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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。
Objective: To observe the safety of pertuzumab biologically-analogous SMMU-27 injected into cynomolgus monkeys for four weeks. Methods: Twenty healthy cynomolgus monkeys were randomly divided into positive control group, SMMU-27 low, medium and high dose groups and adjuvant control group, 4 in each group, with half male and one female. The low, medium and high dose groups were 15, 150 and 450 mg / kg respectively. The positive control group was given Pertuzumab 150 mg / kg and the control group was given blank solvent (0 mg / kg). The animals in each group were given a slow intravenous injection of the corresponding body weight at a dose of 15 m L / kg and a drug delivery rate of about 5 m L / min. Administered once a week for a total of 4 weeks, recovery period of 4 weeks, during the detection of toxicological indicators. Results: The general symptom results showed that diarrhea appeared in animals in low, middle and high dose groups and positive control group after administration and after administration. One animal in the high-dose group was dying to death on day d40, the earliest appeared loose stools, diarrhea state did not improve after stopping the treatment. The biochemical indexes showed that the alkaline phosphatase (ALP) increased at d28, And blood urea (BU) increased at d40, total protein (TP) and albumin (ALB) decreased. The values of white blood cells (WBC) in low, high dose group and positive control group were decreased after administration, and at d14 and in the high dose group and positive control group, BU increased or Increasing trend, the recovery period, there is a recovery trend. Bone marrow examination of high-dose dying animals found more nucleated red blood cells, neutropenia at each stage, there are more naked nuclei; pathological examination revealed multiple nephrotic renal tubules dilated, proximal tubule epithelial mild degeneration. The remaining indicators, including general symptoms, weight, urine, ECG, immunological indicators, such as no obvious change associated with the test. CONCLUSIONS: SMMU-27 is mainly responsible for the gastrointestinal tract (diarrhea), kidneys (elevated serum BU) and hematological system (decreased WBC), and should be related to the expression of these receptors for the test substance Pharmacological effects of goods amplification and extension. Therefore, under the experimental conditions, the safety dose of cynomolgus monkeys (NOAEL) was 150 mg / kg and the lethal dose was 450 mg / kg. SMMU-27 and the equivalent dose of positive control drug toxicity similar.