Characterization and exploitation of antibody to the tumor antigen TF-Ag and peptide mimics of TF-Ag to develop improved tumor immunotherapies
Heimburg, Jamie L
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The Thomsen-Friedenreich Antigen (TF-Ag) is a carbohydrate tumor-associated antigen that is highly surface-expressed on many types of tumor cells, including breast, colon, ovarian, and other adenocarcinomas. TF-Ag expression contributes to cancer cell adhesion and metastasis, by localizing to sites containing TF-Ag-binding lectins. Any interference with tumor cell growth and adhesion would likely affect the severity of the cancer and its ability to metastasize. Antibodies to surface antigens can be blocking or cytotoxic in nature, therefore the development of a vaccine that generates antibodies towards TF-Ag would be clinically valuable. Since carbohydrate antigens generate T cell independent responses, identifying TF-Ag peptide mimics may be useful in generating T cell dependent responses. Antibodies have been developed to saccharide antigens and memory in response to peptide mimic immunizations. Further, T cells primed by peptide mimics react with carbohydrate antigens producing cellular responses, and MHC molecules can display glycopeptides. This leads us to hypothesize that vaccinations using unique peptide mimics of TF-Ag will generate immune responses to TF-Ag epitopes on tumor cells which will be clinically useful in active immunotherapy of many cancers. In vitro and in vivo experiments using JAA-F11 antibody to TF-Ag demonstrated decreased tumor cell growth, blocked adhesion between tumor cells and endothelial cells, and prolonged survival and decreased number of lung metastases in passively treated mice. In vitro experiments using JAA-F11 antibody to TF-Ag, rabbit antibody to TF-Ag, and peanut lectin confirmed mimicry of TF-Ag by peptides and In vitro model systems demonstrated peptide mimics blocked rolling and stable adhesion of tumor cells to vascular endothelium. in vivo experiments utilized linear and multiple antigenic peptides for immunizations and serum analysis by ELISA for TF-Ag-reactive antibody production. Molecular modeling of peptide mimics and JAA-F11 revealed molecular details of the possible binding interactions. This approach could be used to decrease the primary and metastatic tumor burden in cancer patients by specifically targeting TF-Ag positive cancer cells and aid in blocking new tumor formation, as well as prime the immune system for future recurrence of the disease.