Synthetic Glycopeptides for the Development of Antitumour Vaccines

Abstract

Glycoproteins of tumour cells often are aberrantly glycosylated. In its tumour-associated form, the epithelial mucin MUC1 carries short saccharide structures such as TN, T, sialyl-TN, and sialyl-T antigens. Due to the incomplete saccharide components, peptide epitopes of the backbone become accessible to the immune system. For the construction of synthetic antitumour vaccines, glycopeptides have been synthesized which contain tumour-associated saccharide antigens and peptide sequences from the tandem repeat portion of MUC1. In the synthesis of these glycopeptides, preformed glycosyl–amino acid building blocks are applied in solution- or solid-phase strategies. Examples are given for the use of N-Fmoc-protected TN, T, sialyl-TN, and sialyl-T antigen–serine and –threonine conjugates in syntheses of glycopeptides from the tandem repeat region from MUC1 and the N-terminal portion of leukosialin (CD43). In solid-phase syntheses allylic linkers (cleavable under neutral conditions), acid-sensitive linkers, and the novel 2-phenyl-2-trimethylsilyl-ethyl ester linker (detachable with fluoride under neutral conditions) have successfully been applied. The synthetic tumour-associated glycopeptide antigens, identical to nature, often exhibit low immunogenicity. Therefore, their conjugation to carrier proteins is demanded. To this aim, glycopeptide antigens have been equipped with biotin labels or conjugated with T-cell peptide epitopes. Some of these synthetic glycopeptide antigens induce proliferation of T-cells and a cytotoxic T-cell response.