中文摘要：

目的：观察帕妥珠单抗生物类似药SMMU-27四周静脉注射对食蟹猴的安全性。方法：20只健康食蟹猴按体重随机分为阳性对照组、SMMU-27低、中、高剂量组和辅料对照组,每组4只,雌雄各半。低、中、高剂量组剂量分别为15、150和450 mg/kg,阳性对照组给予150 mg/kg帕妥珠单抗（Pertuzumab）,辅料对照组给予空白溶剂（0 mg/kg）。各组动物按相应体重慢速静脉注射给药,给药体积为15 m L/kg,给药速度约5 m L/min。每周给药1次,共给药4周,恢复期4周,期间进行各项毒理学指标检测。结果：一般症状结果显示给药期间与给药后,低、中、高剂量组和阳性对照组陆续有动物出现腹泻症状。高剂量组1只动物在d40时濒死剖解,其最早出现稀便,停药后腹泻状态也未见好转,生化指标显示在d28时碱性磷酸酶（Alkaline Phosphatase,ALP）升高,在d14和d40时尿素（Blood Urea,BU）升高,总蛋白（Total Protein,TP）、白蛋白（Albumin,ALB）降低。低、高剂量组和阳性对照组均有部分动物白细胞（White Blood Cell,WBC）给药后数值降低,各给药组在d14时及高剂量组和阳性对照组在d28时BU升高或有升高的趋势,恢复期时有恢复趋势。高剂量濒死动物骨髓检查发现核红细胞较多,各阶段粒细胞减少,出现较多裸核;病理检查发现肾脏可见散在多发的中度肾小管扩张,近曲小管上皮轻度变性。其余指标包括一般症状、体重、尿液、心电图、免疫学指标等未见明显与供试品相关的异常变化。结论：SMMU-27主要毒性靶部位是胃肠道（腹泻）、肾脏（血清BU升高）和血液系统（WBC下降）,应与这些部位表达供试品结合的相关受体有关,属供试品的药理作用放大和延伸。因此本实验条件下食蟹猴的安全剂量（NOAEL）为150 mg/kg,致死剂量为450 mg/kg。SMMU-27与等剂量阳性对照药物毒性反应基本类似。

英文摘要：

Objective： To evaluate the toxicity of SMMU-27, a biosimilar of pertuzumab, in cynomolgus monkeys following repeated intravenous for 4 weeks. Methods： Twenty healthy cynomolgus monkeys were randomly divided into 5 groups according to the body weight（two male and two female in each group）. Animals were intravenously treated with SMMU-27（0, 15, 150 or 450 mg/kg） or Pertuzumab（150 mg/kg） once a week for 4 weeks following a recovery period of 4 weeks. The injection volume was 15.0 m L/kg with an administration rate of 5 m L/min. Toxicological indexes were recorded during the test. Results： Diarrhea occurred in the monkeys in low dose group, middle dose group, high dose group and pertuzumab. One monkey of high dose group, which had diarrhea firstly was dead on d40.The serum of the dead monkey showed elevated alkaline phosphatase（ALP） on d28, and BU on d14 and d40, Total protein（TP）and albumin（ALB） of this monkey were decreased. Compared with d0（before administration） in the same group, WBC decreased significantly in low dose group, high dose group and pertuzumab, while BU was increased in all groups on d14. BU in high dose group and pertuzumab group were increased on d28. The above changes were reversible at the end of the recovery period. The analysis of the dead animal showed that the red blood cell and bare nucleus were increased, while the granulocyte was decreased. Pathological examination show that there were tubular dilatation and abnormal in proximal tubule. The other indexes were not affected by the administration of the drug. Conclusions： The main toxic target organs of SMMU-27 are gastrointestinal（diarrhea）, kidney（the increased of the BU in serum）and blood system（the decreased of the WBC）. The NOAEL and poisoning dose of SMMU-27 are 150 mg/kg and 450 mg/kg respectively.The SMMU-27 and pertuzumab showed similar toxicity effect on cynomolgus monkey at the same dose.