Kurzfassung

The tumor-associated mucin MUC1 is a target cell-surface structure, expressed on almost all epithelial tissues, and over-expressed on epithelial tumor cells. Tumor-associated MUC1 is characterized by aberrant carbohydrates, which are short and prematurely sialylated, e.g. the tumor-associated antigens Tn, T, Sialyl Tn, Sialyl T. Due to the biological micro-heterogeneity, pure tumor-associated glycopeptides can hardly be isolated from biological material. Chemical methodology now enables the...The tumor-associated mucin MUC1 is a target cell-surface structure, expressed on almost all epithelial tissues, and over-expressed on epithelial tumor cells. Tumor-associated MUC1 is characterized by aberrant carbohydrates, which are short and prematurely sialylated, e.g. the tumor-associated antigens Tn, T, Sialyl Tn, Sialyl T. Due to the biological micro-heterogeneity, pure tumor-associated glycopeptides can hardly be isolated from biological material. Chemical methodology now enables the synthesis of pure glycopeptides of the tumor-associated MUC1 (1), which can be conjugated with carrier proteins, as for example, BSA (2) or with T-cell epitope peptides (3) to afford synthetic vaccines. We could show that immunization of T cells receptor-transgenic mice with a fully synthetic vaccine of this type (3) induced an almost monoclonal antiserum. A monoclonal antibody was obtained by hybridoma fusion which differentiates between glycoforms of MUC1. Furthermore, a new vaccine was constructed from synthetic MUC1-glycopeptides coupled to tetanus toxoid (4) which induced a strong, tolerance-breaking immune response in mice. Such a tetanus toxoid-based vaccine has the potential for an application in humans. In addition, a microarray platform based on tumor-associated MUC1 glycopeptides was developed (5) which allows a rapid validation of the specificity of antisera. The ongoing research aims at modified regioselectivity concerning the position of glycosylation within the MUC1-glycopeptides, at finding out whether there is organ specificity of the tumor-associated cell surface mucin components, and at the development of vaccines consisting of toll-like receptor2-ligand-MUC1-glycopeptide conjugates.
Literature
1. Becker, T., Dziadek, S., Wittrock, S., Kunz, H., 2006. Synthetic glycopeptides from the Mucin Family as Potential Tools in Cancer Immunotherapy. Curr. Cancer Drug Targets 6, 491-517.
2. Dziadek, S., Hobel, A., Schmitt, E., Kunz, H., 2005. A fully synthetic vaccine from consisting of a tumor-associated glycopeptide antigen and a T-cell epitope fort he induction of a highly specific humoral immune response. Angew. Chem. Int. Ed. 44, 7630-7635.
3. Westerlind, U., Hobel, A., Gaidzik, N., Schmitt, E., Kunz, H., 2008. Synthetic vaccines consisting of tumor-associated MUC1 glycopeptide antigens and a T-cell epitope for the induction of a highly specific humoral immune response. Angew. Chem. Int. Ed. 47, 7551-7556.
4. Kaiser, A., Gaidzik, N., Westerlind, U., Kowalczyk, D., Hobel, A., Schmitt, E., Kunz, H., 2009. A synthetic vaccine consisting of a tumor-associated Sialyl-TN-MUC1 tandem-repeat glycopeptide and Tetanus Toxoid: Induction of a strong and highly selective immune response. Angew. Chem. Int. Ed. 48, 7551-7555.
5. Westerlind, U., Schröder, H., Hobel, A., Gaidzik, N., Kaiser, A., Niemeyer, C. M., Schmitt, E., Waldmann, H., Kunz, H., 2009. Tumor-associated MUC1 tandem-repeat glycopeptide microarrays to evaluate serum- and monoclonal-antibody specificity. Angew. Chem. Int. Ed. 48, 8263-8267.» weiterlesen» einklappen