ADC荣昌抗体偶联药物

1ADC药物偶联技术的发展及相关质量研究李壮林烟台荣昌生物 工程 路基工程安全技术交底工程项目施工成本控制工程量增项单年度零星工程技术标正投影法基本原理 有限公司August13,2014Globaltop10drugsin20132http://www.sciencedirect.com/science/article/pii/S0952791599000102临床上单独使用单克隆抗体的抗肿瘤的作用有限。如何增强单克隆抗体的抗肿瘤的作用？那就是在抗体上挂上一个炸弹或称细胞毒素。3ADC（AntibodyDrugConjugate）5ADCDrugs:ANovelClassofTargetedBio-TherapeuticsCurrentCancerDrugTargets,2009,9,982-1004B.A.TeicherAntibody-drugconjugatetargets6CurrentCancerDrugTargets,2009,9,982-1004B.A.Teicher,Antibody-drugconjugatetargets7ADCDesignationsTargetAntigenLinker-DrugClassDevelopmentTumorIndication(s)DeveloperSNG-35(Adcetris)SNG-75Anti-CD19ADCCD30CD70CD19AuristatinAuristatinAuristatinApprovedPhaseⅠ/ⅠbNHLRCC/NHLSeattleGeneticsTrastuzumab-DM1Anti-CD22ADCHer2CD22MaytansineAuristatinApprovedPhaseⅠHER2+BreastCaGastricCaALLGenentechAGS-5ADCAGS-22M6EAGS-16M8FSLC44A4Nectin-4AGS-16AuristatinAuristatinAuristatinPhaseⅠPhaseⅠPhaseⅠPancreatic,GastricCaSolidTumorsKidney,RCC(active,notrecruiting)AstellasPSMA-ADCPSMAAuristatinPhaseⅠ/ⅡProstateProgenicsBIIB015Anti-CriptoAuristatinPhaseⅠSolidTumorBiogenIdecCDX-011GPNMBAuristatinPhaseⅠ/ⅡBreast,MelanomaCelldexBAY79-4620Carbonicanhydrase9AuristatinPhaseⅠSolidTumor(active,notrecruiting/terminated)BayerBAY94-9343mesothelinMaytansinePhaseⅠSolidTumorBayerSAR3419SAR566658AVE9633CD19CA6CD33MaytansineMaytansineMaytansinePhaseⅠ/ⅡPhaseⅠPhaseⅠALL,NHL,BcelllymphomaMalignantneoplasm(solid)AML(terminated)SanofiBT-062CD138MaytansinePhaseⅠ/ⅡMultipleMyeloma(MM)BiotestIMGN242IMGN901IMGN388IMGN368CanAngCD56AvIntegrinAvIntegrinMaytansineMaytansineMaytansineMaytansinePhaseⅠPhaseⅠ/ⅡPhaseⅠSolidTumorMM,LungCa,Ovarian,SCLCSolidTumorImmunoGenCMC-544CD22CalicheamicinPhaseⅠb/Ⅱ/ⅢNHL,ALL,BcelllymphomaPfizerMDX1203CD70DuocarmycinPhaseⅠRCC/NHL(suspended)BMSADCDrugsunderclinicaldevelopment89ADCDrugsApprovedbyUSAFDADrugnamemAb(Antigen)Drug/LinkerDrugs/Ab(average)ConjugateChemistryReducableTriggerStatusMylotargGemtuzumabozogamicin(CD-33)Calicheamicin/Hydrazone4-6(5*)LysineYespHapproved(2000)withdraw(2010)AdcetrisBrentuximabvedotin(CD-30)MonomethylaurisatinE(MMAE)/MC-VC-PAB3-5(4)CysteineNoproteaseapproved(2011)atphaseⅡKadcylaTrastuzumabemtansine(Her-2)Mertansine(DM1)/SMCC0-8(3.5)LysineNononeapproved(2013)accelerated10FourLessonslearnedfromMylotargDosioetal,Toxins,2011,3:848Only50%AmbconjugateddrugsHydrazonebondnotstableinbloodDisulfidebondsprematurebrokenShedCalicheamicincanpenetratecells11CarbohydrateThiobridgeThiophenolNon-naturedAminoacidsCysteineLysineConjugationTechnologiesNH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2NH2SHSHSHSHLysineConjugatevs.CysteineConjugate代 表 关于同志近三年现实表现材料材料类招标技术评分表图表与交易pdf视力表打印pdf用图表说话 pdf Lys，氨基偶联为主代表Cys，巯基偶联为主定点偶联为主1213LysineConjugation#drug/mAbmolecule14Genentech’santi-Her2ADCdrugT-DM1(Kadcyla)15Structureoftrastuzumab(Tmab)–maytansinoidconjugates(stabilityoflinker,leasttogreatest):Tmab-SPDP-DM1,Tmab-SPP-DM1,Tmab-SSNPP-DM3,Tmab-SSNPP-DM4,andTmab-SMCC-DM1(nonreducible).T-DM1linkerevaluationGailD.LewisPhillips,CancerRes2008;68:(22).16T-DM1linkerevaluationGailD.LewisPhillips,CancerRes2008;68:(22).17HerceptinVST-DM1GailD.LewisPhillips,CancerRes2008;68:(22).18DrugDistributionofCysteineConjugation#drug/mAbmoleculeReducedorbrokendisulfidebondsfordrugconjugationleadtoantibodyunstablewithashorterhalflife---challengesolution.19SeattleGenetics’anti-CD-30ADCdrugSGN-35(Brentuximabvedotin)20SGN-35(Brentuximabvedotin)临床试验-SGN-35在Hodgkinlymphoma(HL)表现出非常好的抗肿瘤活性;-SGN-35在Systemicanaplasticlargecelllymphoma(ALCL)也呈现显著的抗肿瘤活性;-2011年8月，FDA根据II期临床试验结果批准SGN-35用于HL治疗，后又批准用于ALCL治疗。