FcRn对新型抗西尼罗河病毒单抗MIL94体内药代动力学的影响  

Effect of FcRn on in vivo pharmacokinetics of a novel monoclonal antibody against West Nile virus MIL94

作　　者：相亚楠 王灵超 高尤 张文鹏 庄笑梅 XIANG Ya-nan;WANG Ling-chao;GAO You;ZHANG Wen-peng;ZHUANG Xiao-mei(School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China;Academy of Military Sciences, Academy of Military Medical Sciences, Institute of Pharmacology and Toxicology, Beijing 100850, China)

机构地区：[1]天津大学化工学院,天津300072 [2]军事科学院军事医学研究院毒物药物研究所,北京100850

出　　处：《中国药理学通报》2021年第7期940-945,共6页Chinese Pharmacological Bulletin

基　　金：国家科技重大专项(No 2018ZX09711003-006)。

摘　　要：目的MIL94是我所研发的一种抗西尼罗河病毒单克隆抗体,对西尼罗河病毒具有中和作用,其体内维持时间与抗病毒作用密切相关。该研究考察不同种属新生儿Fc受体(FcRn)对MIL94体内药动特征的影响。方法比较研究MIL94在表达不同种属FcRn的小鼠(野生型小鼠、表达人源化FcRn小鼠和FcRn基因敲除小鼠)体内药代动力学特征。野生型小鼠和FcRn基因敲除(FcRn-/-)小鼠分别静脉注射MIL94;表达人源化FcRn小鼠(hFcRn小鼠)分为4组,其中两组分别静脉注射MIL94;另外两组先腹腔注射静脉注射用人免疫球蛋白(intravenous immunoglobulin,IVIG),再静脉注射MIL94。应用间接ELISA法测定小鼠血清MIL94浓度,WinNonlin计算药代动力学参数。结果静脉注射MIL94后,体内的药代动力学基本成线性过程。MIL94在动物体内分布容积与FcRn有关。体内半衰期在不同组别之间有较大差异。结论FcRn通过影响MIL94的分布和消除改变其在不同种属体内的半衰期,预期在人体内的半衰期比动物体内长。Aim To investigate the effects of different species Fc receptors(FcRn)on pharmacokinetic characteristics of MIL94,a monoclonal antibody against West Nile virus developed by Academy of Military Sciences,which has a neutralizing effect on West Nile virus and whose maintenance time in vivo is closely related to its antiviral effect.Methods The pharmacokinetic characteristics of MIL94 in mice expressing FcRn of different species(wild-type mice,hFcRn mice and FcRn knockout mice)were compared.Wild-type mice and FcRn knockout mice were injected intravenously with MIL94 respectively.HFcRn mice were randomly divided into four groups.Two groups were injected intravenously with MIL94,and the other two groups were injected intravenously with intravenous immunoglobulin(IVIG)and then intravenously with MIL94.Indirect ELISA was used to determine the MIL94 concentration in mouse serum.WinNonlin software was used to calculate the pharmacokinetic parameters.Results After intravenous injection with MIL94,the in vivo pharmacokinetics were basically linear.The distribution volume of MIL94 in animals was related to FcRn.The half-life in vivo varied greatly between different groups.Conclusions FcRn can affect the half-life of MIL94 in different species mainly via alternation of its elimination and distribution.It is expected that the half-life of FcRn in human will be longer than that in preclinical animals.

关 键 词：西尼罗河病毒 MIL94 新生儿Fc受体(FcRn) IVIG 药代动力学 间接酶联免疫吸附法 

分 类 号：R373[医药卫生—病原生物学] R392.11[医药卫生—基础医学]