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Interconversion of Unexpected Thiol States Affects the Stability, Structure, and Dynamics of Antibody Engineered for Site-Specific Conjugation.

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cam.issuedOnline2021-08-09
dc.contributor.authorOrozco, Carolina T
dc.contributor.authorEdgeworth, Matthew J
dc.contributor.authorDevine, Paul WA
dc.contributor.authorHines, Alistair R
dc.contributor.authorCornwell, Owen
dc.contributor.authorThompson, Christopher
dc.contributor.authorWang, Xiangyang
dc.contributor.authorPhillips, Jonathan J
dc.contributor.authorRavn, Peter
dc.contributor.authorJackson, Sophie E
dc.contributor.authorBond, Nicholas J
dc.contributor.orcidOrozco, Carolina [0000-0001-7274-8833]
dc.contributor.orcidJackson, Sophie [0000-0002-7470-9800]
dc.date.accessioned2021-11-11T00:30:46Z
dc.date.available2021-11-11T00:30:46Z
dc.date.issued2021-08-18
dc.description.abstractAntibody-drug conjugates have become one of the most actively developed classes of drugs in recent years. Their great potential comes from combining the strengths of large and small molecule therapeutics: the exquisite specificity of antibodies and the highly potent nature of cytotoxic compounds. More recently, the approach of engineering antibody-drug conjugate scaffolds to achieve highly controlled drug to antibody ratios has focused on substituting or inserting cysteines to facilitate site-specific conjugation. Herein, we characterize an antibody scaffold engineered with an inserted cysteine that formed an unexpected disulfide bridge during manufacture. A combination of mass spectrometry and biophysical techniques have been used to understand how the additional disulfide bridge forms, interconverts, and changes the stability and structural dynamics of the antibody intermediate. This quantitative and structurally resolved model of the local and global changes in structure and dynamics associated with the engineering and subsequent disulfide-bonded variant can assist future engineering strategies.
dc.description.sponsorshipThis work was supported by AstraZeneca and the Engineering and Physical Sciences Research Council Centre for Doctoral Training in Sensor Technologies and Applications under Grant EP/L015889/1.
dc.identifier.doi10.17863/CAM.78001
dc.identifier.eissn1520-4812
dc.identifier.issn1043-1802
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/330557
dc.languageeng
dc.language.isoeng
dc.publisherAmerican Chemical Society
dc.publisher.urlhttp://dx.doi.org/10.1021/acs.bioconjchem.1c00286
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectAntibodies, Monoclonal
dc.subjectAntibody Specificity
dc.subjectAntineoplastic Agents
dc.subjectBinding Sites
dc.subjectDrug Design
dc.subjectImmunoconjugates
dc.subjectModels, Molecular
dc.subjectProtein Conformation
dc.subjectSulfhydryl Compounds
dc.titleInterconversion of Unexpected Thiol States Affects the Stability, Structure, and Dynamics of Antibody Engineered for Site-Specific Conjugation.
dc.typeArticle
dcterms.dateAccepted2021-07-02
prism.endingPage1844
prism.issueIdentifier8
prism.publicationDate2021
prism.publicationNameBioconjugate Chemistry
prism.startingPage1834
prism.volume32
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/L015889/1)
rioxxterms.licenseref.startdate2021-08-18
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1021/acs.bioconjchem.1c00286

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