抗体药物偶联物即ADC类药物的生物分析.pdf

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1、Bioanalysisofantibody–drugconjugates总结与评论专员章登吉BioanalyticalchallengesfromADCmulticomponentstructure(Mixtures)inherentlyheterogeneousdynamicnatureTherefore,multipleanalytesareutilizedtodeterminePKandfateofADCsinvivoAnalytescommonlyassessedforADC*DAR:DrugtoAntibodyRatioLinke

2、randlinker-smallmoleculeshouldalsobeconsideredbasedonyourcase.assessedforADCPK/TKAssaystrategiesPlatformscommonlyusedforADC:Ligandbindingassay:ELISAorothermethodsLC-MS/MSAssayformat:IntactADC:Targethumantumorantigenoranti-drugAbascapturingreagentsTotalmAb:Targethumantumora

3、ntigenascapturingreagentsusuallyPK/TKAssayvalidationforADCGeneralBioanalyticalguidelinesforbioanalysiscanbeusedforADCPK/TKAssays:生物样品定量分析方法验证指导原则(2015版药典）GuidanceforIndustry:BioanalyticalMethodValidation(FDA,2013)Guidelineonbioanalyticalmethodvalidation(EMA,2011)Validatio

4、nparametersStandardcurveLLOQ/ULOQAccuracyandPrecisionSelectivitySpecificityDilutionlinearityParallelismStabilityAlthoughtherearenospecificguidelinesforvalidatingLBA-orLC-MS/MS-basedPK/TKassaysforADC,thereisstrongscientificrationaletousethegeneralguidelinestherapeuticp

5、roteinandsmallmoleculeassayvalidationasmuchaspossible.Example:TKassays(EIAmethods)foroneADCperfo180000系列1160000140000系列2120000系列3100000系列480000系列56000040000系列620000系列70系列815min24h72h168h336h504hSTD1:totalantibodyTotalantibodyfromonedosegroupinTKstudySTD2:intactADCGoodcorrelati

6、onfromthetwoassaycurves160000.0160000系列1140000140000.0系列2120000120000.0系列3100000100000.080000系列480000.0intactADC60000系列5totalmAb40000系列660000.020000系列740000.00系列820000.015min24h72h168h336h504h0.0IntactADCfromonedosegroupinTKstudy15min24h72h168h336h504hGoodcorrelationbetweenint

7、actADCwithtotalmAb,whichalsoshowedthatgoodperformanceofourassaysReasonsforADAtestingThedevelopmentofanti-drugantibodies(ADA)toproteintherapeuticscanresultin:Rapidclearance,alteringthepharmacokinetic(PK)and/orpharmacodynamicprofileofthedruglossofefficacyduetoneutralizationof

8、druggeneralizedimmuneeffects,suchasanaphylaxis,serumsickness