The development of synthetic antitumour vaccines from mucin glycopeptide antigens

Abstract

Based on important cell-biological and biochemical results concerning the structural difference between membrane glycoproteins of normal epithelial cells and epithelial tumour cells, tumour-associated glycopeptide antigens have been chemically synthesised and structurally confirmed. Glycopeptide structures of the tandem repeat sequence of mucin MUC1 of epithelial tumour cells constitute the most promising tumour-associated antigens. In order to generate a sufficient immunogenicity of these endogenous structures, usually tolerated by the immune system, these synthetic glycopeptide antigens were conjugated to immune stimulating components: in fully synthetic two-component vaccines either with T-cell peptide epitopes or with Toll-like receptor2 lipopeptide ligands or in three-component vaccines with both these stimulants. Alternatively, the synthetic glycopeptide antigens were coupled to immune stimulating carrier proteins. In particular, MUC1 glycopeptide conjugates with Tetanus toxoid proved to be efficient vaccines inducing very strong immune responses in mice. The antibodies elicited with the fully synthetic vaccines showed selective recognition of the tumour-associated glycopeptides as was shown by neutralisation and micro-array binding experiments. After booster immunisations, most of the immune responses showed the installation of an immunological memory. Immunisation with fully synthetic three-component vaccines induced immune reactions with therapeutic effects in terms of reduction of the tumour burden in mice or in killing of tumour cells in culture, while MUC1 glycopeptide-Tetanus toxoid vaccines elicited antibodies in mice which recognised tumour cells in human tumour tissues. The results achieved so far are considered to be promising for the development of an active immunisation against tumours.

Chemically tunable mucin chimeras assembled on living cells

“…In previous work, the synthesis of mucin-type glycopeptides has generally been accomplished by solid-phase peptide synthesis and native chemical or expressed protein ligation methods using glycosylated amino acid building blocks (3). These methods have proved particularly useful for recapitulating mucin structure and function in the context of eliciting an immune response for vaccine development (10). However, the low efficiency and multistep nature of these techniques has restricted peptide size to ca.…”

Synthesis of a Liposomal MUC1 Glycopeptide-Based Immunotherapeutic and Evaluation of the Effect of l-Rhamnose Targeting on Cellular Immune Responses

“…22 Based on these reports, numerous laboratories have explored innovative approaches to increasing the immunogenicity of MUC1 to develop an immunotherapeutic that could kill cancer cells or even be used in the context of immunoprevention. 23–35 Goydos et al demonstrated that a synthetic MUC1-based vaccine could safely be used in humans 36 and a phase I clinical study was reported with a 100 amino acid long MUC1-based vaccine against advanced pancreas and bile duct cancer. 37, 38 In addition, MUC1 peptide pulsed DCs have been used safely as a vaccine in humans with advanced metastatic breast and ovarian cancer.…”

Convergent Solid-Phase Synthesis of Macromolecular MUC1 Models Truly Mimicking Serum Glycoprotein Biomarkers of Interstitial Lung Diseases

“…The present results may motivate us to challenge the synthesis of various mucin domains towards insights into the significance of the posttranslational glycosylations [10][11][12]39,40 and the discovery of the disease-relevant glycopeptidic epitopes of the antibodies/vaccines against cancers, neurodegenerative diseases, and inflammatory diseases. [41][42][43][44] …”