最新：肺癌中的ADCs（抗体偶联药物）进展和实施策略.docx
最新：肺癌中的ADCs（抗体偶联药物）进展和实施策略摘要抗体偶联药物（ADCs）是发展最快的肿瘤治疗药物之一，它将结合有效毒性的载荷与靶向特定肿瘤细胞膜抗原的单克隆抗体高特异性和选择性的结合在一起。ADC选择的主要靶点通常是肿瘤细胞表达的抗原，但在正常组织中不表达。包括人表皮生长因子受体2（HER2）、人表皮生长因子受体3（HER3）、滋养层细胞表面抗原2、C-MEK癌胚抗原相关细胞粘附分子5（CEACAM5）和B7-H3,每个靶点都具有一个或多个特异性ADC,在肺癌领域（非小细胞癌症的研究数量高于小细胞癌症）显示出令人鼓舞的研究结果。迄今为止，多个ADC正在单独或与不同的药物分子（如化疗药物或免疫检查点抑制剂）进行研究探索，选择可能从治疗中受益的患者的最佳策略也在发展中。包括对生物标志物的理解，除了对抗体选择的靶点以外，对ADC有效载荷pay1oad耐药和反应的生物标记物也是研究的热点。AG1.OvervMwotADCsforImgcan<wIntheBuivationanreportedthemiADCafoe1cjcrMmnt.FofMChAOCmotecukIheCCrrEPOndbngXya4XdBeE3nKM)C.MnbO6rdmg8ju9"CEC35.M0t*>reiMedcdIdhEOnmo4ec1e&HER.hucnanBderg1growthfjdorreceptorYROp2.IroPbOeiwOeemt<3c*t>gen2图1.肺癌中ADCS概览对于每个ADC,药物抗体比（DAR）,对应于与每个mAb连接的中等数量的有效载荷部分（在目前批准的ADC中为2至8）,预计将反映药物效力和更高的细胞毒性（表1）。然而，尽管具有更高DAR的ADC具有更强的体外活性，但体内模型显示肝脏清除速度更快，这可能与化合物的总体大小有关，使其更容易通过肝脏被清除。因此，肝脏清除率的增加可能会降低药物在体内对肿瘤细胞的暴露量，并可能降低治疗指数。TAB1E1.OverviewofMainAntibody-DrugConjugatesinC1inica1Deve1opmentin1ungCancerTargetDrugPay1oad1inkerRP2DandSchedu1eDARHER2Trastuzumab-OM1DM1Nondeavab1e(Unoether)3.6mgkg,onceevery3weeks3.1Trastuzumab-DXdDenwtecanC1eavab1e(IaraPePtk1e)64mgkg,onceevy3weeks8HER3PatntumaMXdDeruxtecanC1eavab1e(tetrapepude)5.6mgkg,onceevery3weeks8TR0P2Datopotamab-DXdDenjxtecanC1eavabie(tetrapeptide)6mg/kg.onceevery3weeks4SacituzumabgovrtecanSN38C1eavab1e(CafbOnate)10mg/kgonday1and8.onceevey3weeks7.6CEACAM5TusamitamabravtansieDM4CIedvab1e(SPDB)100mgmj.onceevery2weeks3.8C-METTeksotuzumabVedO(inMMAEC1eavab1e(Vahnedtru1ie)27mg/kg,onceevery3weeks3.1B7H3H)Xd(DS-7300a)DeruxtecanC1eavabie(tetrapepude)TBD4MGCO18DUBACfeavabte(Va1inedtru1ine)TBD27CD561orvotuzumabmertansineDM1C1eavab1e(disufide)AX1EnapotamabVedomMMAEC1eavab1e(protease)22onceevery3weeks-MecbotamabVedainMMAEC1eavab1e(aiine-dtru1ine)TBD-PK7Cofetuzumabpd>dotinAufistatin-O1O1C1eavab1e(vaiine<itru1ine)TBD4PVR14EnfortumabVedo(inMMAEC1eavab1e(vaiinedtru1ine)TBD4TFTisoiumaMedotinMMAEC1eavab1e(VahnearU1ine)TBD4EGFRMRGOO3MMAEC1eavab1e(VaIinedtruIine)20mgAg,onceevery3weeks4R0R2OzuriftamabVedOtnMMAEC1eavab1e(vaiine-dtru1ine)TBD4NaPi2bUpifitamabn1sodotinAFKjAC1eavabte(protease)TBD12-151ifaStUZumabvedotinMMAECteavab1e(Vaiine<itru1ine)TBD3-4NOTE.Topoisomerase-Iinhibitors:deruxtecan(exatecanderivative)andSN38(camptOthecinderivative);microtubu1einhibitors:DM1(maytamsinederivativeemtansine),DM4(maytansinoid),MMAE(momethy1aristatinE),auristatin01O1,andARHPA(auristatinF-ydroxypropy1amide);DUBA:duocarmycir>basedDNA-a1ky1atingpay1oad.Abbreviatis:AF-HPA,auristatiF-hydroxypropy1amide;CEACAM5,CarCinOe<nbryoicantigen-re1atedce11adhesimo1ecu1e5;DAR,drug-to-antibodyratio;DUBA,duocarmycin-hydroxybenzamide-azaindo1e;EGFR1epiderma1growthfactorreceptor;HER,humanepiderma1growthfactorreceptor;MMAE1monomethy1auristatinE;TBD1tobedetermined;TF1tissuefactorTR0P2,trophob1astce11surfaceantigen2.表1.肺癌领域在研的主要ADC药物研究概况TAB1E2.MaOngoingC1inica1Tria1sWithADCsin1ungSneerDrugTargTriaiNo.P1meSehgTreatmentsPrimaryEndPointTraStUZUmaM)XdHER2NCT044237(QEST)NY-IirgO?)Pretee1cd由2mutantNSC1CTOW54ar&4m9¾gORANcTMO48797(DESnNY-1gO4)IIIFAHheHERmuuntNSC1CT-OXdvPiabeUYVPefneirexedPembfoi0JnabPFSNCT04042701bHER2press*ngNSC1CwohadnetIBCeWtdanyPnortreatmentWthartt-PO1.atrP0-11.HER2T-OXdbsPembrahumabD1TsORRNCT(M68W05(PESnNKUnga3)bHER?GercCPreSSingonsqHSC1C(firsHeandpretested)T-OXdPUSPtetrIgPefnetEcrianddurv1unabAEsNCTO524的4PEST)NY-1rgO6)PrereatedHB2auantNSUCT-OXdORRNCToa50879IaPrercatcdH02<nutatNSC1CarmTOXdbsE1VNQO2D1TssafctyA166HER2NCTO3602079V11HER2-ecprettgUrnorSA166mcotefayD1TsXM1S22HER2NCT-1/11HER2cpreasmgtumorsXMT-1522mootherap,fD1TsPWIIUmabOxdHER3NcTo<19004(HERBCWungOI)PreteatedEGFRwutantNScICHER3-0KdORRNen)S338970(HERTKNAungO2)IIIPreteatedEGFFWnutantNSC1CHER3-0Xdvptathndoub1etPFSHERTHENA1ugO3IIIFrsHheEGFR*xiartNSC1CHER30dPiUS05nerrwbvOernertnibPFSNeTo<764771/11FrsHneandpretextedEGnV<nmNSC1CHER3-CXdpbs0mtnbD1TsORRNCTO3260491INSC1Cmu1tip1ecohortsHER3-WD1TsORRDa1opotomabDXdTROP?NCT03M1385RQP10H4Tumortn)INSaC(mU6p1ecohorts)PretreaiedSC1CDat>D×dD1TsAEsNCT050273(TROp1oNPaYumO2)V11PrcrcatcdNSC1CwthoutAGAinChrescpatientsDatoOXdORRNCT(M612751(TRoPK)NIgM)IFrsHneandPrdyatcdNSC1CWitxxJAGADakH)Xdp1us»(diffcntogerts)CartiopbtrO1TsNCT0¼56b52(TPtOHg01)IIIPrereatedNSC1CWi命atMthoutAGAOatD*O×dvdoceta«1PFSOSNCTo4484IH(TROP1OHInJ05)PrcteetcdNSacWthAGAD3to*0×dORRNCT04q403?5QCMUs<ug1)PretextedNSaCwtfOrwthoutAGADak>D×dORRNcTo452附1(TAOMON1gQ2)INSC1CwitfxxMAGA(itwoprxEneS)
