抗体偶联药物临床前安全性评价关注点

Concerns of the safety evaluation of antibody-drug conjugates

抗体偶联药物(ADCs)是将具有靶向性质的抗体和强细胞毒性的药物偶联而成的一种抗肿瘤药。ADCs可看作一前药,增大了细胞毒类药物的安全窗,但仍存在安全担忧。其毒性主要与细胞毒类药物全身暴露和ADC介导的非期望的细胞毒性有关。常见的毒性反应为骨髓抑制、肝功能损伤、外周神经病变、免疫毒性等。ADCs安全性评价总的原则与ICH S6及ICH S6附录一致,在重复给药毒性试验(种属选择、剂量设计、实验周期、恢复期)、毒代动力学试验、免疫原性试验以及生殖和发育毒性试验等方面应重点关注。ADCs有望成为肿瘤靶向治疗中较有前景的发展方向。

Antibodydrug conjugates （ADCs） combine the antigentargeting specificity ofantlbodes wltn the cytotoxic potency of chemotherapeutic drugs by means of relatively stable linker. ADCs can be defined as pro drugs. ADCs improve the therapeutic window, but still have safety issues. The toxicities of ADCs were mainly relat ed to systemic release of toxicants and unwanted ADCmediated cytotoxicities. Commonly reported toxicities include manifestations of myelosuppression, hepatic injury, peripheral neuropathy and immunotoxicity. The safety evalua tion of ADCs should follow the general principles in ICH S6 and ICH S6 Addendum, and attentions should be paid to repeatdose toxicity study （ e. g. , species selection, dose selection, duration of studies and recovery）, toxicoki netics, immunogenicity assessments, and reproductive and developmental toxicity studies. ADC represents a prom isinz theraDeutic approach for cancer.