RCBiotechLTDAndrewC.HuangPh.D.201405SeattleGeneticsInc.完成7个临床实验表明Adcetris安全有效2122Site-specificConjugation#drug/mAbmolecule23Site-specificConjugationAxupetal，ＰＮＡＳ，２０１２24Site-specificConjugationAxupetal，ＰＮＡＳ，２０１２HIC-HPLCAnalysisonADCdrugwithCysteineConjugationAdityaWakankaretal,mAbs,2011,3:2,161-17225(A–D)DTT-reducedcAC10-vcMMAEconjugatesproducedusingdifferentreduction/reoxidationprotocols.(E–H)Analysisofthesameconjugatesamplesin(A–D),undernon-reducingconditions,AdityaWakankaretal,mAbs,2011,3:2,161-17226Reversed-phaseHPLCanalysis27ConjugationsiteanalysisinT-DM1(Enzymaticcleavage)byRP-HPLC•EnzymaticcleavageofADCscanbeusedtoidentifydrug-containingpeptides.•PeptideslabeledwithahydrophobicdrugwouldbeexpectedtoelutelaterthantheirunmodifiedformsintheRP-HPLCchromatogramduetoincreasedretentionbythecolumn.•Trastuzumabhas88lysinesforpossiblelinkage.DM1chromophore(λmax=252nm)canbeusedtoidentifypeptidescontainingbounddrug.28ChargeHeterogeneityDetectedbyCiEF12345S17.978.148.338.508.67S27.988.158.358.508.67pImarker7.05pImarker9.33mAb-CiEFpImarker7.05pImarker9.33ADC-CiEF12345S18.198.378.568.738.84S28.218.398.588.748.8629DrugtoAntibodyRatio(DAR)byHICHydrophobicinteractionchromatography(HIC)analysisofamAb-vc-MMAEonaTOSOHBiosciencesButyl-NPRcolumnyieldsfivepredominantpeaksthatcorrespondtomAbcontainingzero,two,four,sixandeightdrugs.min02468101214mAU051015202530350Drugs2Drugs4Drugs6Drugs8DrugsD0=5%D2=25%D4=43%D6=20%D8=7%•HICisgentleanddoesnotdisruptnon-covalentinteractions.ThisretainsMAbstructureslackingnormaldisulfidebondsasfoundinsomeconjugates30DrugDistribution＆LocationbyLC/MSD0D1D2D3D4D5D6D7T-DM1,glycosylatedSEC/ESI-MSanalysisofdeglycosylatedhuC242-DM4showingthedeconvolutedmassspectrum.AdityaWakankaretal,mAbs,2011,3:2,161-1723132DARAnalysisbyHIC＆LC/MS•Relativelevelsofthemolarratios(MR)ofmcMMAFperIgG1ADC-A(panelA)andvcMMAEperIgG1ADC-B(panelB)asdeterminedbyMSbasedquantitationfromthedeconvolutedmassspectraandbyUVintegrationofthespeciesseparatedbyHIC.JohnF.Valliere-Douglass,AnalChem，201205010015020025030035040010100100010000100000DAR0DAR2.01DAR4.13DAR5.79DAR6.79Concentration(ng/ml)Time(hr)EffectsofDARonpKinRatsinCys-conjugatedADCLocationsofconjugationsiteimpactinvivostabilityofADCdrugShenNatBiotech20123435ShenNatBiotech2012LocationsofconjugationsiteimpactinvivostabilityofADCdrug36SummaryADCdrugsareverycomplexinstructureandproductqualitywhichgreatlyaffectdrugefficacyandsafety.ConjugationtechnologyisfundamentalforADCstructureandquality.Lysineandcysteine-basedconjugationhasbeensuccessfulinclinicaldevelopment.Site-specificconjugationmayprovidesomeadvantages.AnumberofanalyticmethodshavebeendevelopedtofacilitatecharacterizationADCdrugs.AnalyticalcharacterizationsofbothnakedantibodyandADCarecriticalforunderstandingbiologyofADCdrugsandforinsuringoptimaldrugefficacyandsafety.