| 王欣,田超,赵锐,孙立,潘东升,屈哲,苗玉发,李路路,王田田,李劲风,耿兴超.食蟹猴重复给予溶瘤病毒药物HSV-1/hPD-1的毒性研究[J].中国药事,2024,38(4):393-400 |
| 食蟹猴重复给予溶瘤病毒药物HSV-1/hPD-1的毒性研究 |
| Toxicity Study of Repeated Administration of Oncolytic Virus Drug HSV-1/ hPD-1 in Cynomolgus Macaques |
| 投稿时间：2023-11-10 |
| DOI：10.16153/j.1002-7777.2024.04.005 |
| 中文关键词: 溶瘤病毒 基因治疗 食蟹猴 重复给药毒性 生物分布 免疫原性 PD-1抗体 |
| 英文关键词: oncolytic virus gene therapy cynomolgus macaques repeated administration toxicity biodistribution immunogenicity PD-1 antibody |
| 基金项目:中国食品药品检定研究院关键技术研究基金（编号 GJJS-2022-6-3） |
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| 中文摘要: |
| 目的：考察食蟹猴重复给予溶瘤病毒药物HSV-1/hPD-1后的体内毒性，探索安全剂量范围，为后续临床试验提供参考信息。方法：30只食蟹猴随机分成3组，包括溶媒对照组和低、高剂量 （1.0×108 、4.0×108 pfu）组，每组10只，雌雄各半。采用肌肉注射给药，每周给药2次，连续给药6周， 恢复期8周。试验期间，每天观察动物的临床症状和摄食量，每次给药后1~2天观察注射部位症状，每周称量体重。分别在检疫期、首次给药后、给药期结束、恢复期结束的不同时间点进行安全药理（体温、 血压、心电图）测定、临床病理（血液学、血凝、血清生化、尿生化）检查、免疫学（T淋巴细胞、细胞因子、免疫原性）测定、组织病理学检查和脏器称重。结果：给药后，动物未见异常症状、注射部位刺激性、体重和摄食量改变，未见安全药理和临床病理指标有意义的变化。与溶媒对照组比较，第41 天，低剂量会引起动物CD3+ CD4+ T细胞比例升高，高剂量未见明显变化。第13至97天，低、高剂量均能引起动物产生抗载体结合抗体、抗抗体，以及个别动物检出hPD-1表达产物。证明药物在体内产生免疫活性和介导免疫原性。组织病理学检查显示，给药期结束时，低、高剂量组动物注射部位极轻度至中度混合细胞浸润，高剂量组动物坐骨神经极轻度髓鞘/轴突变性；恢复期结束时注射部位病变减为极轻度， 坐骨神经病变未见恢复趋势。低、高剂量组动物未见组织脏器重量改变。结论：食蟹猴重复给予溶瘤病毒药物HSV-1/hPD-1后，动物体内耐受良好，受试物未见毒性反应剂量（NOAEL）是1.0×108 pfu。上述研究结果为药物开展临床试验提供了数据支持。 |
| 英文摘要: |
| Objective: To conduct the in vivo toxicity study of repeated administration of oncolytic virus drug HSV-1/hPD-1 in cynomolgus macaques, and to find out the safety dose range, so as to provide informative references for subsequent clinical trials. Methods: Thirty cynomolgus macaques were randomly divided into three groups including control group, HSV-1/hPD-1 low and high-dose groups (1.0×108 , 4.0×108 pfu), with five animals per sex per group. The monkeys were intramuscularly injected twice a week for consecutive six weeks following an eight-week recovery phase. Animals were observed clinical symptoms daily and irritation of injective sites on days 1 and 2 post injection. Body weight was measured once weekly and food consumption was visually estimated daily. Other toxicological parameters including safety pharmacology (body temperature, blood pressure, electrocardiogram), clinical pathology (hematology, coagulation, biochemical, urinalysis), immunology (T lymphocyte, cytokine, immunogenicity), histopathology and organ weight were scheduled to be detected at the quarantine period, after the fi rst dosing, the end of dosing and recovery period. Results: All animas tolerated well and didn’t show obvious changes in clinical signs, injective irritation, body weight, food consumption, and pharmacology and clinical pathology indexes. On day 41, increased CD3+ CD4+ T lymphocytes were inspected in low dose animals. From days 13 to 97, antibody against HSV-1 vector, expressed PD-1 protein and antiantibody were continuously detected in low and high dose animals, which were considered correlation with immunostimulation and immunogenicity attributed to test articles. The histopathological fi ndings were recoverable minimal to moderate mixed cell infiltration in injection site of low and high dose animals and unrecoverable minimal myelin/axonal damage in sciatic nerve of high dose animals. The change of organ weight wasn’t detected in both groups. Conclusion: After repeated administration of oncolytic virus drug HSV-1/hPD-1, cynomolgus macaques showed good tolerance in vivo, and the no-observed-adverse-eff ect-level (NOAEL) of the test substance was 1.0×108 pfu. Our research data could be used to support subsequent clinical trials. |
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