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• W4321749717 endingPage "1545" @default.
• W4321749717 startingPage "1533" @default.
• W4321749717 abstract "Background: Antibody-drug conjugates (ADCs) are a promising modality for cancer treatment; however, considering their complicated nature, analytical complexity in understanding their pharmacokinetics and pharmacodynamics in the body presents a significant challenge. Results: Vorsetuzumab maleimidocaproyl valine-citrulline p-aminobenzyloxycarbonyl monomethyl auristatin E was used to develop pretreatment and analytical workflows suitable for ADCs. Monomethyl auristatin E release and drug-to-antibody ratio retention were consistent in mouse plasma but inconsistent in monkey and human plasma. Further, metabolites were species-specific. Microflow-liquid chromatography/high-resolution mass spectrometry (LC-HRMS) resulted in a 4-7-fold improvement in detection sensitivity compared with conventional flow LC-HRMS. Conclusion: Microflow-LC-HRMS can be a useful tool in understanding the complex properties of ADCs in the body from a drug metabolism and pharmacokinetics point of view.Drug-to-antibody ratio (DAR), payload release and metabolite profile of deconjugated payload-linker of vorsetuzumab maleimidocaproyl valine-citrulline p-aminobenzyloxycarbonyl monomethyl auristatin E, an antibody–drug conjugate (ADC) with cleavable linker and monomethyl auristatin E as payload, are reported. Species-specific retention of DAR, payload release and metabolite patterns of deconjugated payload-linker of the ADC are summarized. Exploring the fate of payload-linker moieties deconjugated from ADCs in the body is also vital to understanding pharmacological activity and toxicity. Species-specific metabolite patterns of the ADC provided insight into the importance of optimization of the payload-linker moiety in biological samples, especially in humans. In terms of a more sensitive analytical platform for drug metabolism and pharmacokinetic evaluation, microflow-liquid chromatography/high-resolution mass spectrometry (LC–HRMS) in DAR analysis was found to take advantage of the improvement of detection sensitivity compared with conventional LC–HRMS. Because ADCs are a complex drug modality, these results indicated the importance of evaluation of ADCs from a drug metabolism and pharmacokinetics point of view to understand the pharmacology and toxicology of ADCs, more precisely." @default.
• W4321749717 created "2023-02-25" @default.
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• W4321749717 date "2022-12-01" @default.
• W4321749717 modified "2023-09-23" @default.
• W4321749717 title "Determination of drug-to-antibody ratio of antibody–drug conjugate in biological samples using microflow-liquid chromatography/high-resolution mass spectrometry" @default.
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• W4321749717 doi "https://doi.org/10.4155/bio-2022-0219" @default.
• W4321749717 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36825963" @default.
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