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Single mutation on Trastuzumab modulates the stability of antibody–drug conjugates built using acetal-based linkers and thiol-maleimide chemistry

2022Journal article Open access
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dc.contributor.authorFerhati, Xhenti
dc.contributor.authorJiménez-Moreno, Ester
dc.contributor.authorHoyt, Emily A.
dc.contributor.authorSalluce, Giulia
dc.contributor.authorCabeza-Cabrerizo, Mar
dc.contributor.authorNavo, Claudio D.
dc.contributor.authorCompañón, Ismael
dc.contributor.authorAkkapeddi, Padma
dc.contributor.authorMatos, Maria J.
dc.contributor.authorSalaverri, Noelia
dc.contributor.authorGarrido, Pablo
dc.contributor.authorMartínez, Alfredo
dc.contributor.authorLaserna, Víctor
dc.contributor.authorMurray, Thomas V.
dc.contributor.authorJiménez-Osés, Gonzalo
dc.contributor.authorRavn, Peter
dc.contributor.authorBernardes, Gonçalo J. L.
dc.contributor.authorCorzana, Francisco
dc.date.accessioned2022-04-05T13:11:08Z
dc.date.available2022-04-05T13:11:08Z
dc.date.issued2022
dc.descriptionCopyright © 2022 The Authors. Published by American Chemical Societypt_PT
dc.description.abstractAntibody-drug conjugates (ADCs) are a class of targeted therapeutics used to selectively kill cancer cells. It is important that they remain intact in the bloodstream and release their payload in the target cancer cell for maximum efficacy and minimum toxicity. The development of effective ADCs requires the study of factors that can alter the stability of these therapeutics at the atomic level. Here, we present a general strategy that combines synthesis, bioconjugation, linker technology, site-directed mutagenesis, and modeling to investigate the influence of the site and microenvironment of the trastuzumab antibody on the stability of the conjugation and linkers. Trastuzumab is widely used to produce targeted ADCs because it can target with high specificity a receptor that is overexpressed in certain breast cancer cells (HER2). We show that the chemical environment of the conjugation site of trastuzumab plays a key role in the stability of linkers featuring acid-sensitive groups such as acetals. More specifically, Lys-207, located near the reactive Cys-205 of a thiomab variant of the antibody, may act as an acid catalyst and promote the hydrolysis of acetals. Mutation of Lys-207 into an alanine or using a longer linker that separates this residue from the acetal group stabilizes the conjugates. Analogously, Lys-207 promotes the beneficial hydrolysis of the succinimide ring when maleimide reagents are used for conjugation, thus stabilizing the subsequent ADCs by impairing the undesired retro-Michael reactions. This work provides new insights for the design of novel ADCs with improved stability properties.pt_PT
dc.description.sponsorshipWe thank the Agencia Estatal Investigación of Spain (AEI; Grants RTI2018-099592-B-C21 to F.C. and RTI2018-099592-B-C22 to G.J.-O.). This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 675007. E.J.-M. thanks Universidad de la Rioja for a postdoctoral fellowship and Ministerio de Universidades of Spain for a Beatriz Galindo fellowship (BG20/00103) M.J.M. thanks Xunta da Galicia (Plan I2C-ED481B 2014/086-0 and ED481B 2018/007). M.C.-C. thanks Schmidt Science Fellowship program. G.S. thanks MINECO for her F. P. I. fellowship (PRE2018-085973). C.D.N. and G.J.-O. thank the Agencia Estatal de Investigacion for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationJ Am Chem Soc. 2022 Mar 30;144(12):5284-5294pt_PT
dc.identifier.doi10.1021/jacs.1c07675pt_PT
dc.identifier.eissn1520-5126
dc.identifier.issn0002-7863
dc.identifier.urihttp://hdl.handle.net/10451/52182
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherACS Publicationspt_PT
dc.relationA training network for the chemical site-selective modification of proteins: Preparation of the next-generation of therapeutic chemically-defined protein conjugates
dc.relation.publisherversionhttps://pubs.acs.org/journal/jacsatpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleSingle mutation on Trastuzumab modulates the stability of antibody–drug conjugates built using acetal-based linkers and thiol-maleimide chemistrypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleA training network for the chemical site-selective modification of proteins: Preparation of the next-generation of therapeutic chemically-defined protein conjugates
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/675007/EU
oaire.citation.endPage5294pt_PT
oaire.citation.issue12pt_PT
oaire.citation.startPage5284pt_PT
oaire.citation.titleJournal of the American Chemical Societypt_PT
oaire.citation.volume144pt_PT
oaire.fundingStreamH2020
person.familyNameAkkapeddi
person.familyNameBernardes
person.givenNamePadma
person.givenNameGonçalo
person.identifier.orcid0000-0002-4012-9568
person.identifier.orcid0000-0001-6594-8917
person.identifier.scopus-author-id14046757500
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameEuropean Commission
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication0e94354a-087a-4afd-b27b-c351809d5e99
relation.isAuthorOfPublicationd1a48067-77b1-4413-b1c7-602fb18c62c0
relation.isAuthorOfPublication.latestForDiscovery0e94354a-087a-4afd-b27b-c351809d5e99
relation.isProjectOfPublication07de2f0d-a18a-414b-92e5-ae271a0de907
relation.isProjectOfPublication.latestForDiscovery07de2f0d-a18a-414b-92e5-ae271a0de907

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