重组单克隆抗体相关物质和相关杂质的研究与评价

ChineseJournalofNewDrugs20142389062014238。[e-mail]。··100038。、、。。、。。Ｒ95C1003－3734201408－0906－06CommentsonthedevelopmentandassessmentofthedrugimpuritiesandsubstancesrelatedtorecombinantmonoclonalantibodiesWEIWeiLUOJian-huiYINHong-zhangXIANGJin-zhongCenterforDrugEvaluationChinaFoodandDrugAdministrationBeijing100038ChinaAbstractＲecombinantmonoclonalantibodieshavebeenestablishedasamajorproductclassofbiotech-nology-derivedmedicinalproductsandwidelyappliedintheclinicalfieldsofoncologyautoimmunediseaseaswellasneurologyophthalmologyandsoonduetotheirpreciselytargetedbiologicalactivatesofcytotoxicandneutrali-zingeffectinrecentyears．NowadayspharmaceuticalenterprisesofChinausuallypaymoreattentiontowardsthestructureandqualitycontrolofthemainsubstanceproducedfromeukaryoticcellsratherthantherelatedimpuritiesandsubstances．Howevertheseimpuritiesandsubstancesarepartsoftheproductcomponentsandmayimpactonproductquality、clinicalsafetyandeffectiveness．Thereforetheyshouldberecognizedasequallyimportantasthemainsubstanceandbeinvestigated．Thisarticlewillpresentcommentsontheresearchandevaluationoftherelatedimpuritiesandsubstancesinrecombinantmonoclonalantibodyproducts．Keywordsrecombinantmonoclonalantibodyproduct-relatedsubstancesproduct-relatedimpuritiesprocess-relatedimpurities、、、、heterogeneityvariants、、。、、。、product-relatedsubstancesproduct-relatedimpurities。、ChineseJournalofNewDrugs20142389072014238/process-relatedimpurities。3。1、、、、。1081。、、、、。1．1、、、、、、C、、、、、。Bcar-boxypeptidase-BC1～2C。AsnGlnpH2。、、。、、3－7。FcCH2AsnFabVHN-8。、、FcFcγＲC1q、ADCCCDC9－1112－13、、14。glycationN-NH2。、15－17。、、、、、、、pH、、。CDＲ1819。1．2、、FabFc。、。、。。3。。、、、。C、20。Lee211。1、22－23。CHOIgG1pI8．7～8．9、pI9．1pI9．020。1。124。、。FabFcChineseJournalofNewDrugs20142389082014238。CDＲisoAsp1022。Asn436、FcFcFcＲn25－26。FcＲn27－28。FcＲn3～4PK29。FcＲnFc30。FcＲnFcFcγＲ26。FcFcγＲC1q。ADCCCDC。C1qCDC31。A。FcA32。。α13-N-N-glycolylneuraminicacid33。。2process-relatedimpurities、、、34。。2．1AA。A。AELISA。USP4ANaturalProteinA46800Ｒe-combinantProteinA44600Cys-rpA34300MahselecSuＲe@26700A。2．2。。CHOSp2/0NS0。ELISA。2．3DNADNA。。DNA、、。PCＲDNAELISA35。10A、DNA0．01%0．01%10pg/。。33．1、、、1。、34。ChineseJournalofNewDrugs20142389092014238、PD/PK。。、、34。。、。CNcasebycase。ICHQ3B。、。IECCIEFSEC、SDS-PAGE-CE-SDS-NGSCEMAILDI-TOF36IEC、ＲP-HPLC。。3．2。、。、、。、、。。2re-leasespecificationendofshelflifespecification。。、、。。35。3．3、、“”。。。、ChineseJournalofNewDrugs20142389102014238、。。4、、。、、、。。。1KOZLOWSKISSWANNP．CurrentandfutureissuesinthemanufacturinganddevelopmentofmonoclonalantibodiesJ．AdvDrugDelivＲev2006585－6S707－S722．2HAＲＲISＲJKABAKOFFBMACCHIAFDetal．Identifica-tionofmultiplesourcesofchargeheterogeneityinarecombinantantibodyJ．ChenJChromatographyB20017522S233－S245．3LIPSCOMBMLPALOMAＲESLAHEＲNANDEZVetal．EffectofproductionmethodandgeneamplificationonthegIyco-sy1ationpatternofasecretedreporterproteininCHOcellsJ．BiotechnolProg2005211S40－S49．4TＲUMMEＲEKATHAＲINAFSILKESetal．Processparam-etershiftingPartII．Biphasiccultivation-AtoolforenhancingthevolumetricproductivityofbatchprocessesusingEpo-Fcexpress-ingCHOcellsJ．BiotechnolBioeng2006946S1045－S1052．5ELBEINAD．InhibitorsofthebiosynthesisandprocessingofN-linkedoligosaccharidechainsJ．AnnＲevBiochem198756S497－S534．6CＲOWELLCKGＲAMPPGEＲOGEＲSGNetal．AminoacidandmanganesesupplementationmodulatestheglycosylationstateoferythropoietininaCHOculturesystemJ．BiotechnolBioeng2007963S538－S549．7GENNAＲOLSALAS-SOLANOO．On-lineCE-LIF-MSTech-nologyfoethedirectcharacterizationofN-linkedglycansfromtherapeuticantibodiesJ．AnalChem20088010S3838－S3845．8QIANJLIUTYANGLetal．StructuralcharacterizationofN-linkedoligosaccharidesonmonoclonalantibodycetuximabbythecombinationoforthogonalmatrix-assistedlaserdesorption/i-onizationhybridquadrupole-quadrupoletime-of-flighttandemmassspectrometryandsequentialenzymaticdigestionJ．AnalBiochem20073641S8－S18．9JEFFEＲISＲ．GlycosylationofrecombinantantibodytherapeuticsJ．BiotechnolProg2005211S11－S16．10JEFFEＲISＲ．Antibodytherapeuticsisotypeandglycoformselec-tionJ．ExpOpinBiolTher200779S1401－S1413．11AＲNOLDJNWOＲMALDMＲSMIＲBetal．TheimpactofglycosylationonthebiologicalfunctionandstructureofhumanimmunoglobulinsJ．AnnＲevImmunol20072521－50．12WＲIGHTAMOＲＲISONSL．EffectofglycosylationonantibodyfunctionimplicationsforgeneticengineeringJ．TrendsBio-technol1997151S26－S32．13FUJOMUＲAYTACHIBANAHETONetal．Antigenbindingofanovomucoid-specificantibodyisaffectedbyacarbohydratechainlocatedonthelightchainvariableregionJ．BiosciBio-technolBiochem20006411S2298－S2305．14JEFFEＲISＲ．Chapter4AntibodyGlycosylationM．WeinheimWILEY-VCHVerlagGmbH＆Co．KGaA200979－108．15QUANCPWUSDASOVICHNetal．Canova-DavisSuscep-tibilityofrhDNAaseItoglycationinthedry-powderstateJ．A-nalChem19997120S4445－S4454．16GADGILHSBONDAＲENKOPVPIPESGetal．TheLC/MSanalysisofglycationofIgGmoleculesinsucrosecontainingformu-lationsJ．JPharmaceuticalSci200796102607－2621．17FISHEＲSHOEＲNSCHEMEYEＲJMAHLEＲHC．Glycationduringstorageandadministrationofmonoclonalantibodyformula-tionsJ．EurPharmBiopharm2008701S42－S50．18LEECC．PEＲCHIACCAJM．Towardaggregation-resistantanti-bodiesbydesignJ．TrendsBiotechnol20133111S612－S620．1