Development of a LC-MS/MS method for the quantification of toxic payload DM1 cleaved from BT1718 in a Phase I study
| Autor: | Catherine Gowland, Gareth J. Veal, Philip Berry, Phillip Jeffrey, Marc Pittman, Andrew Niewiarowski, Julie Errington, Lisa Godfrey, Stefan Symeonides, Gavin Bennett |
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| Rok vydání: | 2021 |
| Předmět: |
Protein Conformation
Clinical Biochemistry Peptide Peptides Cyclic Analytical Chemistry 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Tandem Mass Spectrometry Lc ms ms General Pharmacology Toxicology and Pharmaceutics 030304 developmental biology chemistry.chemical_classification 0303 health sciences Metalloproteinase Chromatography Bicyclic molecule Chemistry Protein Stability Payload (computing) General Medicine Hydrogen-Ion Concentration Anticancer drug Phase i study Medical Laboratory Technology 030220 oncology & carcinogenesis Chromatography Liquid |
| Zdroj: | Gowland, C, Berry, P, Errington, J, Jeffrey, P, Bennett, G, Godfrey, L, Pittman, M, Niewiarowski, A, Symeonides, S N & J Veal, G 2021, ' Development of a LC-MS/MS method for the quantification of toxic payload DM1 cleaved from BT1718 in a Phase I study ', Bioanalysis . https://doi.org/10.4155/bio-2020-0256 |
| ISSN: | 1757-6199 |
| DOI: | 10.4155/bio-2020-0256 |
| Popis: | Background: BT1718 is a novel bicyclic peptide anticancer drug targeting membrane type I matrix metalloproteinase to release its toxic payload DM1. A LC–MS/MS method was validated to quantify DM1 generated from BT1718 in a Phase I/IIa clinical trial. Materials & methods: Plasma samples underwent a reduction reaction to artificially cleave BT1718 into DM1 and its bicycle components. An alkylation step was carried out to stabilize the reaction products, and plasma proteins extracted using acetonitrile. LC–MS/MS analysis utilized a C18 column and Agilent 6460 triple quadrupole mass spectrometer (Agilent, Cheshire, UK). Results: The method was fully validated over a linear range of 200–50,000 ng/ml BT1718, with overall precision ≤10% and accuracy 89–102%. Conclusion: A novel method for quantifying DM1 yielded from BT1718 has been validated and is now being utilized clinically. |
| Databáze: | OpenAIRE |
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