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Coupling and Decoupling of Diverse Molecular Units in Glycosciences pp 37–65Cite as

Synthetic Antitumor Vaccines Through Coupling of Mucin Glycopeptide Antigens to Proteins

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Abstract

The requirements for coupling reactions of carbohydrate molecules very much depend upon the biological recognition processes that should be investigated and upon the target structures of the desired carbohydrate ligand. If the carbohydrate conjugate itself is the recognized ligand, as for example, the binding site of a P-selectin ligand comprising sialyl-LewisX and a specific peptide sequence, the natural glycoside bond must be installed. A stereoselective and regioselective block glycosylation between a sialyl-LewisX trichloroacetimidate and a partially deprotected Thomsen–Friedenreich antigen derivative was developed to achieve this aim. In contrast, the coupling reactions by which glycopeptides from tumor-associated glycoproteins are conjugated to immune stimulating components in order to afford efficient vaccines can entail artificial linkages as long as they do not interfere with the immune reactions. For example, the coupling of glycophorin glycopeptides to bovine serum albumin was successfully achieved by carboxylic activation with a water-soluble carbodiimide in the presence of a supernucleophilic additive. This conjugation method is only recommendable if the glycopeptide does not contain several carboxylic and/or amino functions. The photochemically or radical initiator promoted thiol-ene coupling succeeded in couplings of MUC1 glycopeptide antigens to bovine serum albumin, however, is accompanied by oxidative disulfide formation. The conjugation of glycopeptide antigens from the tandem repeat region of the tumor-associated mucin MUC1 to bovine serum albumin or tetanus toxoid is efficiently accomplished using diethyl squarate as the coupling reagent. The intermediate squaric monoamide esters can be isolated and characterized, and then applied to a mild connecting process to the carrier proteins. The MUC1 glycopeptide-tetanus toxoid conjugates proved to be particularly useful vaccines. They induce extraordinarily strong immune responses in mice. The induced antibodies are prevailingly of the IgG1 isotype and show efficient binding to the glycoproteins exposed on epithelial tumor cells.

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  1. Institut Für Organische Chemie, Johannes Gutenberg-Universität Mainz, 55099, Mainz, Germany

    Markus Glaffig & Horst Kunz

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  1. Markus Glaffig
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  2. Horst Kunz
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Correspondence to Horst Kunz .

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  1. Pharmaceutical Sciences Department, Wilkes University, Wilkes-Barre, Pennsylvania, USA

    Zbigniew J. Witczak

  2. Pharmaceutical Sciences Department, Nesbitt School of Pharmacy, Wilkes University, Wilkes-Barre, Pennsylvania, USA

    Roman Bielski

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Glaffig, M., Kunz, H. (2018). Synthetic Antitumor Vaccines Through Coupling of Mucin Glycopeptide Antigens to Proteins. In: Witczak, Z., Bielski, R. (eds) Coupling and Decoupling of Diverse Molecular Units in Glycosciences. Springer, Cham. https://doi.org/10.1007/978-3-319-65587-1_2

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