The structure-function relationship of disulfide bonds in etanercept
Open Access
- 21 June 2017
- journal article
- research article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 7 (1), 3951
- https://doi.org/10.1038/s41598-017-04320-5
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.This publication has 24 references indexed in Scilit:
- Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journeyBlood, 2012
- Disulfide bond structures of IgG moleculesmAbs, 2012
- Acceptable changes in quality attributes of glycosylated biopharmaceuticalsNature Biotechnology, 2011
- Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritisNature Reviews Rheumatology, 2009
- Structural and Functional Characterization of Disulfide Isoforms of the Human IgG2 SubclassOnline Journal of Public Health Informatics, 2008
- Tumor necrosis factor antagonist mechanisms of action: A comprehensive reviewPharmacology & Therapeutics, 2008
- Removal of Cysteinylation from an Unpaired Sulfhydryl in the Variable Region of a Recombinant Monoclonal IgG1 Antibody Improves Homogeneity, Stability, and Biological ActivityJournal of Pharmaceutical Sciences, 2008
- Immune-mediated inflammatory diseases (IMIDs) and biologic therapy: a medical revolutionPublished by Oxford University Press (OUP) ,2007
- Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-αNature, 1997
- A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cellsNature, 1997