Abecassis Pierre-Yves, Amara Céline
DSAR (Disposition, Safety & Animal Research), Sanofi, Vitry-sur-Seine, France.
Methods Mol Biol. 2013;1045:101-16. doi: 10.1007/978-1-62703-541-5_6.
Antibody-drug conjugates (ADCs) are promising biotherapeutics designed to selectively deliver highly cytotoxic drugs to tumor cells while sparing normal tissues. They can be viewed as prodrugs, stable in the bloodstream in order to minimize drug release in circulation and efficiently converted into active drugs in the tumor tissues. Designing the right combination of monoclonal antibody (mAb), linker and drug, requires monitoring and understanding the behavior of all three components in the bloodstream and tumor. In particular, linkers have been shown to influence efficacy and safety profiles of ADCs, and monitoring in vivo "drug-linker stability" is therefore critical to help the linker choice and is performed by identifying the pharmacokinetics (PK) profiles. PK properties of ADCs are measured by following the profiles of three entities: (a) the conjugate (mAb entity carrying at least one drug), (b) the total antibody (mAb entity regardless of drug load), as well as (c) the free drugs and metabolites entities. This chapter focuses on the key analytical methods (ELISA immunoassays, TFC-MS/MS, and HRMS) used to support the PK profiles assessment of the three entities, allowing the characterization of ADC "drug-linker stability".
抗体药物偶联物（ADCs）是一种很有前景的生物治疗药物，旨在将高细胞毒性药物选择性地递送至肿瘤细胞，同时使正常组织免受损伤。它们可被视为前药，在血流中稳定，以尽量减少循环中的药物释放，并在肿瘤组织中有效转化为活性药物。设计单克隆抗体（mAb）、连接子和药物的正确组合，需要监测和了解这三种成分在血流和肿瘤中的行为。特别是，连接子已被证明会影响ADC的疗效和安全性，因此监测体内“药物-连接子稳定性”对于帮助选择连接子至关重要，并且通过确定药代动力学（PK）特征来进行。ADCs的PK特性通过跟踪三个实体的特征来测量：（a）偶联物（携带至少一种药物的mAb实体），（b）总抗体（无论药物负载量如何的mAb实体），以及（c）游离药物和代谢物实体。本章重点介绍用于支持这三个实体的PK特征评估的关键分析方法（ELISA免疫测定、TFC-MS/MS和HRMS），从而能够表征ADC的“药物-连接子稳定性”。
