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Development of synthetic, self-adjuvanting, and self-assembling anticancer vaccines based on a minimal saponin adjuvant and the tumor- associated MUC1 antigen
dc.contributor.author | Pifferi, Carlo | |
dc.contributor.author | Aguinagalde, Leire | |
dc.contributor.author | Ruiz de Angulo Dorronsoro, Ane | |
dc.contributor.author | Sacristán, Nagore | |
dc.contributor.author | Tonon Baschirotto, Priscila | |
dc.contributor.author | Poveda, Ana | |
dc.contributor.author | Jiménez Barbero, Jesús | |
dc.contributor.author | Anguita Castillo, Juan de Dios | |
dc.contributor.author | Fernández Tejada, Alberto | |
dc.date.accessioned | 2023-05-16T17:31:16Z | |
dc.date.available | 2023-05-16T17:31:16Z | |
dc.date.issued | 2023-04 | |
dc.identifier.citation | Chemical Science 14(13) : 3501-3513 (2023) | es_ES |
dc.identifier.issn | 2041-6520 | |
dc.identifier.issn | 2041-6539 | |
dc.identifier.uri | http://hdl.handle.net/10810/61126 | |
dc.description.abstract | The 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.sponsorship | Funding 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.iso | eng | es_ES |
dc.publisher | Royal Society of Chemistry | es_ES |
dc.relation | info:eu-repo/grantAgreement/EC/ERC/716878 | es_ES |
dc.relation | info:eu-repo/grantAgreement/EC/ERC/788143 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/PID2020-117911RB-I00 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/CTQ2017-87530-R | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/RYC-2015-17888 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICIU/RTI2018-096494-B-100 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICIU/RTI2018-094751-B-C21 | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc/3.0/es/ | * |
dc.title | Development of synthetic, self-adjuvanting, and self-assembling anticancer vaccines based on a minimal saponin adjuvant and the tumor- associated MUC1 antigen | es_ES |
dc.type | info:eu-repo/semantics/article | es_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.holder | Atribución-NoComercial 3.0 España | * |
dc.relation.publisherversion | https://pubs.rsc.org/en/content/articlelanding/2023/SC/D2SC05639A | es_ES |
dc.identifier.doi | 10.1039/d2sc05639a | |
dc.contributor.funder | European Commission | |
dc.departamentoes | Química Orgánica e Inorgánica | es_ES |
dc.departamentoeu | Kimika Organikoa eta Ez-Organikoa | es_ES |