The structure-function relationship of disulfide bonds in etanercept

Abstract Etanercept is a TNFα receptor Fc fusion protein used for the treatment of rheumatic disease and psoriasis. Physicochemical and functional investigation of process fractions during development of the etanercept biosimilar GP2015 (Erelzi®) revealed a correlation between reduced potency and in...

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Autores principales:	William C. Lamanna, Robert Ernst Mayer, Alfred Rupprechter, Michael Fuchs, Fabian Higel, Cornelius Fritsch, Cornelia Vogelsang, Andreas Seidl, Hansjoerg Toll, Martin Schiestl, Johann Holzmann
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c7209dcd6ffd42fea8b0b256f819198c
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spelling	oai:doaj.org-article:c7209dcd6ffd42fea8b0b256f819198c2021-12-02T12:32:42ZThe structure-function relationship of disulfide bonds in etanercept10.1038/s41598-017-04320-52045-2322https://doaj.org/article/c7209dcd6ffd42fea8b0b256f819198c2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04320-5https://doaj.org/toc/2045-2322Abstract Etanercept is a TNFα receptor Fc fusion protein used for the treatment of rheumatic disease and psoriasis. Physicochemical and functional investigation of process fractions during development of the etanercept biosimilar GP2015 (Erelzi®) revealed a correlation between reduced potency and incorrect disulfide bridging between specific cysteines in the receptor domain. This novel structure-function relationship was found to be the molecular basis for reduced potency in recent Enbrel® batches, which exhibit higher levels of incorrect disulfide bridging. Interestingly, incorrect disulfide bridging was found to be reversible under serum-like redox conditions, restoring potency to normal levels. This redox dependent reversibility suggests that these variants are likely not relevant for clinical efficacy once the drug enters the bloodstream. Nonetheless, incorrect disulfide bridging in etanercept represents a new quality attribute that is critical for biopharmaceutical functionality and should thus be carefully monitored and controlled to guarantee patient safety.William C. LamannaRobert Ernst MayerAlfred RupprechterMichael FuchsFabian HigelCornelius FritschCornelia VogelsangAndreas SeidlHansjoerg TollMartin SchiestlJohann HolzmannNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-8 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q William C. Lamanna Robert Ernst Mayer Alfred Rupprechter Michael Fuchs Fabian Higel Cornelius Fritsch Cornelia Vogelsang Andreas Seidl Hansjoerg Toll Martin Schiestl Johann Holzmann The structure-function relationship of disulfide bonds in etanercept
description	Abstract Etanercept is a TNFα receptor Fc fusion protein used for the treatment of rheumatic disease and psoriasis. Physicochemical and functional investigation of process fractions during development of the etanercept biosimilar GP2015 (Erelzi®) revealed a correlation between reduced potency and incorrect disulfide bridging between specific cysteines in the receptor domain. This novel structure-function relationship was found to be the molecular basis for reduced potency in recent Enbrel® batches, which exhibit higher levels of incorrect disulfide bridging. Interestingly, incorrect disulfide bridging was found to be reversible under serum-like redox conditions, restoring potency to normal levels. This redox dependent reversibility suggests that these variants are likely not relevant for clinical efficacy once the drug enters the bloodstream. Nonetheless, incorrect disulfide bridging in etanercept represents a new quality attribute that is critical for biopharmaceutical functionality and should thus be carefully monitored and controlled to guarantee patient safety.
format	article
author	William C. Lamanna Robert Ernst Mayer Alfred Rupprechter Michael Fuchs Fabian Higel Cornelius Fritsch Cornelia Vogelsang Andreas Seidl Hansjoerg Toll Martin Schiestl Johann Holzmann
author_facet	William C. Lamanna Robert Ernst Mayer Alfred Rupprechter Michael Fuchs Fabian Higel Cornelius Fritsch Cornelia Vogelsang Andreas Seidl Hansjoerg Toll Martin Schiestl Johann Holzmann
author_sort	William C. Lamanna
title	The structure-function relationship of disulfide bonds in etanercept
title_short	The structure-function relationship of disulfide bonds in etanercept
title_full	The structure-function relationship of disulfide bonds in etanercept
title_fullStr	The structure-function relationship of disulfide bonds in etanercept
title_full_unstemmed	The structure-function relationship of disulfide bonds in etanercept
title_sort	structure-function relationship of disulfide bonds in etanercept
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/c7209dcd6ffd42fea8b0b256f819198c
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The structure-function relationship of disulfide bonds in etanercept

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