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dc.contributor.authorPifferi, Carlo
dc.contributor.authorAguinagalde, Leire
dc.contributor.authorRuiz de Angulo Dorronsoro, Ane
dc.contributor.authorSacristán, Nagore
dc.contributor.authorTonon Baschirotto, Priscila
dc.contributor.authorPoveda, Ana
dc.contributor.authorJiménez Barbero, Jesús ORCID
dc.contributor.authorAnguita Castillo, Juan de Dios
dc.contributor.authorFernández Tejada, Alberto
dc.date.accessioned2023-05-16T17:31:16Z
dc.date.available2023-05-16T17:31:16Z
dc.date.issued2023-04
dc.identifier.citationChemical Science 14(13) : 3501-3513 (2023)es_ES
dc.identifier.issn2041-6520
dc.identifier.issn2041-6539
dc.identifier.urihttp://hdl.handle.net/10810/61126
dc.description.abstractThe overexpression of aberrantly glycosylated tumor-associated mucin-1 (TA-MUC1) in human cancers makes it a major target for the development of anticancer vaccines derived from synthetic MUC1-(glyco) peptide antigens. However, glycopeptide-based subunit vaccines are weakly immunogenic, requiring adjuvants and/or additional immunopotentiating approaches to generate optimal immune responses. Among these strategies, unimolecular self-adjuvanting vaccine constructs that do not need coadministration of adjuvants or conjugation to carrier proteins emerge as a promising but still underexploited approach. Herein, we report the design, synthesis, immune-evaluation in mice, and NMR studies of new, self-adjuvanting and self-assembling vaccines based on our QS-21-derived minimal adjuvant platform covalently linked to TA-MUC1-(glyco)peptide antigens and a peptide helper T-cell epitope. We have developed a modular, chemoselective strategy that harnesses two distal attachment points on the saponin adjuvant to conjugate the respective components in unprotected form and high yields via orthogonal ligations. In mice, only tri-component candidates but not unconjugated or di- component combinations induced significant TA-MUC1-specific IgG antibodies able to recognize the TA-MUC1 on cancer cells. NMR studies revealed the formation of self-assembled aggregates, in which the more hydrophilic TA-MUC1 moiety gets exposed to the solvent, favoring B-cell recognition. While dilution of the di-component saponin–(Tn)MUC1 constructs resulted in partial aggregate disruption, this was not observed for the more stably-organized tri-component candidates. This higher structural stability in solution correlates with their increased immunogenicity and suggests a longer half-life of the construct in physiological media, which together with the enhanced antigen multivalent presentation enabled by the particulate self-assembly, points to this self-adjuvanting tri-component vaccine as a promising synthetic candidate for further development.es_ES
dc.description.sponsorshipFunding from the European Research Council (ERC-2016-STG-716878 to A. F.-T.; ERC-2017-AdG-788143 to J. J. B.) and the Spanish Ministry of Science and Innovation MCIN/AEI (PID2020-117911RB-I00, CTQ2017-87530-R, RYC-2015-17888 to A. F.-T.; RTI2018-096494-B-100 to J. A.; RTI2018-094751-B-C21 to J. J. B) is gratefully acknowledged. We thank Felix Elortza and Ibon Iloro from the CIC bioGUNE Proteomics Platform and Javier Calvo from the CIC biomaGUNE Mass Spectrometry Platform for their support with MALDI and HRMS analyses. A. F. T. thanks Raquel Fernandez for inspiration.es_ES
dc.language.isoenges_ES
dc.publisherRoyal Society of Chemistryes_ES
dc.relationinfo:eu-repo/grantAgreement/EC/ERC/716878es_ES
dc.relationinfo:eu-repo/grantAgreement/EC/ERC/788143es_ES
dc.relationinfo:eu-repo/grantAgreement/MICINN/PID2020-117911RB-I00es_ES
dc.relationinfo:eu-repo/grantAgreement/MINECO/CTQ2017-87530-Res_ES
dc.relationinfo:eu-repo/grantAgreement/MINECO/RYC-2015-17888es_ES
dc.relationinfo:eu-repo/grantAgreement/MICIU/RTI2018-096494-B-100es_ES
dc.relationinfo:eu-repo/grantAgreement/MICIU/RTI2018-094751-B-C21es_ES
dc.rightsinfo:eu-repo/semantics/openAccesses_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc/3.0/es/*
dc.titleDevelopment of synthetic, self-adjuvanting, and self-assembling anticancer vaccines based on a minimal saponin adjuvant and the tumor- associated MUC1 antigenes_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.rights.holder© 2023 The Author(s). Published by the Royal Society of Chemistry. This article is licensed under a Creative Commons Attribution-Non Commercial 3.0 Unported licence.es_ES
dc.rights.holderAtribución-NoComercial 3.0 España*
dc.relation.publisherversionhttps://pubs.rsc.org/en/content/articlelanding/2023/SC/D2SC05639Aes_ES
dc.identifier.doi10.1039/d2sc05639a
dc.contributor.funderEuropean Commission
dc.departamentoesQuímica Orgánica e Inorgánicaes_ES
dc.departamentoeuKimika Organikoa eta Ez-Organikoaes_ES


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© 2023 The Author(s). Published by the Royal Society of Chemistry. This article is licensed under a Creative Commons Attribution-Non Commercial 3.0 Unported licence.
Except where otherwise noted, this item's license is described as © 2023 The Author(s). Published by the Royal Society of Chemistry. This article is licensed under a Creative Commons Attribution-Non Commercial 3.0 Unported licence.