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Synthesis, conformational analysis and in vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp 2 -iminosugar fragment

DOI: 10.1039/C9SC06334J DOI Help

Authors: Iris A. Bermejo (Universidad de La Rioja) , Claudio D. Navo (Universidad de La Rioja; CIC BioGUNE) , Jorge Castro-López (University of Zaragoza) , Ana Guerreiro (Universidade de Lisboa) , Ester Jiménez-Moreno (Universidad de La Rioja) , Elena M. Sánchez Fernández (Universidad de Sevilla) , Fayna García-Martín (Hokkaido University) , Hiroshi Hinou (Hokkaido University) , Shin-Ichiro Nishimura (Hokkaido University) , José M. García Fernández (CSIC–Universidad de Sevilla) , Carmen Ortiz Mellet (Universidad de Sevilla) , Alberto Avenoza (Universidad de La Rioja) , Jesús H. Busto (Universidad de La Rioja) , Gonçalo J. L. Bernardes (Universidade de Lisboa; University of Cambridge) , Ramon Hurtado-Guerrero (University of Zaragoza; University of Copenhagen; Fundación ARAID) , Jesús M. Peregrina (Universidad de La Rioja) , Francisco Corzana (Universidad de La Rioja)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemical Science , VOL 11 , PAGES 3996 - 4006

State: Published (Approved)
Published: April 2020
Diamond Proposal Number(s): 10121

Open Access Open Access

Abstract: 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 their potential use as anticancer vaccines. Herein, the conformational preferences of a glycopeptide with an unnatural Tn antigen, characterized by a threonine decorated with an sp2-iminosugar-type α-GalNAc mimic, have been studied both in solution, by combining NMR spectroscopy and molecular dynamics simulations, and in the solid state bound to an anti-mucin-1 (MUC1) antibody, by X-ray crystallography. The Tn surrogate 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 in the bound state, plays a critical role in the efficacy of the designed cancer vaccines. Moreover, the outcomes derived from this vaccine prove that there is room for exploring further adjustments at the carbohydrate level that could contribute to designing more efficient cancer vaccines.

Diamond Keywords: Immunotherapy

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-Macromolecular Crystallography

Added On: 21/04/2020 15:00


Discipline Tags:

Vaccines Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)