Targeting Moiety Peptide Epitope Complexes Having a Plurality of T-Cell Epitopes

Abstract

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.

What is claimed is: 
     
         1 . A method of treating cancer in a patient comprising administering a composition comprising a targeting moiety peptide epitope complex (TPEC) to the patient, 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 an HLA molecule on the surface of the cancer cells of the human subject and has an 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 method of  claim 1 , wherein the method comprises retargeting an immune response of a patient to cancer cells. 
     
     
         3 . The method of  claim 2 , wherein the composition comprises a plurality of more than 10 T-cell epitopes conjugated to the targeting moiety with at least one cleavage site, optionally wherein the plurality of T-cell epitopes are not all identical. 
     
     
         4 . The method of  claim 2 , wherein at least one T-cell epitope is an MHC Class I restricted peptide or an MHC Class II restricted peptide. 
     
     
         5 . The method of  claim 2 , wherein the plurality of T-cell epitopes are from about 7 to about 14 amino acids in length. 
     
     
         6 . The method of  claim 2 , wherein the composition comprises at least about 2, 3, 4, 5, 6, 7, 8, 9, or 10 T cell epitopes. 
     
     
         7 . The method of  claim 2 , 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. 
     
     
         8 . The method of  claim 2 , wherein the composition comprises T-cell epitopes from at least two different viruses. 
     
     
         9 . The method of  claim 2 , wherein the T-cell epitopes are chosen from HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, HLA-G, CD1d, and MR1. 
     
     
         10 . The method of  claim 2 , 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. 
     
     
         11 . The method of  claim 2 , wherein the composition comprises at least the following T-cell epitopes: HLA-A*02, HLA-A*01, and HLA-A*03. 
     
     
         12 . The method of  claim 2 , wherein the T-cell epitopes comprise at least one of SEQ ID NOS: 1-2, 5-7, 15-57. 
     
     
         13 . The method of  claim 2 , wherein the T-cell epitopes are flanked on one or both ends by at least one human protein domain. 
     
     
         14 . The method of  claim 2 , wherein the enzyme expressed by the cancer cells is a protease. 
     
     
         15 . The method of  claim 2 , wherein the antibody or antigen-binding fragment thereof is an anti-CEA or anti-CEACAM antibody or antigen-binding fragment thereof. 
     
     
         16 . The method of  claim 2 , wherein the patient does not develop an immune response against the composition sufficient to inactivate the composition. 
     
     
         17 . The method of  claim 2 , wherein the patient receives multiple doses of the composition over at least 30, 45, 60, 75, 90, 120, 150, or more days or on an ongoing basis. 
     
     
         18 . The method of  claim 2 , wherein the patient receives multiple doses of the composition over at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or on an ongoing basis. 
     
     
         19 . The method of  claim 2 , wherein the composition can be administered to a patient in relapse who received the composition for an earlier round of therapy. 
     
     
         20 . The method of  claim 2 , wherein the cancer is breast cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, renal cancer, melanoma, lung cancer, prostate cancer, testicular cancer, thyroid cancer, brain cancer, esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, liver cancer, leukemia, myeloma, nonHodgkin's lymphoma, Hodgkin's lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, lymphoproliferative disorder, myelodysplastic disorder, myeloproliferative disease, or premalignant disease 
     
     
         21 . The method of  claim 2 , wherein the composition is administered in conjunction with surgery, radiation, traditional chemotherapy, or an immunostimulatory agent.