Synthesis of MUC1 glycopeptides and generation of antibodies for the indentificat

University Of Texas El Paso, El Paso TX

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Abstract

DESCRIPTION (provided by applicant): Synthesis of MUC1 glycopeptides and generation of antibodies for the identification of epitopes on cancer cells. Most carcinomas over-express cell surface glycoproteins that are aberrantly glycosylated with truncated O-glycans, which are tumor-associated antigens. This distinct difference in cell surface make-up of healthy and cancerous cells make tumor- associated antigens attractive targets for the development of cancer-specific immunotherapies. Recently, it was discovered that combined sugar and peptide epitopes make excellent targets for immunotherapy of cancer. Of all aberrantly glycosylated cancer cell surface glycoproteins the one best studied is the mucin "MUC1", however, the structural features of immunogenic MUC1 glycopeptides, dynamically expressed by cancer cells, remain understudied. Tools to analyze the sugar part and peptide part of an epitope are unavailable. In order to address this question the research proposed here combines the chemical synthesis of candidate glycopeptides (a library of 14 Tn or STn containing glycopeptides), and the generation of monoclonal antibodies, which will later be used to specifically identify cancer cell surface epitopes (long-term goal). Furthermore, these probes will be used to study changes in epitope expression as the cancer progresses. The objective of this SC2 pilot project is to synthesize a MUC1 glycopeptide library, to generate a first set of monoclonal antibody probes, and to validate their binding specificity to the glycopeptides they have been elicited against. The availability of a comprehensive set of such monoclonal antibodies would have major implications for the development of novel cancer-specific immunotherapies, diagnostics and vaccines. All glycopeptides will be synthesized in the P.I.'s laboratory at the University of Texas at El Paso. The P.I.'s laboratory will also determine the binding affinities and binding specificities of the monoclonal antibodies to the MUC1 derived glycopeptides at the Border Biomedical Core Facility at the University of Texas at El Paso. Mice will be immunized and monoclonal antibodies will be raised in collaboration with Dapeng Zhou, M.D., Ph.D., Department of Melanoma and Medical Oncology;Department of Immunology, University of Texas MD Anderson Cancer Center in Houston, TX. PUBLIC HEALTH RELEVANCE: MUC1 is a cell surface glycoprotein that is over-expressed and aberrantly glycosylated in many carcinoma. The tumor-associated antigens present on the cell surface are ideal targets for the development of effective immunotherapies, however, the exact structural features of the epitopes expressed by cancer cells are not known. It is our goal to develop the tools, a set of monoclonal antibodies, which can specifically identify these cell surface glycopeptide epitopes.