Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc., 1120 Veterans Boulevard, South San Francisco 94080, California, United States.
Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks 91320, California, United States.
Anal Chem. 2021 Apr 6;93(13):5562-5569. doi: 10.1021/acs.analchem.1c00149. Epub 2021 Mar 25.
As the pharmaceutical industry places greater emphasis on pairing biological pathways with appropriate therapeutic intervention, an increase in the use of biologic drugs has emerged. With increasing complexity of biotherapeutics, absorption, distribution, metabolism, and excretion (ADME) studies have also become increasingly complex. The characterization of ADME properties is critical to tuning the pharmacokinetic profiles of next generation biologics (NGBs). The knowledge of the fate of a drug is essential for the enhancement of the design processes, elongation of exposure at the desired site of action, and achieving efficacy with minimum toxicity. proteolytic cleavage of biotherapeutics may lead to undesirable properties, such as rapid clearance, low bioavailability, and loss of pharmacodynamic effect. All of these may affect drug efficacy and/or generate safety concerns through increases in immunogenicity or off-target toxicity. The work herein describes the development of a robust, fully automated immunoaffinity purification (IA)-capillary electrophoresis-mass spectrometry (CE-MS) workflow. The reagents were carefully optimized to maximize isolation yields while minimizing the number of experimental steps to analytical results. The result is the development of a comprehensive integrated platform for the characterization of a wide range of biotherapeutics, including peptibodies, monoclonal antibodies, and bispecific antibodies. Empowered by this automated IA-CE-MS approach, implementing biotransformation studies at an early drug discovery stage can speed up the drug development process.
随着制药行业越来越重视将生物途径与适当的治疗干预相结合，生物药物的使用也越来越多。随着生物疗法的复杂性不断增加，吸收、分布、代谢和排泄（ADME）研究也变得越来越复杂。ADME 特性的表征对于调整下一代生物制剂（NGB）的药代动力学特征至关重要。了解药物的命运对于增强设计过程、延长期望作用部位的暴露时间以及以最小的毒性实现疗效至关重要。生物疗法的蛋白水解切割可能导致不理想的特性，如快速清除、低生物利用度和药效丧失。所有这些都可能通过增加免疫原性或脱靶毒性来影响药物疗效和/或产生安全性问题。本文描述了一种强大的、全自动免疫亲和纯化（IA）-毛细管电泳-质谱（CE-MS）工作流程的开发。对试剂进行了仔细优化，以最大限度地提高分离产率，同时最大限度地减少实验步骤到分析结果的数量。其结果是开发了一个广泛的生物疗法的综合集成平台，包括肽抗体、单克隆抗体和双特异性抗体。通过这种自动化的 IA-CE-MS 方法，在药物发现的早期阶段进行生物转化研究可以加快药物开发过程。
