阿达木单抗类似药SMMU-16皮下注射对食蟹猴的重复给药毒性研究

目的：探讨阿达木单抗类似药SMMU-16重复皮下注射对食蟹猴的安全性。方法30只健康食蟹猴按体重随机分为溶媒对照组，阳性对照组，SMMU-16低、中、高剂量组，其中SMMU-16低、中、高剂量组分别给予SMMU-1610、33、200 mg/kg，每组6只，雌雄各半。阳性对照组给予33.0 mg/kg 阿达木单抗，溶媒对照组给予SM-MU-16空白溶液。给药体积均为4.0 ml/kg（分4个点注射）。每周1次皮下注射给药，共给药4周，恢复期4周，期间进行各项毒理学指标检测。结果与自身给药前（d0）相比，给药期间中剂量组、高剂量组及阳性对照组的红细胞计数、Hb定量、红细胞压积（HCT）降低（P均＜0.05），中、高剂量组网织红细胞比例升高（P＜0.05）。骨髓检查发现SM-MU-16中、高剂量组及阳性对照组食蟹猴骨髓红细胞系轻度增生。组织病理学检查发现d28时阳性对照组和高剂量组各3只、中剂量组2只动物出现胸腺萎缩和脾脏萎缩。上述变化在恢复期结束时可逐渐恢复。各组动物肝脏和肾脏未见明显病理改变。其余指标包括一般症状、呼吸、体温、瞳孔、尿液、心电图、免疫和生化指标等未见明显与供试品相关的异常变化和量效、时效关系。结论 SMMU-16主要毒性靶器官为免疫系统（胸腺和脾脏）和血液系统，毒性作用具有一定的可逆性。此毒性作用考虑与SMMU-16免疫抑制药理作用的延伸和放大有关。SMMU-16皮下注射对食蟹猴的无毒性剂量为10 mg/kg。 SMMU-16与等剂量阳性对照药在本实验条件下出现的毒性反应基本类似。

Safety evaluation of SMMU-16, a biosimilar of HUMIRA,in Cynomolgus monkeys following a 4-week repeated administration

Objective To evaluate the toxicity of SMMU-16, a biosimilar of HUMIRA, in Cynomolgus monkeys following repeated subcutaneous administration. Methods According to the body weight, thirty healthy Cynomol-gus monkeys were randomly divided into 5 groups with 6 animals (half male and half female) in each group. Animals were subcutaneously treated once a week for 4 weeks with SMMU-16 (10 ,33 or 200 mg/kg), HUMIRA (33 mg/kg) or vehicle solution following a recovery period of 4 weeks. The injection volume was 4.0 ml/kg in all groups. Toxicological indexes were recorded during the testing. Results Compared with d0 (before administration) in the same group, RBC, Hb, HCT decreased significantly in SMMU-16 33, 200 mg/kg group and HUMIRA 33 mg/kg group, and the proportion of reticulo-cyte increased significantly in SMMU-16 33, 200 mg/kg group (P<0.05). Mild hyperplasia of bone marrow red cells were also found in these groups. Histopathological examination indicated thymic and splenic atrophy in SMMU -16 33, 200 mg/kg group and HUMIRA 33 mg/kg group at the end of the treatment. The above changes were reversible at the end of recovery period. The other indexes were not affected by the drug administration. Conclusion The main toxic target organs of SMMU-16 are immune system (thymus and spleen) and hematological system (erythrocyte series), and all the toxic effects are reversible. The NOAEL of SMMU-16 with continuous subcutaneous injection (4 weeks, once a week) is 10 mg/kg. The toxicities of SMMU-16 are comparable to those of HUMIRA at the same dose.