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

Bermejo, Iris A. [0000-0001-8864-4852]; Guerreiro, Ana; Eguskiza, Ander; Martínez-Sáez, Nuria [0000-0002-0799-5106]; Lazaris, Foivos S. [0000-0003-4292-8723]; Asín, Alicia; Somovilla, Víctor J. [0000-0001-5067-6568]; Compañón, Ismael; Raju, Tom K.; Tadic, Srdan; Garrido, Pablo; García-Sanmartín, Josune [0000-0003-4391-5537]; Mangini, Vincenzo; Grosso, Ana S.; Marcelo, Filipa [0000-0001-5049-8511]; Avenoza, Alberto [0000-0002-5465-3555]; Busto, Jesús H. [0000-0003-4403-4790]; García-Martín, Fayna [0000-0001-9118-3874]; Hurtado-Guerrero, Ramón [0000-0002-3122-9401]; Peregrina, Jesús M. [0000-0003-3778-7065]; Bernardes, Gonçalo J. L.; Martínez, Alfredo; Fiammengo, Roberto [0000-0002-6087-6851]; Corzana, Francisco [0000-0001-5597-8127]

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...

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Autores:	Bermejo, Iris A. [0000-0001-8864-4852], Guerreiro, Ana, Eguskiza, Ander, Martínez-Sáez, Nuria [0000-0002-0799-5106], Lazaris, Foivos S. [0000-0003-4292-8723], Asín, Alicia, Somovilla, Víctor J. [0000-0001-5067-6568], Compañón, Ismael, Raju, Tom K., Tadic, Srdan, Garrido, Pablo, García-Sanmartín, Josune [0000-0003-4391-5537], Mangini, Vincenzo, Grosso, Ana S., Marcelo, Filipa [0000-0001-5049-8511], Avenoza, Alberto [0000-0002-5465-3555], Busto, Jesús H. [0000-0003-4403-4790], García-Martín, Fayna [0000-0001-9118-3874], Hurtado-Guerrero, Ramón [0000-0002-3122-9401], Peregrina, Jesús M. [0000-0003-3778-7065], Bernardes, Gonçalo J. L., Martínez, Alfredo, Fiammengo, Roberto [0000-0002-6087-6851], Corzana, Francisco [0000-0001-5597-8127]
Tipo de recurso:	artículo
Estado:	Versión publicada
Fecha de publicación:	2024
País:	España
Institución:	Universidad de La Rioja (UR)
Repositorio:	RIUR. Repositorio Institucional de la Universidad de La Rioja
OAI Identifier:	oai:portal.dialnet.es:doc/6579a57eb874b2702ed33e33
Acceso en línea:	https://investigacion.unirioja.es/documentos/6579a57eb874b2702ed33e33
Access Level:	acceso abierto

