The validation and clinical bioanalysis of the Bicycle® Toxin Conjugate zelenectide pevedotin in human plasma.

IF 1.9 4区医学 Q3 BIOCHEMICAL RESEARCH METHODS Bioanalysis Pub Date : 2025-01-19 DOI:10.1080/17576180.2025.2452837

Joseph A Tweed, Fern Adams-Dam, Justin Bader, Ying Zhang, Jane Allanson, Kevin Holmes, Ryan Senior, Mike Rigby, Phil Jeffrey, Hongmei Xu

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Abstract

Background: The Bicycle® toxin conjugate (BTC) zelenectide pevedotin, formerly known as BT8009, is a novel bicyclic peptide targeting the Nectin-4 tumor antigen conjugated to the cytotoxin monomethyl auristatin E (MMAE) via a valine-citrulline cleavable linker. Zelenectide pevedotin is currently being investigated in a Phase 1/2 (Duravelo-1, NCT04561362) clinical trial to determine safety and efficacy in patients with tumors associated with Nectin-4 expression. A simple regulated bioanalytical assay was developed to quantify intact zelenectide pevedotin in patient plasma samples.

Methodology: Quantitation of the intact zelenectide pevedotin and its analog internal standard BCY6063 encompassed a routine protein precipitation procedure followed by reverse phase chromatographic separation paired with tandem mass spectrometric detection.

Results: Intact zelenectide pevedotin was quantified over the assay range of 5-2500 ng/mL using 50 µL of human plasma. The method was validated according to local standard operating procedures and has met all US Food and Drug Administration and European Medicines Agency regulatory guidance criteria.

Conclusion: A bioanalytical method for measuring zelenectide pevedotin in plasma samples was developed and successfully applied in evaluating over 3000 samples from patients in a Phase 1/2 clinical study of zelenectide pevedotin in patients with advanced solid tumors.

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人血浆中脚踏车®毒素偶联泽连奈德-佩韦多汀的验证和临床生物分析。

背景：Bicycle®toxin conjugate (BTC) zelenectide pevedotin，原名BT8009，是一种新型双环肽，靶向Nectin-4肿瘤抗原，通过缬氨酸-瓜氨酸可切割连接物与细胞毒素monomethyl auristatin E （MMAE）结合。Zelenectide pevedotin目前正在进行1/2期临床试验（Duravelo-1, NCT04561362），以确定与Nectin-4表达相关的肿瘤患者的安全性和有效性。建立了一种简单的调节生物分析方法来定量患者血浆样品中完整的泽连奈德培韦多丁。方法：完整的zelenectide pevedotin及其类似内标BCY6063的定量包括常规蛋白质沉淀程序，然后是反相色谱分离和串联质谱检测。结果：使用50µL人血浆，在5-2500 ng/mL范围内定量完整的泽连奈德培韦多汀。该方法根据当地标准操作程序进行了验证，并符合美国食品和药物管理局和欧洲药品管理局的所有监管指导标准。结论：开发了一种测定血浆样品中zelenectide pevedotin的生物分析方法，并成功应用于zelenectide pevedotin治疗晚期实体瘤患者的1/2期临床研究中3000多例患者样本的评估。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioanalysis BIOCHEMICAL RESEARCH METHODS-CHEMISTRY, ANALYTICAL

CiteScore

3.30

自引率

16.70%

发文量

审稿时长

2 months

期刊介绍： Reliable data obtained from selective, sensitive and reproducible analysis of xenobiotics and biotics in biological samples is a fundamental and crucial part of every successful drug development program. The same principles can also apply to many other areas of research such as forensic science, toxicology and sports doping testing. The bioanalytical field incorporates sophisticated techniques linking sample preparation and advanced separations with MS and NMR detection systems, automation and robotics. Standards set by regulatory bodies regarding method development and validation increasingly define the boundaries between speed and quality. Bioanalysis is a progressive discipline for which the future holds many exciting opportunities to further reduce sample volumes, analysis cost and environmental impact, as well as to improve sensitivity, specificity, accuracy, efficiency, assay throughput, data quality, data handling and processing. The journal Bioanalysis focuses on the techniques and methods used for the detection or quantitative study of analytes in human or animal biological samples. Bioanalysis encourages the submission of articles describing forward-looking applications, including biosensors, microfluidics, miniaturized analytical devices, and new hyphenated and multi-dimensional techniques. Bioanalysis delivers essential information in concise, at-a-glance article formats. Key advances in the field are reported and analyzed by international experts, providing an authoritative but accessible forum for the modern bioanalyst.