Synthetic Glycopeptides from the Mucin Family as Potential Tools in Cancer Immunotherapy

Torsten      Becker; Sebastian      Dziadek; Sven      Wittrock; Horst      Kunz

doi:10.2174/156800906778194577

Abstract

Compared to glycoproteins of healthy cells, glycoproteins of tumor cells are often aberrantly glycosylated. Thus, glycopeptide fragments of surface glycoproteins of tumor cells are of interest as tumorassociated antigens for the distinction between normal and tumor cells. Cancer immunotherapy directed at selectively targeting these tumor-associated glycoprotein structure alterations deficient glycosylation and, thus, exposure of peptide epitopes which are masked in normal cells is considered a promising approach for the treatment of cancer. For this purpose, glycoproteins from the mucin family are of particular interest. Mucins belong to a class of heavily O-glycosylated, high-molecular weight glycoproteins present on the surface of many epithelial cells. The mucin core protein consists of numerous tandem repeats rich in serine, threonine and proline. In their tumor-associated forms, epithelial mucins carry cryptic saccharide structures such as TN-, T-, sialyl-TN- and sialyl-T antigens and more complex oligosaccharides (e.g. Lewisy). In contrast to glycoproteins isolated from natural sources, synthetic glycopeptides can be obtained in high purity and with exactly defined structure. In this review, methodologies for the synthesis of mucin-type glycopeptides containing complex tumorassociated antigen structures are described. Due to the low immunogenicity often exhibited by synthetic tumor-associated glycopeptide antigens, their conjugation to carrier proteins or suitable T-cell epitopes is essential for the development of anti-tumor vaccines. The results of immunological evaluations of synthetic (glyco)peptides and oligosaccharides are described. Some of these synthetic vaccines show promising activities inducing proliferation of T-cells and cytotoxic T-cell responses.

Keywords: Glycopeptides, synthetic vaccines, biomimetic synthesis of O-glycosyl amino acids, tumor-associated antigens, MUC1 mucin, anti-tumor vaccines, solid-phase synthesis, glycopeptide protein conjugates