Synthesis, conformational analysis and In vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment

The Tn antigen (GalNAc-a-1-O-Thr/Ser) is a well-known tumor-associated carbohydrate determinant. The use of glycopeptides that incorporate this structure has become a significant and promising niche of research owing to their potential use as anticancer vaccines. Herein, the conformational preferenc...

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Autores: Bermejo, I.A., Navo, C.D., Castro-López, J., Guerreiro, A., Jiménez-Moreno, E., Sánchez Fernández, E.M., García-Martín, F., Hinou, H., Nishimura, S.I., García Fernández, J.M., Mellet, C.O., Avenoza, A., Busto, J.H., Bernardes, G.J.L., Hurtado-Guerrero, R., Peregrina, J.M., Corzana, F.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Universidad de Zaragoza
Repositorio:Zaguán. Repositorio Digital de la Universidad de Zaragoza
OAI Identifier:oai:zaguan.unizar.es:89679
Acceso en línea:http://zaguan.unizar.es/record/89679
Access Level:acceso abierto
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spelling Synthesis, conformational analysis and In vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragmentBermejo, I.A.Navo, C.D.Castro-López, J.Guerreiro, A.Jiménez-Moreno, E.Sánchez Fernández, E.M.García-Martín, F.Hinou, H.Nishimura, S.I.García Fernández, J.M.Mellet, C.O.Avenoza, A.Busto, J.H.Bernardes, G.J.L.Hurtado-Guerrero, R.Peregrina, J.M.Corzana, F.The Tn antigen (GalNAc-a-1-O-Thr/Ser) is a well-known tumor-associated carbohydrate determinant. The use of glycopeptides that incorporate this structure has become a significant and promising niche of research owing to their potential use as anticancer vaccines. Herein, the conformational preferences of a glycopeptide with an unnatural Tn antigen, characterized by a threonine decorated with an sp2-iminosugar-type a-GalNAc mimic, have been studied both in solution, by combining NMR spectroscopy and molecular dynamics simulations, and in the solid state bound to an anti-mucin-1 (MUC1) antibody, by X-ray crystallography. The Tn surrogate can mimic the main conformer sampled by the natural antigen in solution and exhibits high affinity towards anti-MUC1 antibodies. Encouraged by these data, a cancer vaccine candidate based on this unnatural glycopeptide and conjugated to the carrier protein Keyhole Limpet Hemocyanin (KLH) has been prepared and tested in mice. Significantly, the experiments in vivo have proved that this vaccine elicits higher levels of specific anti-MUC1 IgG antibodies than the analog that bears the natural Tn antigen and that the elicited antibodies recognize human breast cancer cells with high selectivity. Altogether, we compile evidence to confirm that the presentation of the antigen, both in solution and in the bound state, plays a critical role in the efficacy of the designed cancer vaccines. Moreover, the outcomes derived from this vaccine prove that there is room for exploring further adjustments at the carbohydrate level that could contribute to designing more efficient cancer vaccines.2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://zaguan.unizar.es/record/89679reponame:Zaguán. Repositorio Digital de la Universidad de Zaragozainstname:Universidad de ZaragozaInglésinfo:eu-repo/grantAgreement/ES/DGA/E34-R17info:eu-repo/grantAgreement/ES/DGA/LMP58-18info:eu-repo/grantAgreement/EC/FP7/283570info:eu-repo/grantAgreement/ES/MEC/BFU2016-75633-Pinfo:eu-repo/grantAgreement/ES/MEC/CTQ2013-44367-C2-2-Pinfo:eu-repo/grantAgreement/ES/MICINN/RTI2018-097609-B-C21info:eu-repo/grantAgreement/ES/MICINN/RTI2018-099592-B-C21info:eu-repo/grantAgreement/ES/MINECO/SAF2016-76083-Rinfo:eu-repo/semantics/openAccessoai:zaguan.unizar.es:896792026-05-29T13:59:51Z
dc.title.none.fl_str_mv Synthesis, conformational analysis and In vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment
title Synthesis, conformational analysis and In vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment
spellingShingle Synthesis, conformational analysis and In vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment
Bermejo, I.A.
title_short Synthesis, conformational analysis and In vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment
title_full Synthesis, conformational analysis and In vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment
title_fullStr Synthesis, conformational analysis and In vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment
title_full_unstemmed Synthesis, conformational analysis and In vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment
title_sort Synthesis, conformational analysis and In vivo assays of an anti-cancer vaccine that features an unnatural antigen based on an sp2-iminosugar fragment
dc.creator.none.fl_str_mv Bermejo, I.A.
