促红细胞生成素的研究进展-廖飞龙

ChineseJournalofNewDrugs2016,25(1)642016251。[e-mail]。。[e-mail]。。[e-mail]。··1221212100092100143recombinanthumanerythropoietinrHuEPO20。10erythropoietinEPO。、、。、。Ｒ973A1003－3734201601－0064－07ＲesearchadvancesoferythropoietinLIAOFei-long12YANGZhong-fan2LIUYu1WUYan-zhuo21CollegeofLifeScienceandTechnologyChinaPharmaceuticalUniversityNanjing210009China2BeijingSLPharmaceuticalCo．Ltd．Beijing100143ChinaAbstractＲecombinanthumanerythropoietinrHuEPOhasbeenusedsuccessfullyforover20yearstotreatanemiainmillionsofpatients．Howeverfrequentdosingmayberequiredtoachieverequiredhemoglobinlev-elsduetotherelativelyshorthalf-lifeofthemoleculewhichresultsinpoorpatientcompliance．Inthepasttenyearsseveralnewerythropoietinshavebeenapprovedanderythropoietinsisstillthemaindrugforthetreatmentofrenalanemiainclinic．Currentlythemethodsfordesigninglong-actingerythropoietinsincludeincreasingglycosyla-tionsitespegylationfusionproteinsanderythropoietinmimeticproteins．Thedevelopmentoferythropoietinsandmethodsfordesigninglong-actingerythropoietinsarediscussedinthisreview．Keywordserythropoietinglycosylationpegylationfusionproteinserythropoietinmimeticproteins、。、。1．2。201533750%。、erythropoiesisstimulatingagentsESAs。erythropoietinEPO1。1989re-combinanthumanerythropoietinrHuEPOEpo-genFDA。rHuEPO、、2。rHuEPOrHuEPOrHuEPO。10EPOEPO1。EPO、EPO。ChineseJournalofNewDrugs2016,25(1)6520162511FDAEMAEPO1EPOEpogen/ProcritepoetinalfaCHO1989AmgenNeoＲecormonepoetinbetaCHO1997ＲocheEprexepoetinalfaCHO1999OrthoBiologicsDynepoepoetindeltahumanHT10802002HexalAGEporatio/BiopoinepoetinthetaCHO2009TevaGmbH2EPOAranesp/NESPdarbepoetinalfaCHO2001AmgenMircera/CEＲAmethoxypolyethyleneglycol-epoetinbetaCHO2007Ｒoche3EPOOmontyspeginesatide—2012AffymaxTakedaBinocritepoetinalfaCHO2007SandozGmbHAbseamedepoetinalfaCHO2007MediceEpoetinAlfaHexalepoetinalfaCHO2007HexalAGＲetacrit/SilapoepoetinzetaCHO2007Hospira/Stada201571EPOEPO。19327EPO165330．4KDa。EPO40%。EPO4Asn24Asn38Asn83Ser1263N4O。EPO7161、29334α1。EPO1。1EPO2EPOerythropoietinreceptorEPOＲEPOＲ1。EPO22JAK2ChineseJournalofNewDrugs2016,25(1)662016251EPOＲ。3-PI3K/Akt、JAK2-5STAT5、MAPK、-κBNF-κB、GＲAS、C4。EPOEPOＲCD131EPOＲEPO5。Broxmeyer6Spi2A---EPO。Duan7EPOＲ-JAK2-STAT3、、。3EPO3．11EPO3．1．1epoetinalfaepoetinbetaepoetinalfaepoetinbetaChinesehamsterovaryCHO。epoetinalfaepoetinbeta8。epoetinalfaepoe-tinbeta。、9。1989EpogenepoetinalfaFDA。1997NeoＲecormonepoetinbetaEMA。3．1．2epoetindeltaepoetindeltagene-activatederythropoietin。DNA。EpoetinDelta1HumanHT1080rHuEPOEPO10。2002EMAepoetindelta。