Department of Investigative Toxicology and Pathology, AbbVie, North Chicago, IL 60064, USA.
Department of Investigative Toxicology and Pathology, AbbVie, North Chicago, IL 60064, USA.
Pharmacol Ther. 2019 Aug;200:110-125. doi: 10.1016/j.pharmthera.2019.04.008. Epub 2019 Apr 24.
Antibody-drug conjugates (ADCs) are a promising therapeutic modality for oncology indications. The concept of an ADC platform is to increase the therapeutic index (TI) of chemotherapeutics through more selective delivery of cytotoxic agents to tumor cells while limiting exposure to healthy normal cells. Despite the use of antibodies targeting antigens abundantly and/or exclusively expressed on cancer cells (i.e., target cells), dose limiting toxicities (DLTs) in normal cells/tissues are frequently reported even at suboptimal therapeutic doses. Although advancement of ADC technology has helped to optimize all three key components (i.e., mAb, linker, and payload), DLTs remain a key challenge for ADC development. Mechanisms of ADC toxicity in normal cells/tissues are not clearly understood, but the majority of DLTs are considered to be target-independent. In addition to linker-drug instability contributing to the premature release of cytotoxic drug (payload) in circulation, uptake/trafficking of intact ADCs by both receptor-dependent (FcγRs, FcRn and C-type lectin receptors), and-independent (non-specific endocytosis) mechanisms may contribute to off-target toxicity in normal cells. In this article, we review potential mechanisms of target-independent ADC uptake and toxicity in normal cells, as well as discuss components of ADCs which may influence these mechanisms. This information will provide a deeper understanding of the underlying mechanisms of ADC off-target toxicity and prove helpful toward improving the overall TI of the next generation of ADCs.
抗体药物偶联物（ADC）是一种有前途的肿瘤学治疗方式。ADC 平台的概念是通过更选择性地将细胞毒性药物递送到肿瘤细胞，同时限制对健康正常细胞的暴露，从而提高化疗药物的治疗指数（TI）。尽管使用针对在癌细胞（即靶细胞）上丰富和/或特异性表达的抗原的抗体，但即使在低于最佳治疗剂量的情况下，正常细胞/组织中的剂量限制毒性（DLT）也经常报道。尽管 ADC 技术的进步有助于优化所有三个关键组成部分（即 mAb、连接子和有效载荷），但 DLT 仍然是 ADC 开发的一个关键挑战。正常细胞/组织中 ADC 毒性的机制尚不清楚，但大多数 DLT 被认为是与靶标无关的。除了连接子-药物不稳定导致细胞毒性药物（有效载荷）在循环中过早释放外，完整 ADC 通过受体依赖性（FcγRs、FcRn 和 C 型凝集素受体）和非依赖性（非特异性内吞作用）机制的摄取/转运也可能导致正常细胞的脱靶毒性。在本文中，我们综述了正常细胞中与靶标无关的 ADC 摄取和毒性的潜在机制，并讨论了可能影响这些机制的 ADC 成分。这些信息将深入了解 ADC 脱靶毒性的潜在机制，并有助于提高下一代 ADC 的整体 TI。
