抗体-药物偶联物毒性的发生机制与优化方法研究进展

Research Progress on Mechanisms and Optimization Methods for Toxicity Induced by Antibody–Drug Conjugates

自2000年抗体-药物偶联物(ADC)——针对CD33的Gemtuzumab ozogamicin(吉妥珠单抗)获批以来,到目前为止,获得FDA批准的药物已经有13种。该类药物虽然明显改善了多种类型晚期癌症患者的生存,但其明显的毒性却导致患者的治疗获益受损。ADC药物的不良反应具有复杂性,包括靶内和靶外毒性,其中载荷药物是决定因素,但抗体、连接剂均可能影响毒性程度。随着联合治疗成为抗肿瘤治疗的重要策略,在增加疗效的同时,治疗相关不良反应也相应增加。因此,本综述全面分析了当前ADC药物的毒性发生机制,并提出通过多方面优化策略来减小ADC药物毒性,如优化连接分子、升级抗体设计、改变给药策略等。

Since the approval of gemtuzumab ozogamicin,an antibody-drug conjugate(ADC)targeting CD33 in 2000,13 ADC drugs have been approved by the FDA.Although these drugs have clearly improved the survival of patients with various types of advanced cancers,their significant toxicity has compromised their therapeutic benefits.The adverse reactions of ADC drugs are complex and include on-target and offtarget toxicities,where the payload drug is a determining factor.Antibody and linker may also affect the degree of toxicity.Combination therapy becomes an important strategy in anticancer treatment because of its increased efficiency,but treatment-related adverse reactions also increase accordingly.This review comprehensively analyzes the toxicity mechanisms of current ADC drugs and proposes various optimization strategies,including but not limited to optimizing linker molecules,upgrading antibody design,and changing drug administration strategies,to improve the overall safety profile of ADC drugs.