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spelling	Structure-Guided Approach for the Development of MUC1-Glycopeptide-Based Cancer Vaccines with Predictable ResponsesBermejo, Iris A. [0000-0001-8864-4852]Guerreiro, AnaEguskiza, AnderMartínez-Sáez, Nuria [0000-0002-0799-5106]Lazaris, Foivos S. [0000-0003-4292-8723]Asín, AliciaSomovilla, Víctor J. [0000-0001-5067-6568]Compañón, IsmaelRaju, Tom K.Tadic, SrdanGarrido, PabloGarcía-Sanmartín, Josune [0000-0003-4391-5537]Mangini, VincenzoGrosso, Ana S.Marcelo, Filipa [0000-0001-5049-8511]Avenoza, Alberto [0000-0002-5465-3555]Busto, Jesús H. [0000-0003-4403-4790]García-Martín, Fayna [0000-0001-9118-3874]Hurtado-Guerrero, Ramón [0000-0002-3122-9401]Peregrina, Jesús M. [0000-0003-3778-7065]Bernardes, Gonçalo J. L.Martínez, AlfredoFiammengo, Roberto [0000-0002-6087-6851]Corzana, Francisco [0000-0001-5597-8127]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.2024info:eu-repo/semantics/articleSubtype: Articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://investigacion.unirioja.es/documentos/6579a57eb874b2702ed33e33reponame:RIUR. Repositorio Institucional de la Universidad de La Riojainstname:Universidad de La Rioja (UR)Inglésinfo:eu-repo/semantics/altIdentifier/doi/10.1021/JACSAU.3C00587info:eu-repo/semantics/altIdentifier/pissn/2691-3704info:eu-repo/semantics/altIdentifier/pissn/2691-3704Structure-Guided Approach for the Development of MUC1-Glycopeptide-Based Cancer Vaccines with Predictable Responses, 2024, vol. 4, núm. 1, pág. 150-163info:eu-repo/semantics/openAccessoai:portal.dialnet.es:doc/6579a57eb874b2702ed33e332026-06-14T12:47:17Z
dc.title.none.fl_str_mv	Structure-Guided Approach for the Development of MUC1-Glycopeptide-Based Cancer Vaccines with Predictable Responses
title	Structure-Guided Approach for the Development of MUC1-Glycopeptide-Based Cancer Vaccines with Predictable Responses
spellingShingle	Structure-Guided Approach for the Development of MUC1-Glycopeptide-Based Cancer Vaccines with Predictable Responses Bermejo, Iris A. [0000-0001-8864-4852]
title_short	Structure-Guided Approach for the Development of MUC1-Glycopeptide-Based Cancer Vaccines with Predictable Responses
title_full	Structure-Guided Approach for the Development of MUC1-Glycopeptide-Based Cancer Vaccines with Predictable Responses
title_fullStr	Structure-Guided Approach for the Development of MUC1-Glycopeptide-Based Cancer Vaccines with Predictable Responses
title_full_unstemmed	Structure-Guided Approach for the Development of MUC1-Glycopeptide-Based Cancer Vaccines with Predictable Responses
title_sort	Structure-Guided Approach for the Development of MUC1-Glycopeptide-Based Cancer Vaccines with Predictable Responses
dc.creator.none.fl_str_mv	Bermejo, Iris A. [0000-0001-8864-4852] Guerreiro, Ana Eguskiza, Ander Martínez-Sáez, Nuria [0000-0002-0799-5106] Lazaris, Foivos S. [0000-0003-4292-8723] Asín, Alicia Somovilla, Víctor J. [0000-0001-5067-6568] Compañón, Ismael Raju, Tom K. Tadic, Srdan Garrido, Pablo García-Sanmartín, Josune [0000-0003-4391-5537] Mangini, Vincenzo Grosso, Ana S. Marcelo, Filipa [0000-0001-5049-8511] Avenoza, Alberto [0000-0002-5465-3555] Busto, Jesús H. [0000-0003-4403-4790] García-Martín, Fayna [0000-0001-9118-3874] Hurtado-Guerrero, Ramón [0000-0002-3122-9401] Peregrina, Jesús M. [0000-0003-3778-7065] Bernardes, Gonçalo J. L. Martínez, Alfredo Fiammengo, Roberto [0000-0002-6087-6851] Corzana, Francisco [0000-0001-5597-8127]
author	Bermejo, Iris A. [0000-0001-8864-4852]
author_facet	Bermejo, Iris A. [0000-0001-8864-4852] Guerreiro, Ana Eguskiza, Ander Martínez-Sáez, Nuria [0000-0002-0799-5106] Lazaris, Foivos S. [0000-0003-4292-8723] Asín, Alicia Somovilla, Víctor J. [0000-0001-5067-6568] Compañón, Ismael Raju, Tom K. Tadic, Srdan Garrido, Pablo García-Sanmartín, Josune [0000-0003-4391-5537] Mangini, Vincenzo Grosso, Ana S. Marcelo, Filipa [0000-0001-5049-8511] Avenoza, Alberto [0000-0002-5465-3555] Busto, Jesús H. [0000-0003-4403-4790] García-Martín, Fayna [0000-0001-9118-3874] Hurtado-Guerrero, Ramón [0000-0002-3122-9401] Peregrina, Jesús M. [0000-0003-3778-7065] Bernardes, Gonçalo J. L. Martínez, Alfredo Fiammengo, Roberto [0000-0002-6087-6851] Corzana, Francisco [0000-0001-5597-8127]
author_role	author
author2	Guerreiro, Ana Eguskiza, Ander Martínez-Sáez, Nuria [0000-0002-0799-5106] Lazaris, Foivos S. [0000-0003-4292-8723] Asín, Alicia Somovilla, Víctor J. [0000-0001-5067-6568] Compañón, Ismael Raju, Tom K. Tadic, Srdan Garrido, Pablo García-Sanmartín, Josune [0000-0003-4391-5537] Mangini, Vincenzo Grosso, Ana S. Marcelo, Filipa [0000-0001-5049-8511] Avenoza, Alberto [0000-0002-5465-3555] Busto, Jesús H. [0000-0003-4403-4790] García-Martín, Fayna [0000-0001-9118-3874] Hurtado-Guerrero, Ramón [0000-0002-3122-9401] Peregrina, Jesús M. [0000-0003-3778-7065] Bernardes, Gonçalo J. L. Martínez, Alfredo Fiammengo, Roberto [0000-0002-6087-6851] Corzana, Francisco [0000-0001-5597-8127]
author2_role	author author author author author author author author author author author author author author author author author author author author author author author
description	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.
publishDate	2024
dc.date.none.fl_str_mv	2024
dc.type.none.fl_str_mv	info:eu-repo/semantics/article Subtype: Article info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	https://investigacion.unirioja.es/documentos/6579a57eb874b2702ed33e33
url	https://investigacion.unirioja.es/documentos/6579a57eb874b2702ed33e33
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	info:eu-repo/semantics/altIdentifier/doi/10.1021/JACSAU.3C00587 info:eu-repo/semantics/altIdentifier/pissn/2691-3704 info:eu-repo/semantics/altIdentifier/pissn/2691-3704 Structure-Guided Approach for the Development of MUC1-Glycopeptide-Based Cancer Vaccines with Predictable Responses, 2024, vol. 4, núm. 1, pág. 150-163
dc.rights.none.fl_str_mv	info:eu-repo/semantics/openAccess
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Structure-Guided Approach for the Development of MUC1-Glycopeptide-Based Cancer Vaccines with Predictable Responses

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