聚乙二醇化重组人改构白介素11对骨髓抑制的小鼠促血小板生成作用的评价  

Thrombocytopoietic Efficacy of Pegylated Recombinant Human Interleukin-11 Mutein in Myelosuppressed Mice

作　　者：马杉姗[1,2] 胡成炫 王洪领 聂李亚[2] 许松山[2] 

机构地区：[1]天津大学化工学院制药工程系,天津300072 [2]北京诺思兰德生物技术股份有限公司,北京100085 [3]韩国ViroMed株式会社,首尔151-818 [4]生物制品安全性评价北京市重点实验室,北京昭衍新药研究中心股份有限公司,北京100176

出　　处：《中国实验血液学杂志》2016年第5期1511-1517,共7页Journal of Experimental Hematology

摘　　要：目的:观察聚乙二醇化重组人改构白介素11(PEGylated IL-11 mutein,PEG-m IL 11)不同给药次数和给药剂量对骨髓抑制的小鼠血小板减少症的治疗作用,并与m IL-11进行比较,为临床应用提供参考。方法:BALB/c小鼠经2.5 Gy全身^(60)Coγ射线照射后,腹腔注射50 mg/kg卡铂制备血小板减少症模型。在给药次数研究中,将30只造模成功的BALB/c小鼠随机分为5组:溶剂对照组:d 1,4,7每日1次,共3次;m IL-11组:m IL-11 200μg/(kg·d)×9 d;PEG-m IL 11 A组:PEG-m IL 11 1800μg/(kg·d)×1 d(d 1);PEG-m IL 11 B组:900μg/(kg·d)×2 d(d 1,5)和PEG-m IL 11 C组:600μg/(kg·d)×3 d(d 1,4,7),各组小鼠均为皮下注射给药。监测5周内血小板的变化情况;在给药剂量研究中将100只造模成功的BALB/c小鼠随机分为5组:溶剂对照组:d 1,5每日1次,共2次;m IL-11组:m IL-11 200μg/(kg·d)×9 d、PEG-m IL 11低、中、高剂量组(200、420、900μg/(kg·d)×2 d,d 1,5),对各组小鼠均皮下注射给药,在5周内每隔2-3 d检测外周血细胞,并于给药后d 8选取部分动物安乐死后进行骨髓细胞培养。结果:与造模前相比,溶剂对照组Plt在最低点时降低幅度达到80%以上。给药次数研究中,PEG-m IL 11各给药组在最低点时的Plt值均明显高于溶剂对照组和m IL-11组(P<0.05),但不同给药次数的3组间差异不显著;在给药剂量研究中,PEG-m IL 11各治疗组在Plt最低点的降低幅度明显低于溶剂对照组和m IL-11治疗组(P<0.05),在最低点后Plt的恢复速度明显快于溶剂对照组,在d 10呈剂量依赖性的升高(r=0.92);PEG-m IL 11各治疗组的RBC在最低点的降低幅度明显减小并且恢复明显加快;各组WBC的变化趋势基本一致。CFU-M eg测定结果显示,PEG-m IL 11和m IL-11组同溶剂对照比相比CFU-M eg有增多的趋势,且PEG-m IL 11治疗组动物的集落数更高。结论:PEG-m IL 11对骨髓抑制小鼠血小板减少症有明显的治疗作用,而且同m IL-11相比,可以减少给药次数,提高治疗的Objective：To evaluate the effect of PEGylated IL-11 mutein（PEG-mIL 11） with different dose or injection frequency on thrombocytopenia in myelosuppressed mice and to compare its effect with mIL-11,so as to provide reference data for clinical use.Methods：Myelosuppressive model with thrombocyopenia was produced in BALB/c mice by whole body 60Co γ-ray irradiation in dose of administration 2.5 Gy followed by i.p.injections of carboplatin at 50 mg/kg.In study of injection frequency,30 thrombocytopenic BALB/c mice were randomly divided into 5 groups：vehicle control group（once daily on d1,4,7）,mIL-11 group[200 μg/（kg · d）×9 d],PEG-mIL 11 A group[11 1800 μg/（kg · d）× 1 d（d 1）],PEG-mIL 11 B group 900 μg/（kg · d） ×2 d（d 1,5）,and PEG-mIL11 C group[600 μg/（kg · d）×3 d（d 1,4,7）].The route of administration is subcutaneous injection.The platelet counts were monitored in the subsequant 5 weeks.In study of dose administration,100 thrombocytopenic BALB/c mice were randomly divided into 5 groups：vehicle control group（once daily on dl and 5）,mIL-11 group 200 μg/（kg · d）×9 d,and PEG-mIL 11 low-,mid-,and high-dose groups（200,420 and 900 μg /（kg · d）×2 d,once a day on d1 and 5）.The route of administration is subcutaneous injection.The platelet counts were monitored every 2-3 days in the subsequant 5 weeks,and CFU-Meg was determined on d 8 of the bone marrow cells collection.Results：After 60Co irradition and carboplatin injection,Plt level decreased with time,and a 〉 80%reduction was noted at nadir when comparing with baseline.In frequency of administration study,the platelet nadir of the 3 PEG-mIL 11 groups were significantly higher than that of vehicle control and mIL-11 groups（P〈0.05）,while no significant difference was noted among the 3 groups of different administration frequences;In dose level study,the reduction of Plt count at the nadir in the 3 PEG-mIL 11 groups was significantly less than that of vehicle control and mIL-11 groups（P〈0.0

关 键 词：聚乙二醇化 重组人白介素11 骨髓抑制 血小板 小鼠 

分 类 号：R973[医药卫生—药品] R558.2[医药卫生—药学]