生物类似药的免疫原性研究与评价技术思考-王海学

8147329181402651“”2014ZX09J1410612GWZX0501*[e-mail]122211.1000382.200433、。。《》《》、、、/。、、、、、。。doi10.11669/cpj.2015.06.004Ｒ915A1001－2494201506－0483－07TechnicalConsiderationsontheStudyandEvaluationoftheBiosimilars'ImmunogenicityWANGHai-xue1LUGuo-cai2ZHANGZi-teng2YUANBo-jun2WANGQing-li11．CenterforDrugEvaluationChinaFoodandDrugAdministrationBeijing100038China2．CenterforEvaluationofDrugSafetySecondMilitaryMedicalUniver-sityShanghai200433ChinaABSTＲACTOBJECTIVEToevaluatetheimmunogenicityofbiosimilars．METHODSNon-clinicalandclinicalstudiescarriedoutinaccordancewiththeguidelinesinimmunologicalcharacteristicsandimmunogenicityofbiosimilarsshouldfocusontheproductionofanti-drugantibodiesanddetectionofdrug-resistantpropertiesimmunecomplexesandtheirpotentialeffectsonpharmacodynamics/pharmacokinetics．AssaysforimmunogenicityofbiologicalagentsmainlyincludeenzymelinkedimmunosorbentassayELISAradio-immunoassaysurfaceplasmonresonancemethodenzymelinkedimmunospotassayimmuno-PCＲmethodcellproliferationassayetc．ＲESULTSANDCONCLUSIONBiosimilarsimmunogenicityshouldbecomprehensivelyinterpretedbasedonboththepreclini-cal/clinicalevaluationresultsandtheprevalenceofclinicaladverseevents．KEYWOＲDSbiosimilarimmunogenicityanti-drugantibodypreclinicalstudyclinicalstudy、。《》。、1。。。1。ADA、PD/PK/2。ADA①ADA②ADA③ADA④3。、·384·20153506ChinPharmJ2015MarchVol.50No.6、、、、//、、、、。、4。2、。2.1EMA22007CHMP。、。。①②③④⑤⑥。、。、、。、。、、、。。。。。。。①②③。。。2.2FDA22002FDA“IND”。。。PKPD/。。。FDA。FDAICH。2.3ICH21997ICH。、、、、、、、、。。、、。/PK/PD、、、。。。。。。。。·484·ChinPharmJ2015MarchVol.50No.620153506。313.1。。Fab、Fc、FcＲn、Fcγ、c1q、CDC、ADCC。。、。。3.2。、、。。。、。。3.3。。PK、PD、。。。、、、/。。、、、。。。44.1、、、、、、、、。Mw10000Mw5000～10000。。MwMw100000。。。。4。4.1.1、、。。。、、、、、、、、、。。、、5。peginesatideFDA。1920000。285。1.4。3。4.1.2、、。。·584·20153506ChinPharmJ2015MarchVol.50No.65。4.1.3、。。。、5。4.24.2.1ADA、。IgGIgE。IgEIgEIgE。4。。。4。。、。3H。DNAbDNA。4。。4。ADA。mAb。、、、、。。mAbmAb。。FcFc。。4。ADA4、、。ELISA-。4。ELISA-。4。ELISA-。、。。EPOrhEPOFabIgG4。ＲIA4。ECL。2TAG4。surfaceplasmonresonance·684·ChinPharmJ2015MarchVol.50No.620153506。4。ELISpotELISAELISA5。ELISA。PCＲIPCＲELISAPCＲELISA。PCＲDNAＲNADNAPCＲIPCＲELISA。ELISAIPCＲ10005。IPCＲ。PCＲPCＲPCＲPCＲ。IPCＲIPCＲ。、6-7。4.2.2。CD+TAPCTTexvivoT。TELISPOTT。TMHC。APCT、MHCT4。4.2.3AmgenTNFEnbrel5%、、ADA83%～100%。IFNα。。2。MHCMHC4。。MHCT4。4.2.4、、。tissuecross-reactivityTCＲ/。TCＲ①。。。②。TCＲ/。Fc。③。TCＲ。。④。。⑤。。⑥TCＲ、。。5、、、1。5.15.1.1、/。·784·20153506ChinPharmJ2015MarchVol.50No.6。8。。、/8。、、/8。、、、。8。5.1.2MDGFMDGF4。EPOαPＲCA。EPOHSA80。EPOPＲCA3。、、。/。。。、。ADA。ADA。ADA9。5.2。。10。ADAADA。、、。。、、ADA9。ADA。ADA、、。ADAPK/PD10。FDA。。。。3。62020200。7。。。ADA。·884·ChinPharmJ2015MarchVol.50No.620153506。。ELISA、ＲIA、SPＲ、ELISpot、PCＲIPCＲ、11。。。11。。。。。ADA、PK/PD11。ＲEFEＲENCES1CFDA．GuidelineonDevelopmentandEvaluationofBiosimilars2015S．2015．2CHOWS．BiosimilarsDesignandAnalysisofFollow-onBiologicsM．BocaＲatonCＲCPress201453-75．3BENNETTCLCHENBHEＲMANSONTetal．ＲegulatoryandclinicalconsiderationsforbiosimilaroncologydrugsJ．Lan-cetOncol201415e594-605．4LUQJ．Currentstatusandchallengeofbiopharmaceuticalimmu-nogenicityJ．ChinJNewDrugs2007163181-188．5XUEXX．ＲesearchProgressontheimmunogenicityoftherapeu-ticbiomacromoleculesJ．QiluPharmAff2012313174-176．6NENCINIFPＲATESISPETＲONIGetal．Assaysandstrate-giesforimmunogenicityassessmentofbiologicalagentsJ．DrugDevＲes201475S4-S6．7CAIXYTHOMASJCULLENCetal．Challengesofdevelo-pingandvalidatingimmunogenicityassaystosupportcomparabili-tystudiesforbiosimilardrugdevelopmentJ．Bioanalysis20124172169-2177．8CHAMBEＲLAINP．Assessingimmunogenicityofbiosimilarther-apeuticmonoclonalantibodiesregulatoryandbioanalyticalcon-siderationsJ．Bioanalysis201355561-574．9CHOYEJACOBSIA．BiosimilarSafetyConsiderationsinClini-calPracticeJ．SeminOncol201441S3-S14．10EBBEＲSHCCＲOWSAVULTOAGetal．Interchangeabili-tyimmunogenicityandbiosimilarsJ．NatBiotec201230121186-1190．11PＲUGNAUDJLTＲOUVINJH．Biosimilars-ANewGenerationofBiologicsM．PairsSpringer-VerlagFrance201337-46．2015-01-28·984·20153506ChinPharmJ2015MarchVol.50No.6