2009EMAepoetindelta。3．1．3epoetinomegaepoetinomegaBioclonesrHuEPOEPOcDNAbabyhamsterkidneyBHK。CHOrHuEPOepoetinomega60%126epoetinomega24N11。3．1．4epoetinthetaepoetinbetaepoetintheta。epoetinthetaCHO30．6kDa40%。epoetinthetaepoetinalfaepoetinbetaepoetindeltaepoetintheta。epoetinthetaepoetinbeta。212。2009epoetinthetaEMA。1EPO1～3。1EPO13。3．22EPO2001novelerythropoiesisstimulatingproteinNESPFDAEMAdar-bepoetinalfa。NESPEPO1EPO。epoetinalfaNESP2NNESPrHuEPO314－15。、、、、、。2007Ｒochecontinuouserythropoietinre-ceptoractivatorCEＲAEMACEＲArHuEPOepoetinbeta。130hCEＲA21ChineseJournalofNewDrugs2016,25(1)672016251116。NESPCEＲArHuEPO。NESPCEＲA2EPO1EPO。3．33EPO2012327AffymaxTakedapeginesatideFDA。pegine-satide。peginesatide48hNESPCEＲA17。peginesatideEPO。20132peginesatideFDA。EPO2。2EPOEPO/hivscrHuEPO6～819～241～3iv＜scNESP25481～41iv=scCEＲA1341392～41iv=scpeginesatide～48～4841iv=sc201574EPOEPOrHuEPO、rHuEPOpolyethyleneglycolPEG、erythropoietinmi-meticpeptideEMP。4．1N-18。rHuEPO3N1O14。rHuEPOrHuEPO19。rHuEPO。EPOAla30His32Pro87Trp88Pro90Asn30Thr32Val87Asn88Thr90。30、882N-NESP30．4kDa37．1kDaN-5NESP2240%51%19。NESPrHuEPO3。Macdougall14NESPrHuEPO3275%。NESP2001FDAEMA。AMG114rHuEPO。rHuEPOAMG1144N。AMG1147N3030．4kDa44．8kDa。AMG114rHuEPONESP。AMG11468．9hNESP20．4h。AMG114130h。NESPAMG11420。4．2PEG。PEGrHuE-POPEGChineseJournalofNewDrugs2016,25(1)682016251。rHuEPOPEGN8ε。PEGrHuEPO。PEG21。PEGrHuEPOCEＲAPEGepoetinbetaCEＲA。PEGN、45、52ε。PEG30kDaCEＲA60kDa。EPOUT-7rHuEPOCEＲACEＲArHuEPO22。CEＲA130h16。CEＲA。MK-2578MerckPEGrHuEPOMK-2578rHuEPO。90%rHuEPO。MK-2578FDAMK-2578II22。4．3EPO。Sytkowski232EPOEPO。EPO626。17EPO。5～6。EPO24。Fares25βcarboxylterminalpeptideCTPrHuEPOCTPrHuE-POC。rHuEPO、EPO-CTP。2011Fares26rHuEPO3CTPEPO-CTP31CTPEPON2CTPEPOC。EPO-CTP3rHuEPOEPO-CTP3ICＲrHuEPO3rHuEPO8。EPO-CTP。Han27EPOIgG4IgDFcGC1113GC1113NESPGC1113。GC1113。IGC1113。NESPGC1113。GC1113。4．4199628EPOYXCXXGPXTWXCXPX。EPO。Johnson28EPO1EPOmimeticpeptide1EMP-1。EMP-1202。EMP-1EPOEPO。EMP-1EPO。FcEMPEMP。AffymaxTakedaPEGEMPpeginesatide。Mller29peginesatide、Boc-、EMPPEGpegin-esatide。peginesatide2ChineseJournalofNewDrugs2016,25(1)692016251EPO。peginesatideEPOJAK-2/STAT-5。30。peginesatidepeginesatide48h17。2peginesatideCentocorMIMETIBODY2EMP1IgG4FcCNTO530。EMP-12Try-4Try-13EPOＲ4Try。FcFcＲn。CNTO53058kDa40dEPOＲEPO31。CNTO530。520。、PEG、rHuEPOrHuEPOrHuE-PO。EPO、、EPO。19971rHuEPO-“”。SFDA13rHuEPO。rHuEPO90%、。rHuEPOrHuEPOrHuEPO。1CHO7SFDA。EPO。1LACOMBECMAYEUXP．BiologyoferythropoietinJ．Haematologica1998838724－732．2GIANELLAPMAＲTINPYSTUCKEＲF．Managementofre-nalanemiain2013J．ＲevueMedicaleSui