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SYNTHESIS, CONFORMATIONAL ANALYSIS AND IN VIVO ASSAYS OF AN ANTI-CANCER VACCINE THAT FEATURES AN UNNATURAL ANTIGEN BASED ON A SP2-IMINOSUGAR FRAGMENT

(AGENPARL) – LONDON (UNITED KINGDOM), ven 27 marzo 2020

The Tn antigen (GalNAc-α-1-O-Thr/Ser) is a well-known tumor-associated carbohydrate determinant. The use of glycopeptides that incorporate this structure has become a significant and promising niche of research owing to its potential use as anticancer vaccines. Herein, the conformational preferences of a glycopeptide with an unnatural Tn antigen, characterized by a threonine decorated with a sp2-iminosugar-type α-GalNAc mimic, have been studied both in solution, by combining NMR spectroscopy and molecular dynamics simulations, and in solid state bound to an anti-mucin-1 (MUC1) antibody, by X-ray crystallography. The Tn subrogate can mimic the main conformer sampled by the natural antigen in solution and exhibits high affinity towards anti-MUC1 antibodies. Encouraged by these data, a cancer vaccine candidate based on this unnatural glycopeptide and conjugated to the carrier protein Keyhole Limpet Hemocyanin (KLH) has been prepared and tested in mice. Significantly, the experiments in vivo have proved that this vaccine elicits higher levels of specific anti-MUC1 IgG antibodies than the analog that bears the natural Tn antigen and that the elicited antibodies recognize human breast cancer cells with high selectivity. Altogether, we compile evidence to confirm that the presentation of the antigen, both in solution and the bound state, plays a critical role in the efficacy of designed cancer vaccines. Moreover, the outcomes derived from this vaccine prove that there is there is room for exploring further adjustments at the carbohydrate level that could contribute to designing more efficient cancer vaccines.

This article is Open Access



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Fonte/Source: http://feeds.rsc.org/~r/rss/SC/~3/uLA3RX8nE40/C9SC06334J

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