Mucin architecture behind the immune response: Design, evaluation and conformational analysis of an antitumor vaccine derived from an unnatural MUC1 fragment

A tripartite cancer vaccine candidate, containing a quaternary amino acid (α-methylserine) in the most immunogenic domain of MUC1, has been synthesized and examined for antigenic properties in transgenic mice. The vaccine which is glycosylated with GalNAc at the unnatural amino acid, was capable of...

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Autores: Martínez-Sáez, N., Supekar, N.T., Wolfert, M.A., Bermejo, I.A., Hurtado-Guerrero, Ramón, Asensio, Juan Luis, Jiménez-Barbero, Jesús, Busto, Jesús H., Avenoza, Alberto, Boons, G.J., Peregrina, Jesús M., Corzana, Francisco
Tipo de recurso: artículo
Fecha de publicación:2016
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/136120
Acceso en línea:http://hdl.handle.net/10261/136120
Access Level:acceso abierto
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spelling Mucin architecture behind the immune response: Design, evaluation and conformational analysis of an antitumor vaccine derived from an unnatural MUC1 fragmentMartínez-Sáez, N.Supekar, N.T.Wolfert, M.A.Bermejo, I.A.Hurtado-Guerrero, RamónAsensio, Juan LuisJiménez-Barbero, JesúsBusto, Jesús H.Avenoza, AlbertoBoons, G.J.Peregrina, Jesús M.Corzana, FranciscoA tripartite cancer vaccine candidate, containing a quaternary amino acid (α-methylserine) in the most immunogenic domain of MUC1, has been synthesized and examined for antigenic properties in transgenic mice. The vaccine which is glycosylated with GalNAc at the unnatural amino acid, was capable of eliciting potent antibody responses recognizing both glycosylated and unglycosylated tumour-associated MUC1 peptides and native MUC1 antigen present on cancer cells. The peptide backbone of the novel vaccine presents the bioactive conformation in solution and is more resistant to enzymatic degradation than the natural counter part. In spite of these features, the immune response elicited by the unnatural vaccine was not improved compared to a vaccine candidate containing natural threonine. These observations were rationalized by conformational studies, indicating that the presentation and dynamics of the sugar moiety displayed by the MUC1 derivative play a critical role in immune recognition. It is clear that engineered MUC1-based vaccines bearing unnatural amino acids have to be able to emulate the conformational properties of the glycosidic linkage between the GalNAc and the threonine residues. The results described here will be helpful to the rational design of efficacious cancer vaccines.We thank the Ministerio de Economía y Competitividad (projects CTQ2012-36365/FEDER, CTQ2012-32025/FEDER, CTQ2013-44367-C2-2-P, UNLR13-4E-1931). N. M.-S. thanks the Universidad de La Rioja for the FPI grant. I. A. B. thanks the Asociacion Española Contra el Cancer en La Rioja for a grant. We also thank CESGA for computer support. G.-J. B. acknowl- edges the National Cancer Institute of the US National Institutes of Health for support (R01CA88986). Animal studies have been approved by the Institutional Animal Care and Use Committee (IACUC) of the University of GeorgiaPeer ReviewedRoyal Society of Chemistry (UK)Universidad de La RiojaAsociación Española Contra el CáncerNational Cancer Institute (US)Ministerio de Economía y Competitividad (España)2016201620162016info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501http://hdl.handle.net/10261/136120reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1039/c5sc04039finfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1361202026-05-22T06:33:51Z
dc.title.none.fl_str_mv Mucin architecture behind the immune response: Design, evaluation and conformational analysis of an antitumor vaccine derived from an unnatural MUC1 fragment
title Mucin architecture behind the immune response: Design, evaluation and conformational analysis of an antitumor vaccine derived from an unnatural MUC1 fragment
spellingShingle Mucin architecture behind the immune response: Design, evaluation and conformational analysis of an antitumor vaccine derived from an unnatural MUC1 fragment
Martínez-Sáez, N.
title_short Mucin architecture behind the immune response: Design, evaluation and conformational analysis of an antitumor vaccine derived from an unnatural MUC1 fragment
title_full Mucin architecture behind the immune response: Design, evaluation and conformational analysis of an antitumor vaccine derived from an unnatural MUC1 fragment
title_fullStr Mucin architecture behind the immune response: Design, evaluation and conformational analysis of an antitumor vaccine derived from an unnatural MUC1 fragment
title_full_unstemmed Mucin architecture behind the immune response: Design, evaluation and conformational analysis of an antitumor vaccine derived from an unnatural MUC1 fragment
title_sort Mucin architecture behind the immune response: Design, evaluation and conformational analysis of an antitumor vaccine derived from an unnatural MUC1 fragment
dc.creator.none.fl_str_mv Martínez-Sáez, N.
Supekar, N.T.
Wolfert, M.A.
Bermejo, I.A.
Hurtado-Guerrero, Ramón
Asensio, Juan Luis
Jiménez-Barbero, Jesús
Busto, Jesús H.
Avenoza, Alberto
Boons, G.J.
Peregrina, Jesús M.
Corzana, Francisco
author Martínez-Sáez, N.
author_facet Martínez-Sáez, N.
Supekar, N.T.
Wolfert, M.A.
Bermejo, I.A.
Hurtado-Guerrero, Ramón
Asensio, Juan Luis
Jiménez-Barbero, Jesús
Busto, Jesús H.
Avenoza, Alberto
Boons, G.J.
Peregrina, Jesús M.
Corzana, Francisco
author_role author
author2 Supekar, N.T.
Wolfert, M.A.
Bermejo, I.A.
Hurtado-Guerrero, Ramón
Asensio, Juan Luis
Jiménez-Barbero, Jesús
Busto, Jesús H.
Avenoza, Alberto
Boons, G.J.
Peregrina, Jesús M.
Corzana, Francisco
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad de La Rioja
Asociación Española Contra el Cáncer
National Cancer Institute (US)
Ministerio de Economía y Competitividad (España)
description A tripartite cancer vaccine candidate, containing a quaternary amino acid (α-methylserine) in the most immunogenic domain of MUC1, has been synthesized and examined for antigenic properties in transgenic mice. The vaccine which is glycosylated with GalNAc at the unnatural amino acid, was capable of eliciting potent antibody responses recognizing both glycosylated and unglycosylated tumour-associated MUC1 peptides and native MUC1 antigen present on cancer cells. The peptide backbone of the novel vaccine presents the bioactive conformation in solution and is more resistant to enzymatic degradation than the natural counter part. In spite of these features, the immune response elicited by the unnatural vaccine was not improved compared to a vaccine candidate containing natural threonine. These observations were rationalized by conformational studies, indicating that the presentation and dynamics of the sugar moiety displayed by the MUC1 derivative play a critical role in immune recognition. It is clear that engineered MUC1-based vaccines bearing unnatural amino acids have to be able to emulate the conformational properties of the glycosidic linkage between the GalNAc and the threonine residues. The results described here will be helpful to the rational design of efficacious cancer vaccines.
publishDate 2016
dc.date.none.fl_str_mv 2016
2016
2016
2016
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/136120
url http://hdl.handle.net/10261/136120
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1039/c5sc04039f
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Royal Society of Chemistry (UK)
publisher.none.fl_str_mv Royal Society of Chemistry (UK)
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869407452858941440
score 15,811543

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