Structure-Guided Approach for the Development of MUC1-Glycopeptide-Based Cancer Vaccines with Predictable Responses

Mucin-1 (MUC1) glycopeptides are exceptional candidates for potential cancer vaccines. However, their autoantigenic nature often results in a weak immune response. To overcome this drawback, we carefully engineered synthetic antigens with precise chemical modifications. To be effective and stimulate an anti-MUC1 response, artificial antigens must mimic the conformational dynamics of natural antigens in solution and have an equivalent or higher binding affinity to anti-MUC1 antibodies than their natural counterparts. As a proof of concept, we have developed a glycopeptide that contains noncanonical amino acid (2S,3R)-3-hydroxynorvaline. The unnatural antigen fulfills these two properties and effectively mimics the threonine-derived antigen. On the one hand, conformational analysis in water shows that this surrogate explores a landscape similar to that of the natural variant. On the other hand, the presence of an additional methylene group in the side chain of this analog compared to the threonine residue enhances a CH/π interaction in the antigen/antibody complex. Despite an enthalpy-entropy balance, this synthetic glycopeptide has a binding affinity slightly higher than that of its natural counterpart. When conjugated with gold nanoparticles, the vaccine candidate stimulates the formation of specific anti-MUC1 IgG antibodies in mice and shows efficacy comparable to that of the natural derivative. The antibodies also exhibit cross-reactivity to selectively target, for example, human breast cancer cells. This investigation relied on numerous analytical (e.g., NMR spectroscopy and X-ray crystallography) and biophysical techniques and molecular dynamics simulations to characterize the antigen-antibody interactions. This workflow streamlines the synthetic process, saves time, and reduces the need for extensive, animal-intensive immunization procedures. These advances underscore the promise of structure-based rational design in the advance of cancer vaccine development.

Descrição

F.C. thanks the Mizutani Foundation for Glycoscience (grant 220115). I.A.B. and A.A. thank the Asociación Española Contra el Cancer (AECC), sección La Rioja, for doctoral fellowship. We thank the ALBA (Barcelona, Spain) synchrotron beamline XALOC. We thank ARAID, the Agencia Estatal de Investigación (AEI, BFU2016-75633-P and PID2019-105451GB-I00 to R.H.-G., PID2021-127622OB-I00 and PDC2022-133725-C21 to F.C., PID2022-136735OB-I00 to A.M.), Universidad de La Rioja (REGI22/47 and REGI22/16), Gobierno de Aragón (E34_R17 and LMP58_18 to R.H.-G.) with FEDER (2014-2020) funds for “Building Europe from Aragón” for financial support, and the COST Action CA18103 INNOGLY: Innovation with Glycans new frontiers from synthesis to new biological targets. The authors thank Dr Vikki Cantrill for her help with the editing of this manuscript. Publisher Copyright: © 2023 The Authors. Published by American Chemical Society

Palavras-chave

antigen cancer vaccine glycopeptides gold nanoparticles MD simulations mucins NMR X-ray crystallography Analytical Chemistry Chemistry (miscellaneous) Physical and Theoretical Chemistry Organic Chemistry SDG 3 - Good Health and Well-being