Collins Denis M, Bossenmaier Birgit, Kollmorgen Gwendlyn, Niederfellner Gerhard
National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
Pieris Pharmaceuticals GmbH, 85354 Freising, Germany.
Cancers (Basel). 2019 Mar 20;11(3):394. doi: 10.3390/cancers11030394.
Antibody-drug conjugates (ADCs) combine the tumor selectivity of antibodies with the potency of cytotoxic small molecules thereby constituting antibody-mediated chemotherapy. As this inherently limits the adverse effects of the chemotherapeutic, such approaches are heavily pursued by pharma and biotech companies and have resulted in four FDA (Food and Drug Administration)-approved ADCs. However, as with other cancer therapies, durable responses are limited by the fact that under cell stress exerted by these drugs, tumors can acquire mechanisms of escape. Resistance can develop against the antibody component of ADCs by down-regulation/mutation of the targeted cell surface antigen or against payload toxicity by up-regulation of drug efflux transporters. Unique resistance mechanisms specific for the mode of action of ADCs have also emerged, like altered internalization or cell surface recycling of the targeted tumor antigen, changes in the intracellular routing or processing of ADCs, and impaired release of the toxic payload into the cytosol. These evasive changes are tailored to the specific nature and interplay of the three ADC constituents: the antibody, the linker, and the payload. Hence, they do not necessarily endow broad resistance to ADC therapy. This review summarizes preclinical and clinical findings that shed light on the mechanisms of acquired resistance to ADC therapies.
抗体药物偶联物（ADCs）将抗体的肿瘤选择性与细胞毒性小分子的效力相结合，从而构成抗体介导的化疗。由于这本质上限制了化疗的副作用，此类方法受到制药和生物技术公司的大力追捧，并已产生了四种获得美国食品药品监督管理局（FDA）批准的ADCs。然而，与其他癌症疗法一样，持久反应受到限制，因为在这些药物施加的细胞应激下，肿瘤可以获得逃逸机制。通过下调/突变靶向细胞表面抗原可产生对ADCs抗体成分的抗性，或通过上调药物外排转运蛋白产生对有效载荷毒性的抗性。还出现了针对ADCs作用方式的独特抗性机制，如靶向肿瘤抗原的内化或细胞表面再循环改变、ADCs细胞内转运或加工变化以及有毒有效载荷向细胞质的释放受损。这些逃避性变化是针对三种ADC成分（抗体、连接子和有效载荷）的特定性质和相互作用而定制的。因此，它们不一定赋予对ADC疗法的广泛抗性。本综述总结了有助于阐明对ADC疗法获得性抗性机制的临床前和临床研究结果。
