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目的评价抗CD20人源化单克隆抗体SM09的急性毒性。方法将食蟹猴随机分为阴性对照组、SM09 10、30和100 mg/kg剂量组,采用注射泵前臂静脉缓慢注射单次给药,阴性对照组给予等体积的生理盐水,于给药前和给药后不同时间进行各项毒理学指标检测。结果食蟹猴注射SM09,在给药速度达600 mg/h时,动物未见明显异常反应;给药后各剂量组动物临床症状、体重、进食量、体温、心电图、血压、血清生化指标均未见明显异常;血液学检测结果显示,100 mg/kg剂量组动物白细胞数量出现一过性降低;给药后第2天,各剂量组动物外周血CD20+B淋巴细胞数量即明显降低,B细胞表现出耗竭状态,给药后3～8周,B细胞水平逐渐回复,且呈剂量相关性。给药后8周剖检,100 mg/kg剂量组雌性动物脾脏呈暗红色且体积增大,镜检可见红髓扩张充血和脾小体数量减少。结论食蟹猴单次静脉注射抗CD20单抗,具有良好的耐受性,除与药理作用相关的外周血B细胞清除效应外,未见其他毒性反应,最大耐受剂量可达100 mg/kg。
Objective To evaluate the acute toxicity of anti-CD20 humanized monoclonal antibody SM09. Methods Cynomolgus monkeys were randomly divided into the negative control group, SM09 10, 30 and 100 mg / kg dose group, with a single injection of slow injection forearm vein injection pump, an equal volume of normal saline in the negative control group, And after administration of different toxicological indicators for testing. Results The cynomolgus monkeys injected with SM09 showed no obvious abnormal reaction at the dose of 600 mg / h. The clinical symptoms, body weight, food intake, body temperature, electrocardiogram, blood pressure and serum biochemical indexes No obvious abnormalities were observed. The results of hematology test showed that the number of white blood cells in the 100 mg / kg dose group had a transient decrease. On the second day after the administration, the number of CD20 + B lymphocytes in the peripheral blood of each dose group was significantly decreased The cells showed depletion status. After 3 to 8 weeks of administration, the B cells gradually recovered in a dose-dependent manner. Eight weeks after the administration, the spleen of the female was dark red and the volume was increased at the dose of 100 mg / kg. The number of dilated spleen and red spleen of the mice in the 100 mg / kg dose group decreased. Conclusion The cynomolgus monkeys injected with anti-CD20 mAb in a single intravenous injection have good tolerability. There is no other toxic reaction besides the pharmacological effects of peripheral blood B cell clearance. The maximum tolerated dose can reach 100 mg / kg .