以TNF_为靶点的大分子拮抗药物及其质控方法研究进展_王光裕

TNF-αTNF-αTNF-αProgessinresearchonTherapeuticMonoclonalAntidedbodyagainstTNF-αanditsqualitycontrolmethodWANGGuang-yuGAOKaiWANGJun-zhi*(NationalInstitutesforFoodandDrugControl,Beijing100050,China)Abstract:RheumatoidarthritisCrohn’sdiseaseandAnkylosingspondylitisareautoimmunediseasesthatendangerthelivesofthepeopleoftheworld'shundredsofmillionsofpeople,amajorcauseofthesediseasesisoverexpressionofTNF-α.ThisreviewmainlydiscussedthebasicstructureandpharmacologicmechanismstoautoimmunediseasesofseveralbiotherapeuticsagainstTNF-αinmarket.Also,weintroductedthequalitycontrolofprojectsandtechniquesofthesedrugbriefly.Keywords:tumornecrosisfactor;antibody;fusionprotein;structureanalysis;glycosylation1TNF-αTIL-lIL-6IL-8TNF-α[1]TNF-αTNFTNF-αTNFIIp75IgGFcEtanerceptEnbrelTNF-αInfliximabRemicadeAdalimumab(Humira)golimumabSimponiFabPEGcertolizumabpegolCimzia5115TNF[2]Fig1Structureof5TNF-αantagonists15Tab1Basicinformationof5TNF-αantagonistsEtanercept1998RAPsAASJIAPs[3]AmgenpfizerInfliximab1998RAPsAASPsOCDUC[4]Centocor,Schering-Plough,Adalimumab2002RAPsAASCDUCJIAPs[5]Abbott,Eisaigolimumab2009RAPsAAS[6]Centocor,certolizumabpegol2008RACD[7]UCBRARheumatoidarthritisPsAPsoriaticarthritisASAnkylosingspondylitisPsOPsoriasisCDCrohn’sdiseaseUCUlcerativecolitisJIAJuvenileidiopathicarthritisPsPlaquepsoriasis2TNFTNF-αTNF-βFasLCD40L19[8]27CD120TCD40BsystemiclupuserythematosusSLETNFRSF13NGF[9]2.1TNF-αTNF-α-TNK2TNFTNF-αmembraneTNF-αmTNF-α2353523177[10]mTNF-αTumornecrosisfactor-aconvertingEnzymeTACEN7755kDTNF-αTNF-αsoluableTNF-αsTNF-αmTNF-αHIVTNKB[2]mTNF-α[11]DibbsZImTNF-α[12]mTNF-αTNFRmTNF-αmTNF-αT/[131415]activationinducedcelldeathAICDmTNF-αsTNF-αmTNF-αmTNF-αsTNF-αmTNF-αsTNF-α[16]mTNF-αsTNFsTNF-αTNFRTNFR[17]RATNF-αIL-1IL-1TNF-αTNF-αRA[18]2mTNFsTNF[2]Fig2TransformationofmTNFtosTNF2.2TNFIITNF-αTNFTNF-αICD120aIICD120bTNFTNF-α[19]4Icaspase3/6/7IIIJNKNFkBTNFsTNF-αTNFFcantibody-dependentcell-mediatedcytotoxicityADCC)complement-dependentcytotoxicityCDC)mTNF-α3TNF-αTNFR[19]4TNFTNFR[9]Fig3BindingofTNF-αtoTNFRFig4SignaltransductionofTNFR3TNFEtanercept150kD75kDTNFII235IgG1Fc232[20,21]30%TNFRTNF1784cysteine-richdomainCRD112N-TNF-α[19]5719O-FcADCCFcFcIgG1CH2CH32CH2CH2CH3CH2N-[22,23]InfliximabAdalimumabgolimumabInfliximab30%144.2kD[24]Adalimumabgolimumab3complementarydeterminantregionCDR144.2kD[25]146.9kD[26]5Etanercept[3]6[28]Fig5StructureofEtanerceptFig6StructureofantibodyandFabcertolizumabpegolFabPEGFc47.8kDPEG[27]4InfliximabADCCCDCmTNF-α[29]RAPsAASPsOCDUCAdalimumabgolimumabInfliximabRAPsAASCDUCJIAPs7[30]8ADCCCDCFig7GlycosylationsitesofantibodyFig8ADCCandCDCeffectofantibodyEtanerceptTNFTNF-αTNFREtanerceptFcADCCmTNF-αC3(CH1)[31]EtanerceptmembraneattackcomplexMACCDCEtanerceptCDEtanercept[32]EtanerceptRAPsAASJIAPsCertolizumabpegolFabADCCCDCTCDCertolizumabpegolCDTCDInfliximabCDCertolizumabpegol[33]CertolizumabpegoRACD5EtanerceptInfliximabAdalimumabMitomaInfliximabAdalimumabEtanerceptmTNF-αCDCADCCADCCCDCmTNF-αEtanerceptCDCmTNF-αsTNF-αRAsTNF-αRAEtanerceptCDCCDmTNF-αCD[34]TarunaADCCFcTNFTNF-αFcTNF-αC1qCDCEtanercept[35]ZehramTNF-αsTNF-αmTNF-αsTNF-αCDCmTNF-αsTNF-αCDC[36]5ICHQ5[37]5.1NC[38]5.1.15.1.1.1NONONNXS/TXO/ONO9N-O-Fig9ThestructureofN-andO-glycanlinkedtoprotein5.1.1.2NPNGaseF[39]EndoH[40]OGalNAcGalGlc10PNGaseFEndoH[3940]11O-[41]Fig10EnzymesiteofPNGaseFandEndoHFig11EnzymesiteofO-glycosidaseOLC-ESI-MS[42]5.1.25.1.2.1NOalditolsYunpingHuangN[43]5.1.2.22-aminobenzamide(2-AB)2-anthranilicacid(2-AA)2-aminopyridine(2-AP)[44][45]-HPACE-PADpH12PAD80MaukoL2-AB[46]12[42]13[43]Fig12MechanismofβeliminationFig13βeliminationinnon-reducingconditionInfliximabAdalimumabFcNOEtanerceptNTNFRFcKyogokuNeuraminidaseFO-glycosidaseEtanerceptO3NTNFR10O[47]5.2TNF-αADCCCDC5.2.1affinityavidity5.2.1.1FabBiacoreSPRSPRSPRELISATNFHRPIgGFcTNF5.2.1.2KinExA5.2.1.3BiacoreKinExAProteOnOctetProteOnBiacoreOctetAbdicheYNNGFBiacoreNGF[48]KaymakcalanBiacoreKinExAmTNF-αInfliximabAdalimumabEtanerceptEtanerceptInfliximabAdalimumab[36]14Biacore15KinExA[49]Fig14MechanismofBiacoreFig15MechanismofKinExA5.2.2TNF-αEtanerceptTNF-α5.2.2.1TNF-αTNF-αL929U937WEHITNF-α5.2.2.2TNF-αKefferJTNF[50]TNFIL-16TNF-αIL-1IL-6TNF-αTNF-αTNF-αTNF-α[1],..ChineseJournalofBiologicals,2007,10(20):778-782.[2]HoriuchiTMHHS.TransmembraneTNF-alpha:structure,functionandinteractionwithanti-TNFagents.Rheumatology(Oxford),2010,7(49):1215-1228.[3][4][e-mail]n(FDA).[5][6][7][e-mail]n(FDA).=Search.Label_ApprovalHistory.Retrieved2009-11-15.[8]htt