抗体-药物偶联药物（ADC）HS630对大鼠中枢神经系统的安全性评价

目的：评价注射用重组抗HER2人源化单克隆抗体偶联美登素衍生物DM1（即HS630）对SD大鼠中枢神经系统的影响。方法：将40只SD大鼠随机分为4组，分别单次尾静脉注射空白对照品（空白对照组）、6 mg&#183;kg^-1 HS630（低剂量组）、20 mg&#183;kg^-1 HS630（中剂量组）及40 mg&#183;kg^-1 HS630（高剂量组）。实验采用功能观测组合（function observational battery，FOB）实验方法，分别在给药前和给药后0.5、4、24、48、72、120及168 h观察大鼠运动功能、感觉功能、自主活动等行为。结果：6 mg&#183;kg^-1剂量下，HS630对大鼠中枢神经系统没有影响；20 mg&#183;kg^-1剂量下，给药后4 h，HS630不同程度降低动物唤醒唤起反应、手指接近反应、触摸头部反应（P<0.05或P<0.01）、惊恐反应及出现震颤动物数明显多于空白对照组（P<0.05），之后时间点该症状逐渐恢复；40 mg&#183;kg^-1剂量下，给药后4、48、72及120 h均出现不同程度唤醒唤起反应、手指接近反应、触摸头部反应、惊恐反应降低，且出现震颤动物数明显多于空白对照组（P<0.05），随着给药时间的延长，上述症状逐渐恢复。结论：本研究结果提示，HS630一定剂量下可能会诱发神经毒性，但是可逐渐恢复。

Objective:To evaluate the effect of recombinant anti-HER2 humanized monoclonal antibody conjugated maytansine derivative DM1(HS630)on the central nervous system of SD rats.Methods:Forty SD rats were randomly divided into four groups:caudal vein injection blank control group(blank control),low dose group(6 mg&#183;kg^-1 HS630),middle dose group(20 mg&#183;kg^-1 HS630)and high dose group(40 mg&#183;kg^-1 HS630),respectively.The motor function,sensory function,autonomic activity of the rats were observed before administration and at 0.5 h,4 h,24 h,48 h,72 h,120 h and 168 h after administration using the method of functional observational battery(FOB).Results:HS630 had no effect on the central nervous system of rats at 6 mg&#183;kg^-1 dose.At 20 mg&#183;kg^-1 dose and 4 h after the administration,HS630 reduced response of arousal,finger approach,head touch(P<0.05 or P<0.01),and fear.And the number of tremor animals in the high dose group was significantly higher than that of the blank control group(P<0.05).These symptoms gradually recovered at the subsequent time point.At the dose of 40 mg&#183;kg^-1 and 4 h,48 h,72 h,and 120 h after the administration,HS630 reduced response of arousal,finger approach,head touch and fear.The number of tremor animals in high dose group was significantly higher than that of the blank control group(P<0.05).The symptoms gradually recovered with the prolongation of administration time.Conclusion:The results of this study suggested that a certain dose of HS630 can induce neurotoxicity,but the symptoms can gradually recover.