经肌肉注射溶瘤腺病毒注射液Ad-TD-nsIL12对叙利亚仓鼠的急性毒性试验  

Acute toxicity of Ad-TD-nsIL12 oncolytic adenovirus injection by intramuscular injection on Syrian hamsters

作　　者：吴小荣 张素才 赵光豪 王贝贝 张佳丽 彭霞 易宗春[3] WU Xiao-rong;ZHANG Su-cai;ZHAO Guang-hao;WANG Bei-bei;ZHANG Jia-li;PENG Xia;YI Zong-chun(Beijing Bio-Targeting Therapeutics Technology Co.,Ltd,Beijing 100176,China;JOINN Laboratories,Beijing 100176,China;School of Biological Science and Medical Engineering,Beihang University,Beijing 100083,China)

机构地区：[1]北京锤特生物科技有限公司,北京100176 [2]北京昭衍新药研究中心股份有限公司,北京100176 [3]北京航空航天大学生物与医学工程学院,北京100083

出　　处：《毒理学杂志》2021年第4期335-339,345,共6页Journal of Toxicology

基　　金：国家重点研发计划“重大慢性非传染性疾病防控研究”专项(SQ2019YFC1316100)。

摘　　要：目的Ad-TD-nsIL12是基于人5型腺病毒改造构建的携带人白介素12基因(nsIL12)的新一代重组复制型溶瘤腺病毒。本研究选用对人5型腺病毒和人IL12反应近似于人体的叙利亚仓鼠作为模型,观察肌肉注射给以Ad-TD-nsIL12的急性毒性作用,评价其对人体的潜在毒性。方法SPF级6~8周龄叙利亚仓鼠随机分为阴性对照组、Ad-TD-nsIL12低剂量组和Ad-TD-nsIL12高剂量组,每组10只,雌雄各半,低和高剂量组动物经肌肉注射剂量分别为1.53×10^(11)VP/只和7.64×10^(11)VP/只的Ad-TD-nsIL12,阴性对照组动物同样途径给以氯化钠注射液。观察动物给药后当天和2周内的表现,定时测量体重、摄食量和体温,2周观察期结束实施安乐死,取血测定血清各项生化指标,并进行系统大体解剖观察。结果各组动物均未见死亡或濒死现象,也未观察到其他异常变化;在D1~D4,低和高剂量组动物呈现食量减少的变化,且有一定的剂量相关性;在D1和D2,雌性高剂量组动物的体温偏高。给药2周后(D15),与阴性对照组比较,雄性高剂量组的血清肌酸磷酸激酶活性水平(2140.6±786.9)U/L的升高,差异有统计学意义(P≤0.05);动物于D15实施安乐死后,经大体解剖观察各剂量组未见明显异常改变。结论Ad-TD-nsIL12经肌肉注射单次给药的最大耐受剂量>6.4×10^(12) VP/kg,约为临床拟用剂量的1910倍,该剂量下未见叙利亚仓鼠死亡或较为严重地毒性表现。Objective Ad-TD-nsIL12 is a new generation of recombinant replicative oncolytic human adenovirus type 5,which carries the modified human interleukin-12 gene(nsIL12).In this study,Syrian hamsters,which show responses to human adenovirus type 5 and human IL12 similar to humans,were used to observe the acute toxic effects of intramuscular injection of Ad-TD-nsIL12 and evaluate its potential toxicity to humans.Methods SPF Syrian hamsters aged 6 to 8 weeks were randomly divided into three groups:negative control group,Ad-TD-nsIL12 low-dose group and Ad-TD-nsIL12 high-dose group,with 10 hamsters in each group,half male and half female.Ad-TD-nsIL12 was injected intramuscular at a dose of 1.53×10^(11) VP/animal in the low-dose group and 7.64×10^(11) VP/animal in the high-dose group,and saline was given in the negative control group.The physiological states of the animals was observed within two weeks after administration.Body weight,food intake and body temperature were measured regularly.Euthanasia was carried out at the end of the 2-week observation period.Results During the experiment,no death or dying phenomenon was observed,and no other abnormal changes were also observed.During D1~D4 period,the low dose group and the high dose group showed a decrease in food intake with a dose-dependence.At D1 and D2,female animals in the high-dose group had higher body temperatures.Two weeks after administration(D15),the serum creatine phosphokinase activity in the male high-dose group increased statistically.After euthanasia of animals in D15,no obvious abnormal changes were observed in each dose group.Conclusion The maximum tolerated dose of Ad-TD-nsIL12 is greater than 6.4×10^(12) VP/kg by intramuscular injection,which is 1910 times of the clinical intended dose.No lethal or severe toxicity was observed in Syrian hamsters at this dose.

关 键 词：溶瘤腺病毒 人白介素-12 最大耐受剂量 急性毒性 叙利亚仓鼠 

分 类 号：R992[医药卫生—毒理学] R114[医药卫生—药学]