基因工程抗癌新药重组人钙调磷酸酶B亚基对食蟹猴重复给药毒性研究

摘要

Objective: To evaluate the safety of recombinant human calcineurin B subunit ( rh CNB), a new anticancer drug, through cynomolgus monkeys by intravenous drip multiple times, to provide reference for clinical design of human dose and clinical toxic side effects. Methods: 40 healthy cynomolgus monkeys were randomly divided into four groups: the auxiliary control group and the low, medium and high dose group ( 10, 30 and 90 mg·kg-1 respectively). Each group was 10, female and male were half, and the female was not pregnant. The drug was administered by intravenous drip, 1 time a day, 1 week stop after a continuous dose of 2 weeks, and then the next period of administration, a total of 26 weeks, and 8 weeks in the recovery period. All the toxicological indexes were measured during the test. Results: rh CNB was used to observe the intravenous drip of cynomolgusmonkeys. The results of immunogenicity showed that the specific immune response was found in the animals after the drug, and the dose effect relationship was obvious. The positive rate of antibody decreased after the drug was stopped. Except the above reactions, the general symptoms, weight, intake of food, blood and blood biochemistry, peripheral blood and bone marrow, electrocardiogram, body temperature and urine analysis in different periods were not related to the changes of the subjects. No significant toxicity or pathological changes were observed in the vital organs of cynomolgus monkeys. Immunogenicity supplementation tests were carried out. Serum samples from each drug group were positive, and the results of antibody test were negative. It shows that the daily dosage of the product is 1 ～ 2. 7 mg·kg-1 ( 60 ～ 160 mg·d-1) with little toxicity. Conclusion: the repeated intravenous drip of rh CNB in cynomolgus monkeys for 6 months have no obvious influence on the other observation indexes except the specific immune response in the immunogenicity test animals, and there is no obvious toxic damage and pathological changes in the important vital organs of the experimental animals, and the NOAEL is 90 mg·kg-1. Clinical use should be concerned with the immunogenicity of the test products.%目的:本研究主要评价食蟹猴静脉多次注射基因工程抗癌新药重组人钙调磷酸酶B亚基 (rh CNB) 的安全性,为临床设计人用剂量及临床不良反应的监测提供参考依据.方法:将40只健康食蟹猴,随机分为4组:辅料对照组和供试品低、中、高剂量组 (给药剂量分别为10,30和90 mg·kg-1),每组10只,雌雄各半,雌性无孕.采用静脉滴注给药途径,每天给药1次,连续给药2周后停药1周,再进行下一周期的给药,共重复给药26周,恢复期8周.试验期间进行各项毒理学指标测定.结果:rh CNB对食蟹猴静脉滴注重复给药观察,免疫原性检测结果显示给药后动物体内出现了特异性免疫反应,呈明显的剂量-效应关系,停药后抗体阳性率明显减少.除上述反应外,不同时间段,各剂量组动物一般症状、体重、摄食量、血液和血生化、外周血和骨髓象、心电图、体温和尿液分析等各项检查均未见与受试物相关的改变.供试品给药剂量组对食蟹猴各重要生命器官结果也未见明显毒性损伤及病理改变.后续进行了免疫原性补充试验,各给药组抗体检测结果为阳性的血清,其中和抗体的检测结果为阴性.说明该供试品所拟定的人日用剂量1～2.7mg·kg-1 (60～160 mg·d-1),毒性较小.结论:食蟹猴重复静脉滴注rh CNB 6个月,除了免疫原性检测动物体内出现了特异性免疫反应外,对其余观察指标未见明显影响;试验动物各重要生命器官也无明显毒性损伤及毒性病理改变,NOAEL为90 mg·kg-1.临床使用时应需要关注供试品有可能引起的免疫原性反应.