抗体偶联药物S037的免疫毒性研究
首发时间:2018-06-01
摘要:目的 抗体偶联药物S037重复静脉输注给予食蟹猴,观察免疫毒性相关指标的变化,为安全性评价提供科学依据。 方法 采用3~5 岁食蟹猴40 只,随机分成4 组,每组10 只,雌雄各半。溶媒组给予0.9% 氯化钠注射液,低、中、高剂量组,剂量分别为0.6 mg/kg、2 mg/kg、10 mg/kg。静脉输注给予8 个周期(每3 周给药1 次为1个给药周期),停药恢复6 周。检测免疫毒性评价指标,包括血液学、血清生化、免疫器官大体解剖、脏器重量、组织学检查和骨髓涂片,免疫球蛋白(IgG、IgA、IgM)、补体(C3 和C4)、循环免疫复合物(CIC)和淋巴细胞分群。 结果 食蟹猴静脉输注8个周期S037, 10 mg/kg 组动物可见外周血单核细胞 计数及百分比(#MONO及%MONO)、IgG 升高,胸腺淋巴细胞减少、脾脏红髓组织细胞有丝分裂象增多、坏死、胸骨骨髓造血细胞减少,以及可见骨髓细胞计数粒系升高、淋巴细胞降低趋势。 结论 在本试验条件下,食蟹猴静脉输注8 个周期S037 10 mg/kg 组可见一定的免疫抑制作用。
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Immunotoxicity Study of Antibody-drug Conjugate S037
Abstract:Objective Observe the changes of general immune toxicity related parameters after S037 repeated intravenous infusion, providing scientific basis for safety evaluation. Methods 40 Cynomolgus monkeys of 3~5 years old, were divided into 4 groups randomly, each group with 5 males and 5 females. The vehicle control group was given 0.9% sodium chloride injection. The dosage of low, middle and high dose groups, were 0.6 mg /kg, 2 mg/kg and 10 mg/kg respectively. Intravenous infusion was given for 8 cycles (once per 3 weeks) and recover day with 6 weeks. Evaluate the immune toxicity, including hematology, serum biochemical and immune organs of gross anatomy, organ weights, histopathology and bone marrow smear, and immune globin (IgG, IgA, IgM), complement (C3 and C4), circulating immune complex (CIC) and the lymphocytes group. Results Cynomolgus monkey intravenous 8 cycles S037 10 mg/kg group, the increase of #MONO, %MONO and IgG, thymus lymphocytes and spleen of red pulp tissue cells mitosis as increased, necrosis of bone marrow hematopoietic cells decreased, bone marrow cell count increased, and lymphocytes depleted. Conclusion Under the conditions of this study, certain immune suppressive was observed in the S037 10 mg/kg group of the Cynomolgus monkey by intravenous infusion.
Keywords: Antibody-drug Conjugate immunotoxicity immune suppression Cynomolgus monkey
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