancing an immune response
The disclosure features compounds comprising an antigen portion, a soluble Major Histocompatibility Complex (MHC) molecule portion (e.g., all or an antigen-binding portion of a soluble MHC class I molecule), and a dynamic anchor portion (e.g., an agent, such as Annexin V, that binds to phosphatidylserine). The featured compounds are useful for a variety of therapeutic applications, including, e.g., enhancing a T cell response to an antigen of interest or enhancing a T cell-driven immune response by a subject to an antigen of interest (e.g., a cancer antigen or a microbial antigen).
1. A compound comprising: (a) a soluble Major Histocompatibility Complex (MHC) molecule; and (b) a dynamic anchor comprising Annexin V, wherein the MHC molecule comprises a class I MHC alpha chain comprising the amino acid sequence set forth in SEQ ID NO: 17 or SEQ ID NO: 18, and a β-2 microglobulin polypeptide comprising the sequence set forth in SEQ ID NO: 5 or SEQ ID NO: 6, and
wherein the dynamic anchor comprises the amino acid sequence depicted in SEQ ID NO: 1 or 2.
2. The compound according to claim 1 , wherein the dynamic anchor further comprises a homodimerization domain, or a calcium ion.
3. The compound according to claim 1 , wherein the compound comprises a fusion protein arranged from amino terminus to carboxy-terminus as (a) and (b).
4. The compound according to claim 3 , wherein the fusion protein comprises at least one linker peptide, wherein the at least one linker peptide comprises a linker peptide joining the MHC molecule of (a) and the dynamic anchor of (b).
5. The compound according to claim 4 , wherein fusion protein comprises a second linker peptide joining the α1 domain of the MHC class I molecule alpha chain to the β-2 microglobulin polypeptide.
6. The compound according to claim 5 , wherein the at least one linker peptide comprises one or more peptide sequences selected from: GS, GGS, and any of SEQ ID NOs: 7-16.
7. The compound according to claim 1 , further comprising a peptide antigen, wherein the compound is made by a method comprising providing the MHC molecule in complex with the peptide antigen.
8. The compound according to claim 7 , wherein the peptide antigen is covalently linked to the MHC molecule.
9. The compound according to claim 8 , wherein a linker peptide joins the peptide antigen to either the class I MHC alpha chain or to the β-2 microglobulin polypeptide.
10. The compound according to claim 7 , wherein the peptide antigen is a tumor-associated antigen.
11. The compound according to claim 7 , wherein the peptide antigen is a microbial antigen.
12. A composition comprising the compound according to claim 7 , and a pharmaceutically acceptable carrier.
13. The compound according to claim 10 , wherein the tumor-associated antigen is a tumor-associated viral antigen selected from a human papillomavirus antigen, an Epstein-Barr virus antigen, a hepatitis B virus antigen, or a human T-cell leukemia-lymphoma virus antigen.