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

Safety evaluation of antibody-drug-conjugates(ADC) HS630 on the central nervous system of rats

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·kg^(-1) HS630(低剂量组)、20 mg·kg^(-1) HS630(中剂量组)及40 mg·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·kg^(-1)剂量下,HS630对大鼠中枢神经系统没有影响;20 mg·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·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·kg^（-1） HS630）,middle dose group（20 mg·kg^（-1） HS630）and high dose group（40 mg·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 6mg·kg^（-1） dose.At 20 mg·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·kg^（-1） and 4 h,48 h,72 h,and 120 h after the administration,HS630reduced 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.