Navo, C.D.
Castro-López, J.
Guerreiro, A.
Jiménez-Moreno, E.
Sánchez Fernández, E.M.
García-Martín, F.
Hinou, H.
Nishimura, S.I.
García Fernández, J.M.
Mellet, C.O.
Avenoza, A.
Busto, J.H.
Bernardes, G.J.L.
Hurtado-Guerrero, R.
Peregrina, J.M.
Corzana, F.
author Bermejo, I.A.
author_facet Bermejo, I.A.
Navo, C.D.
Castro-López, J.
Guerreiro, A.
Jiménez-Moreno, E.
Sánchez Fernández, E.M.
García-Martín, F.
Hinou, H.
Nishimura, S.I.
García Fernández, J.M.
Mellet, C.O.
Avenoza, A.
Busto, J.H.
Bernardes, G.J.L.
Hurtado-Guerrero, R.
Peregrina, J.M.
Corzana, F.
author_role author
author2 Navo, C.D.
Castro-López, J.
Guerreiro, A.
Jiménez-Moreno, E.
Sánchez Fernández, E.M.
García-Martín, F.
Hinou, H.
Nishimura, S.I.
García Fernández, J.M.
Mellet, C.O.
Avenoza, A.
Busto, J.H.
Bernardes, G.J.L.
Hurtado-Guerrero, R.
Peregrina, J.M.
Corzana, F.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
description The Tn antigen (GalNAc-a-1-O-Thr/Ser) is a well-known tumor-associated carbohydrate determinant. The use of glycopeptides that incorporate this structure has become a significant and promising niche of research owing to their potential use as anticancer vaccines. Herein, the conformational preferences of a glycopeptide with an unnatural Tn antigen, characterized by a threonine decorated with an sp2-iminosugar-type a-GalNAc mimic, have been studied both in solution, by combining NMR spectroscopy and molecular dynamics simulations, and in the solid state bound to an anti-mucin-1 (MUC1) antibody, by X-ray crystallography. The Tn surrogate can mimic the main conformer sampled by the natural antigen in solution and exhibits high affinity towards anti-MUC1 antibodies. Encouraged by these data, a cancer vaccine candidate based on this unnatural glycopeptide and conjugated to the carrier protein Keyhole Limpet Hemocyanin (KLH) has been prepared and tested in mice. Significantly, the experiments in vivo have proved that this vaccine elicits higher levels of specific anti-MUC1 IgG antibodies than the analog that bears the natural Tn antigen and that the elicited antibodies recognize human breast cancer cells with high selectivity. Altogether, we compile evidence to confirm that the presentation of the antigen, both in solution and in the bound state, plays a critical role in the efficacy of the designed cancer vaccines. Moreover, the outcomes derived from this vaccine prove that there is room for exploring further adjustments at the carbohydrate level that could contribute to designing more efficient cancer vaccines.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://zaguan.unizar.es/record/89679
url http://zaguan.unizar.es/record/89679
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/ES/DGA/E34-R17
info:eu-repo/grantAgreement/ES/DGA/LMP58-18
info:eu-repo/grantAgreement/EC/FP7/283570
info:eu-repo/grantAgreement/ES/MEC/BFU2016-75633-P
info:eu-repo/grantAgreement/ES/MEC/CTQ2013-44367-C2-2-P
info:eu-repo/grantAgreement/ES/MICINN/RTI2018-097609-B-C21
info:eu-repo/grantAgreement/ES/MICINN/RTI2018-099592-B-C21
info:eu-repo/grantAgreement/ES/MINECO/SAF2016-76083-R
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv
publisher.none.fl_str_mv
dc.source.none.fl_str_mv reponame:Zaguán. Repositorio Digital de la Universidad de Zaragoza
instname:Universidad de Zaragoza
instname_str Universidad de Zaragoza
reponame_str Zaguán. Repositorio Digital de la Universidad de Zaragoza
collection Zaguán. Repositorio Digital de la Universidad de Zaragoza
repository.name.fl_str_mv
repository.mail.fl_str_mv
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