Department of Clinical Pharmacology, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA.
Cancer Chemother Pharmacol. 2021 Jun;87(6):743-765. doi: 10.1007/s00280-021-04250-0. Epub 2021 Apr 1.
Antibody-drug conjugates (ADCs) are important molecular entities in the treatment of cancer. These conjugates combine the target specificity of monoclonal antibodies with the potent anti-cancer activity of small-molecule therapeutics. The complex structure of ADCs poses unique challenges to characterize the drug's pharmacokinetics (PKs) and pharmacodynamics (PDs) since it requires a quantitative understanding of the PK and PD properties of multiple different molecular species (e.g., ADC conjugate, total antibody and unconjugated cytotoxic drug). As a result, clinical pharmacology strategy of an ADC is rather unique and dependent on the linker/cytotoxic drug technology, heterogeneity of the ADC, PK and safety/efficacy profile of the specific ADC in clinical development. In this review, we summarize the clinical pharmacology strategies in supporting development and approval of ADCs using the approved ADCs as specific examples to illustrate the customized approach to clinical pharmacology assessments in their clinical development.
抗体药物偶联物（ADCs）是癌症治疗中的重要分子实体。这些偶联物将单克隆抗体的靶向特异性与小分子治疗药物的强大抗癌活性结合在一起。由于需要定量了解多种不同分子种类（例如 ADC 偶联物、总抗体和未缀合的细胞毒性药物）的 PK 和 PD 特性，因此 ADC 的复杂结构对其 PK 和 PD 特征的描述提出了独特的挑战。因此，ADC 的临床药理学策略相当独特，并且取决于连接子/细胞毒性药物技术、ADC 的异质性、临床开发中特定 ADC 的 PK 和安全性/疗效特征。在这篇综述中，我们总结了支持 ADC 开发和批准的临床药理学策略，使用已批准的 ADC 作为具体示例来说明在其临床开发中对临床药理学评估的定制方法。
