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1、药学学报ActaPharmaceuticaSinica2016,51(4):517−528·517·抗体偶联药物研发中的生物分析*李秀立,陈笑艳,钟大放(中国科学院上海药物研究所,上海药物代谢研究中心,上海201203)摘要:抗体偶联药物(antibody-drugconjugates,ADCs)是一类单克隆抗体通过一段连接臂共价偶联细胞毒性小分子化合物而成的复合物,可以提高抗肿瘤药物的靶向性并减少毒副作用。ADCs结构具有异质性并且其药物−抗体比值(drug-to-antibodyratio,DAR)在体内呈动态变化,其生物分析面临着巨大的挑战,常用的定量分析包括酶联免疫
2、吸附反应(ELISA)和液相色谱−质谱分析(LC-MS)。ADCs同其他生物制品一样,在体内可能会产生抗药抗体(anti-therapeuticantibody,ATA),影响其药效、药动学及安全性,因此有必要评价其免疫原性。本文综述了在ADC研发过程中常见的基于ELISA和LC-MS方法的待测物分析,包括DAR分布、总抗体、结合型抗体、结合型药物、游离药物以及ATA分析,可为我国的ADCs研发提供参考。关键词:抗体偶联药物;药物−抗体比值;免疫原性;酶联免疫吸附反应;液相色谱−串联质谱中图分类号:R917文献标识码:A文章编号:0513-4870(2016)04-0517
3、-12Bioanalysisinthedevelopmentofantibody-drugconjugates*LIXiu-li,CHENXiao-yan,ZHONGDa-fang(ShanghaiCenterforDrugMetabolismandPharmacokineticsResearch,ShanghaiInstituteofMateriaMedica,ChineseAcademyofSciences,Shanghai201203,China)Abstract:Antibody-drugconjugates(ADCs)arecomplexmoleculeswith
4、cytotoxicsmallmoleculardrugscovalentlyboundtomonoclonalantibodiesviaalinkerandcanimprovethetargeteddrugdeliverywithminimizingthesystemictoxicity.ADCsareheterogeneousmixtureswithdifferentdrug-to-antibodyratios(DARs)andtheDARdistributionisdynamicallychanginginvivo,thereforethebioanalysisofth
5、eADCsischallenging.Enzyme-linkedimmunosorbentassay(ELISA)andLC-MShavebeenwidelyusedintheADCsbioanalyticalassays.Justlikeotherbiotherapeutics,ADCsmayelicitthehostimmuneresponseandproducetheanti-therapeuticantibody(ATA),whichcouldaffectitsefficacy,pharmacokinetics,andsafety.Itistherebyimport
6、anttoinvestigateitsimmunogenicityintheADCdevelopment.Inthisreview,wesummarizedtheELISA-andLC-MS-basedbioanalysisstrategiesforthedevelopmentofADCs,includingDARdistribution,thedeterminationoftotalantibody,conjugatedantibody,conjugateddrug,freedrug,andATA,withtheexpectationofprovidinginsights
7、andreferencefortheADCdevelopmentinChina.Keywords:antibody-drugconjugate;drug-to-antibodyratio;immunogenicity;enzyme-linkedimmunosorbentassay;LC-MS抗体偶联药物(antibody-drugconjugates,ADCs)联细胞毒性小分子化合物而成的复合物,用于治疗是一类单克隆抗体通过一段连接臂(linker)共价偶恶性肿瘤。单克隆抗体可以靶向结合肿瘤细胞表面的抗原,通过细胞
