贝伐珠单抗类似药SMMU-13对食蟹猴的毒性
Toxicitystudy of SMMU-13,a biosimilar of bevacizumab, in cynomolgus monkeys

为了探讨贝伐珠单抗类似药SMMU-13重复静脉注射对食蟹猴的安全性,采用毒理学评价方法,将30只食蟹猴按体重随机分为溶媒对照组、阳性对照组,低、中、高剂量组,每组6只,雌雄各半。低、中、高剂量组给药量分别为2、10和50 mg/kg;阳性对照组给予50 mg/kg贝伐珠单抗注射液;溶媒对照组给予SMMU-13安慰剂。给药体积均为2 mL/kg。每周给药2次,共4个给药周期,恢复期4周。期间进行各项毒理学指标检测。试验结果发现:与自身给药前d0相比,给药期间中、高剂量组及阳性对照组的乳酸脱氢酶(LDH)和甘油三脂(TG)升高;高剂量组及阳性对照组雄性动物股骨骨骺板软骨细胞增生,钙化成骨不良,给药部位近端血管及周围损伤。其余各项指标毒理学指标未见明显异常变化。以上结果表明,SMMU-13主要毒性靶部位为股骨骨骺及给药局部。在本实验条件下安全剂量为2 mg/kg,毒性剂量为10 mg/kg,与等剂量阳性对照药物毒性反应基本类似。本研究为贝伐珠单抗类似药SMMU-13的临床用药提供了安全用药依据。
The purpose of this study was to evaluate the toxicity of SMMU-13,a biosimilar of bevacizumab,in cynomolgus monkeys.Thirty healthy cynomolgus monkeys were randomly assigned to 5 groups (each group contained three male and three female monkeys) as follows:negative control,positive control,low-,mid- and high-dose groups.The low-,mid-,and high-dose groups were administered 2,0,and 50 mg/kg test article,respectively.The positive control group was given 50 mg/kg bevacizumab,and the negative control animals were given the SMMU-13 placebo.Animals were intravenously treated twice a week for 4 weeks following a 4-week recovery phase.The dose volume was 2.0 mL/kg in all groups.The abnormal findings were recorded.Compared with d0,lactate dehydrogenase (LDH) and triglyceride (TG) in animals from positive control,mid- and high-dose groups increased after administration of the Bevacizumab or SMMU-13.The femoral epiphyseal plate chondrocytes hyperplasia and calcified ossification were noted at male animals in high-dose group and positive control group.The damage was also observed in several animals at the intravenous injection sites or other tissues.No other abnormal findings were noted.The above results show that the main toxic target organs of SMMU-13 are physeal displasia and administration sites.The digestive system (liver) was also considered to be affected.In these experimental conditions,the no observed adverse effect level (NOAEL) of SMMU-13 is 2 mg/kg,and the toxic dose is 10 mg/kg.The SMMU-13 and bevacizumab showed similar pharmaceutical activity and toxicity profiles.