Targeting moiety peptide epitope complexes having a plurality of T-cell epitopes
A variety of targeting moiety peptide epitope complexes (TPECs) are described in different embodiments. In each of the embodiments, however, a targeting moiety may be used to deliver the TPEC to an area of unwanted cells, allowing for a therapeutic effect to be delivered locally. The TPEC also contains a plurality of T-cell epitopes. The TPEC further comprises cleavage sites that release the T-cell epitopes from the targeting agent, and in some embodiments from each other, when they are in the microenvironment of the unwanted cells. Although the arrangement and number of T-cell epitopes varies in different embodiments described herein, once cleaved from the targeting agent (and any neighboring T-cell epitopes), the T-cell epitopes function by stimulating an immune response against the unwanted cells.
1. A composition for retargeting a virus-specific existing T-cell immune response to cancer cells comprising a targeting moiety peptide epitope complex (TPEC) wherein:
a. T is a targeting moiety that is an antibody or antigen-binding fragment thereof capable of targeting cancer cells;
b. L is at least one linker capable of linkage to T where L is a peptide bond or at least one peptide;
c. C is at least one cleavage site cleaved by an enzyme outside of the cancer cell and expressed by the cancer cell or cleaved by a protease that is outside of the cancer cell and colocalized to the cancer cell by a targeting moiety that is the same or different from the targeting moiety in the TPEC; and
d. E is at least one viral T-cell epitope that elicits an existing immune response in a human subject and binds to a HLA molecule on the surface of the cancer cells of the human subject and has a HLA matched to the subject,
wherein the L, C, and E moieties are arranged in a pattern of at least one of L-(C-E)n, wherein n is an integer of at least 2 and with each C-E attached to the L in series.
2. The composition of claim 1 , wherein the composition comprises a plurality of more than 10 T-cell epitopes conjugated to the targeting moiety with at least one cleavage site.
3. The composition of claims 1 , wherein the plurality of T-cell epitopes are not all identical.
4. The composition of claim 1 , wherein at least one T-cell epitope is an MHC Class I restricted peptide.
5. The composition of claim 1 , wherein at least one T-cell epitope is an MHC Class II restricted peptide.
6. The composition of claim 1 , wherein the plurality of T-cell epitopes are from about 7 to about 14 amino acids in length.
7. The composition of claim 1 , wherein the composition comprises at least about 2, 3, 4, 5, 6, 7, 8, 9, or 10 T cell epitopes.
8. The composition of claim 1 , wherein the T-cell epitopes are chosen from CMV, influenza, EBV, hepatitis, chicken pox, mumps, measles, rubella, polio, rotavirus, vaccinia, and yellow fever T-cell epitopes.
9. The composition of claim 1 , wherein the composition comprises T-cell epitopes from at least two different viruses.
10. The composition of claim 1 , wherein the T-cell epitopes are chosen from HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, HLA-G, CD1d, and MR1.
11. The composition of claim 1 , wherein the T-cell epitopes are chosen from HLA-A*01, HLA-A*02, HLA-A*03, HLA-A*11, HLA-B*44, HLA-B*07, HLA-B*08, HLA-B*15, HLA-B*35, HLA-B*40, HLA-C*07, HLA-C*03, HLA-C*05, HLA-C*04, HLA-C*06, and HLA-E*0101 restricted antigens.
12. The composition of claim 1 , wherein the composition comprises at least the following T-cell epitopes: HLA-A*02, HLA-A*01, and HLA-A*03.
13. The composition of claim 1 , wherein the T-cell epitopes comprise at least one of SEQ ID NOS: 1-2, 5-7, 15-57.
14. The composition of claim 1 , wherein the T-cell epitopes are flanked on one or both ends by at least one human protein domain.
15. The composition of claim 1 , wherein the enzyme expressed by the cancer cells is a protease.
16. The composition of claim 1 , wherein the antibody or antigen-binding fragment thereof is an anti-CEA or anti-CEACAM antibody or antigen-binding fragment thereof.