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• W4309088993 abstract "Therapeutic proteins (TPs) are known to be heterogeneous due to modifications that occur during the production process and storage. Modifications may also occur in TPs after their administration to patients due to <i>in vivo</i> biotransformation. Ligand binding assays, which are widely used in the bioanalysis of TPs in body fluids, are typically unable to distinguish such modifications. Liquid chromatography coupled to mass spectrometry (LC-MS) is being increasingly used to study modifications in TPs but its use to study <i>in vivo</i> biotransformation has been limited until now. We present a novel approach that combines affinity enrichment using Affimer reagents® with ion-exchange chromatography (IEX) to analyze charge variants of the TPs trastuzumab and pertuzumab in plasma of patients undergoing therapy for HER2- positive breast cancer. Affimer reagents® were immobilized via engineered Cys tags to maleimide beads and the TPs were eluted under acidic conditions followed by rapid neutralization. The enriched TPs were analyzed by cation-exchange chromatography (IEX) using pH-gradient elution resulting in the separation of about 20 charge variants for trastuzumab and about 5 charge variants for pertuzumab. A comparison between <i>in vitro</i> stressed TPs spiked into plasma and TPs enriched from patient plasma showed that the observed profiles were highly similar. This indicates that <i>in vitro</i> stress testing in plasma can mimic the situation in patient plasma, as far as the generation of charge variants is concerned. <b>Significance Statement</b> Study of the <i>in vivo</i> biotransformation of Trastuzumab and Pertuzumab in patients undergoing therapy for Her-2-positive breast cancer. Methodology based on enrichment from plasma using Affimers followed by separation of charge variants by pH-gradient, cation-exchange chromatography. Comparative analysis of the chromatographic traces showed that in vitro stress testing mimicks in vivo biotransformation to a large extend as far charge variants are concerned. This paves the way to studies on other therapeutic antibodies." @default.
• W4309088993 created "2022-11-21" @default.
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• W4309088993 date "2022-11-15" @default.
• W4309088993 modified "2023-09-30" @default.
• W4309088993 title "Biotransformation of Trastuzumab and Pertuzumab in Breast Cancer Patients Assessed by Affinity Enrichment and Ion-Exchange Chromatography" @default.
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• W4309088993 doi "https://doi.org/10.1124/dmd.122.001094" @default.
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