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Issue 3, 2016
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Mucin architecture behind the immune response: design, evaluation and conformational analysis of an antitumor vaccine derived from an unnatural MUC1 fragment

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Abstract

A tripartite cancer vaccine candidate, containing a quaternary amino acid (α-methylserine) in the most immunogenic domain of MUC1, has been synthesized and examined for antigenic properties in transgenic mice. The vaccine which is glycosylated with GalNAc at the unnatural amino acid, was capable of eliciting potent antibody responses recognizing both glycosylated and unglycosylated tumour-associated MUC1 peptides and native MUC1 antigen present on cancer cells. The peptide backbone of the novel vaccine presents the bioactive conformation in solution and is more resistant to enzymatic degradation than the natural counter part. In spite of these features, the immune response elicited by the unnatural vaccine was not improved compared to a vaccine candidate containing natural threonine. These observations were rationalized by conformational studies, indicating that the presentation and dynamics of the sugar moiety displayed by the MUC1 derivative play a critical role in immune recognition. It is clear that engineered MUC1-based vaccines bearing unnatural amino acids have to be able to emulate the conformational properties of the glycosidic linkage between the GalNAc and the threonine residues. The results described here will be helpful to the rational design of efficacious cancer vaccines.

Graphical abstract: Mucin architecture behind the immune response: design, evaluation and conformational analysis of an antitumor vaccine derived from an unnatural MUC1 fragment

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Publication details

The article was received on 23 Oct 2015, accepted on 06 Dec 2015 and first published on 15 Dec 2015


Article type: Edge Article
DOI: 10.1039/C5SC04039F
Citation: Chem. Sci., 2016,7, 2294-2301
  • Open access: Creative Commons BY license
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    Mucin architecture behind the immune response: design, evaluation and conformational analysis of an antitumor vaccine derived from an unnatural MUC1 fragment

    N. Martínez-Sáez, N. T. Supekar, M. A. Wolfert, I. A. Bermejo, R. Hurtado-Guerrero, J. L. Asensio, J. Jiménez-Barbero, J. H. Busto, A. Avenoza, G. Boons, J. M. Peregrina and F. Corzana, Chem. Sci., 2016, 7, 2294
    DOI: 10.1039/C5SC04039F

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