基于LBA和LC-MS/MS的FDA018 （Trop-2靶向抗体-药物偶联物）综合生物分析方法

IF 3.1 3区医学 Q2 CHEMISTRY, ANALYTICAL

Journal of pharmaceutical and biomedical analysis Pub Date : 2025-05-13 DOI:10.1016/j.jpba.2025.116964

Minlu Cheng , Xianjing Li , Ya Li , Yiya Wang , Wenjia Li , Shuai Wang , Chang Shu , Qinxin Song , Li Ding

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引用次数: 0

摘要

最近，Trop-2靶向抗体药物偶联物（ADC）的批准改变了晚期三阴性乳腺癌患者依赖化疗来提高生存的困境。FDA018是一种ADC，由抗trop -2抗体与拓扑异构酶抑制剂SN-38通过酸可切割连接物偶联组成，目前正在临床试验中进行研究。基于评价FDA018临床药代动力学的迫切需求，建立了测定游离SN-38及其代谢产物SN-38G和总SN-38的配体结合测定法（LBAs）和LC-MS/MS测定法。强调了sn -38偶联抗体和总抗体的ELISA策略的可比性和DAR敏感性评价。LC-MS/MS法同时测定SN-38和SN-38G的灵敏度分别达到0.500 ng/mL和0.250 ng/mL。针对生物样品预处理过程中FDA018可切割连接剂的光学不稳定性，提出了一种有效的解决方案。对所建立的生物分析方法进行了全面验证，结果满足ICH M10可接受标准。验证的生物分析方法已成功应用于FDA018在trop -2阳性恶性肿瘤患者体内的单剂量药代动力学研究，并对FDA018及其主要成分的药代动力学特征进行了研究。

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LBA and LC-MS/MS based comprehensive bioanalytical methods for FDA018, a Trop-2 targeted antibody-drug conjugate

Recently, the approval of Trop-2 targeted antibody drug conjugate (ADC) has changed the dilemma of patients with advanced triple-negative breast cancer who rely on chemotherapeutics to improve their survival. FDA018, an ADC consisting of an anti-Trop-2 antibody conjugated with a topoisomerase inhibitor SN-38 via an acid-cleavable linker, is currently being investigated in clinical trials. Based on the urgent demand to evaluate the clinical pharmacokinetics of FDA018, ligand binding assays (LBAs) for the determination of SN-38-conjugated antibody and total antibody and LC-MS/MS methods for the determination of the free SN-38, its metabolite SN-38G and total SN-38 were developed. The comparability and DAR sensitivity evaluation of the ELISA strategies for SN-38-conjugated antibody and total antibody were emphasized. The sensitivity of the LC-MS/MS method for the simultaneous determination of SN-38 and SN-38G reached 0.500 ng/mL and 0.250 ng/mL, respectively. An effective solution has been proposed for the optical instability of the cleavable linker of FDA018 during the pretreatment process of biological samples. The established bioanalytical methods were comprehensively validated and the results satisfied the acceptable criteria of ICH M10. The validated bioanalytical methods have been applied to the single-dose pharmacokinetic study of FDA018 in patients with Trop-2-positive malignant tumors successfully, and the pharmacokinetic profiles of FDA018 and its constituent components were investigated.

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来源期刊

Journal of pharmaceutical and biomedical analysis 医学-分析化学

CiteScore

6.70

自引率

5.90%

发文量

588

审稿时长

37 days

期刊介绍： This journal is an international medium directed towards the needs of academic, clinical, government and industrial analysis by publishing original research reports and critical reviews on pharmaceutical and biomedical analysis. It covers the interdisciplinary aspects of analysis in the pharmaceutical, biomedical and clinical sciences, including developments in analytical methodology, instrumentation, computation and interpretation. Submissions on novel applications focusing on drug purity and stability studies, pharmacokinetics, therapeutic monitoring, metabolic profiling; drug-related aspects of analytical biochemistry and forensic toxicology; quality assurance in the pharmaceutical industry are also welcome. Studies from areas of well established and poorly selective methods, such as UV-VIS spectrophotometry (including derivative and multi-wavelength measurements), basic electroanalytical (potentiometric, polarographic and voltammetric) methods, fluorimetry, flow-injection analysis, etc. are accepted for publication in exceptional cases only, if a unique and substantial advantage over presently known systems is demonstrated. The same applies to the assay of simple drug formulations by any kind of methods and the determination of drugs in biological samples based merely on spiked samples. Drug purity/stability studies should contain information on the structure elucidation of the impurities/degradants.