文章摘要
王欣,黄瑛,海岗,林志,苗玉发,王超,姜华,李路路,王海彬,霍艳.抗HER2靶点抗体偶联药物大鼠重复给药毒性研究[J].中国药事,2019,33(6):686-697
抗HER2靶点抗体偶联药物大鼠重复给药毒性研究
Repeated Dose Toxicity Study of Humanized Anti-HER2 Antibody-Drug Conjugate in Rats
投稿时间：2019-02-19  
DOI：10.16153/j.1002-7777.2019.06.013
中文关键词: 抗体偶联药  大鼠  重复给药毒性  HER2靶点  ADC
英文关键词: antibody-drug conjugate  rats  repeated dose toxicity  HER2 target  ADC
基金项目:国家“重大新药创制”科技重大专项资助项目（编号2015ZX09501007-004）
作者单位E-mail
王欣 中国食品药品检定研究院 国家药物安全评价监测中心药物非临床安全评价研究北京市重点实验室, 北京 100176  
黄瑛 中国食品药品检定研究院 国家药物安全评价监测中心药物非临床安全评价研究北京市重点实验室, 北京 100176  
海岗 浙江海正药业股份有限公司, 台州 318000  
林志 中国食品药品检定研究院 国家药物安全评价监测中心药物非临床安全评价研究北京市重点实验室, 北京 100176  
苗玉发 中国食品药品检定研究院 国家药物安全评价监测中心药物非临床安全评价研究北京市重点实验室, 北京 100176  
王超 中国食品药品检定研究院 国家药物安全评价监测中心药物非临床安全评价研究北京市重点实验室, 北京 100176  
姜华 中国食品药品检定研究院 国家药物安全评价监测中心药物非临床安全评价研究北京市重点实验室, 北京 100176  
李路路 中国食品药品检定研究院 国家药物安全评价监测中心药物非临床安全评价研究北京市重点实验室, 北京 100176  
王海彬 浙江海正药业股份有限公司, 台州 318000 hbwang@hiusnpharm.com 
霍艳 中国食品药品检定研究院 国家药物安全评价监测中心药物非临床安全评价研究北京市重点实验室, 北京 100176 yanhuo@nifdc.org.cn 
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中文摘要:
      目的：通过对大鼠尾静脉重复注射给药重组抗HER2人源化单克隆抗体偶联美登素衍生物DM1，对其进行临床前安全性评价。方法：大鼠随机分成5个试验组，包括空白对照组、受试物低（5 mg·kg-1）、中（11 mg·kg-1）、高（22 mg·kg-1）剂量组和已知对照药品组（22 mg·kg-1，Kadcyla?），每组30只动物，雌性各半。尾静脉注射给药，每周给药1次，连续给药3次，末次给药后恢复3周。研究期间，在不同时间点对动物临床症状、体重、摄食量、体温、尿液、血液学、血清生化及组织病理学等指标进行检测。结果：给药后，动物出现一定程度的不良反应，且作用强度呈剂量依赖性递增。毒副反应症状包括摄食量减少、尿液pH值改变；血液学检查发现，动物Lymph、RBC、HGB、HCT、MCV、MCH、MCHC、APTT下降，WBC、Neut、Mono、Eos、Baso、Retic计数升高；血清生化检查发现，动物TG、A/G、Na+、K+下降，ALT、AST、ALP、GGT、CHO、LDH、BUN、TP升高；骨髓检查发现，受试物影响动物红系细胞成熟分化；受试物引起动物肝脏、脾脏、肺（含支气管）重量增加，睾丸、附睾重量减少；组织病理学检查发现，肝脏、肾脏、脾脏、垂体、肾上腺、舌、皮肤细胞有丝分裂项增加，睾丸生精细胞数目减少和变性坏死，附睾精子减少和纤维组织增生。对照品组动物，给药后出现上述同样的改变。试验结果表明，受试物和已知对照药品两种药物的大鼠毒性研究结果具有相似性。结论：大鼠尾静脉重复注射给予重组抗HER2人源化单克隆抗体偶联美登素衍生物DM1后，毒性靶器官为肝脏、肾脏、脾脏、胸腺、肺（含支气管）、肠系膜淋巴结、十二指肠、睾丸、附睾、眼球、垂体、肾上腺、皮肤、舌、胸骨（骨髓）。未见毒性反应剂量（NOAEL ≤ 5 mg·kg-1）。上述研究结果支持该药物成功获得临床试验批准，为后续开展临床研究提供了参考依据。
英文摘要:
      Objective:To carry out preclinical safety evaluation on humanized anti-HER2 antibody-drug conjugate, magtansine derivative DM1 through injection of repeated tail vein administration in Sprague-Dawley rats. Methods:Rats were randomly divided into five groups including the vehicle control group, low-dose(5 mg·kg-1), middle-dose(11 mg·kg-1), high-dose(22 mg·kg-1) of test article groups and the positive control group (22 mg·kg-1, Kadcyla®). Each group had 30 rats with 15 females and 15 males. These animals were administered by tail vein injection once per week for 3 weeks and followed by a three-week recovery phase after the last dosing. A series of toxicological parameters such as clinical signs, body weight, food consumption, body temperature, urinalysis, hematology, serum biochemistry and histopathological examination were detected at different points of time during the study. Results:The tested animals exhibited some certain of adverse reactions after administration and the effects had dose-response relationship. Clinical signs of the adverse reactions included decreased food consumption and changed urine pH. Decreased Lymph, RBC, HGB, HCT, MCV, MCH, MCHC, APTT levels and increased WBC, Neut, Mono, Eos, Baso, Retic were found in the hematological examination of animals in the test article group compared to the vehicle control animals. Decreased TG, A/G, Na+, K+ levels and increased ALT, AST, ALP, GGT, CHO, LDH, BUN, TP were found in the serum biochemical analysis of animals in the test article group compared to the vehicle control animals. The maturation of erythroblasts was also affected. The organ weights of liver, spleen, lung increased while the weights of testicle and epididymis decreased. The histopathological examination results showed that cellular mitotic arrest in liver, kidney, spleen, pituitary body, adrenal gland, tongue and skin increased, the number and degeneration/necrosis of spermatogenic cells in testis decreased, and the sperm and fibrosis in epididymis decreased. Animals from the positive control group showed the same changes mentioned above. The test results showed that test article and positive control medicine had similarity in the repeated dose toxicity study in rats. Conclusion:After repeated administration of the humanized anti-HER2 antibody-drug conjugate, magtansine derivative DM1 for injection to the rats, the toxic target organs were liver, kidney, spleen, thymus, lung, mesenteric lymph node, duodenum, testicle, epididymis, eye, pituitary body, adrenal gland, skin, tongue, and sternum (marrow). The NOAEL is no more than 5 mg·kg-1. These data supported the successful approval of Phase I clinical trial of the drug and provided references for the follow-up clinical study.
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