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

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 tumor-associated 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 T(N)-, T-, sialyl-T(N)- and sialyl-T antigens and more complex oligosaccharides (e.g. Lewis(y)). 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 tumor-associated 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.

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

“…Hence, not only the saccharide, [8] but also the peptide backbone from the extracellular tandemrepeat region contribute to the tumor specific glycopeptide epitopes. [9] Fully synthetic vaccines, consisting of MUC1 glycopeptides linked through an oligoethylene glycol spacer to an ovalbumin (OVA) T-cell epitope were shown to induce highly selective antisera in transgenic mice. [10,11] These sera are virtually monoclonal.…”

Ein synthetischer Impfstoff aus einem tumorassoziierten Sialyl‐TN‐MUC1‐Tandem‐Repeat‐Glycopeptid und Tetanustoxoid zur Induktion einer starken, hochselektiven Immunantwort

“…Daher sind nicht nur die Saccharide, [8] sondern auch Peptidsequenzen aus der extrazellulären Tandem-Repeat-Region an den tumortypischen Glycopeptidepitopen beteiligt. [9] Mit vollsynthetischen Impfstoffen, die aus Glycopeptiden von MUC1 und einem über einen Oligoethylenglycol-Spacer verknüpften T-Zellepitop aus dem Ovalbumin (OVA) bestehen, konnten in transgenen Mäusen hochselektive Antiseren induziert werden. [10,11] Die Seren sind nahezu monoklonal.…”

Engineering Antibody Heavy Chain CDR3 to Create a Phage Display Fab Library Rich in Antibodies That Bind Charged Carbohydrates

“…The relatively low affinities that are characteristic of carbohydrate binding proteins (e.g., Abs, selectins) constitute a major challenge for efforts to produce therapeutics that will intervene in carbohydrate recognition events. Given the low immunogenicity of carbohydrates (12,13), immunization procedures often result in only a weak primary IgM response or no response at all. Conventional hybridoma techniques have generated anti-carbohydrate Abs of the IgM class, unsuitable for in vivo diagnostics or therapy (14 -16).…”