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One-pot stapling of interchain disulfides of antibodies using an isobutylene motif.

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cam.issuedOnline2019
dc.contributor.authorSun, Shuang
dc.contributor.authorAkkapeddi, Padma
dc.contributor.authorMarques, Marta C
dc.contributor.authorMartínez-Sáez, Nuria
dc.contributor.authorTorres, Vukosava M
dc.contributor.authorCordeiro, Carlos
dc.contributor.authorBoutureira, Omar
dc.contributor.authorBernardes, Gonçalo JL
dc.contributor.orcidSun, Shuang [0000-0002-4384-7338]
dc.contributor.orcidLopes Bernardes, Goncalo [0000-0001-6594-8917]
dc.date.accessioned2018-12-22T00:31:52Z
dc.date.available2018-12-22T00:31:52Z
dc.date.issued2019-02-13
dc.description.abstractMonoclonal antibodies have emerged as an important class of therapeutics in oncological and autoimmune diseases due to their several attractive properties, such as high binding affinity and specificity. However, it has recently become clear that antibodies recovered from serum show a significantly decreased potency owing to various reasons, including deamidation, oxidation, fragment antigen binding (Fab) exchange, and disulfide shuffling. Fab exchange and disulfide shuffling result because of the instability of disulfides in serum. Herein, we reported a 'one-pot' stapling strategy using isobutylene motifs to stabilise the interchain disulfides of antibodies. This general method was applied to a Fab fragment of the anti-HER2 antibody. The stapled Fab was completely stable in the presence of biological thiols. The approach was further applied to two different full-length IgGs, trastuzumab and rituximab, under mild and biocompatible conditions. The binding affinity of the antibody was enhanced, relative to its native form, after being stapled. The stapled structure maintained its effector functions and behaved similarly to its native form in vivo. This work provides a straightforward and scalable method for the stabilisation of antibodies in various formats.
dc.format.mediumPrint
dc.identifier.doi10.17863/CAM.34724
dc.identifier.eissn1477-0539
dc.identifier.issn1477-0520
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/287420
dc.languageeng
dc.language.isoeng
dc.publisherRoyal Society of Chemistry (RSC)
dc.publisher.urlhttp://dx.doi.org/10.1039/c8ob02877j
dc.subject1107 Immunology
dc.subjectBiotechnology
dc.titleOne-pot stapling of interchain disulfides of antibodies using an isobutylene motif.
dc.typeArticle
dcterms.dateAccepted2018-11-27
prism.endingPage2012
prism.issueIdentifier7
prism.publicationDate2019
prism.publicationNameOrg Biomol Chem
prism.startingPage2005
prism.volume17
pubs.funder-project-idThe Royal Society (uf110046)
pubs.funder-project-idEuropean Research Council (676832)
pubs.funder-project-idRoyal Society (URF\R\180019)
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/M003647/1)
pubs.funder-project-idEuropean Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (675007)
rioxxterms.licenseref.startdate2019-02
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1039/c8ob02877j

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