HuatengPharma https://ushuatengscicom
Top2TargetsofADC:HER2&Trop2
Antibody-DrugConjugates(ADCs)aredrugsthatconjugatemonoclonal antibodiestodifferentnumbersofsmallmoleculesofcytotoxicagents(effector molecules)throughchemicallinkersADCcombinesthepotentcytotoxicityof smallmoleculedrugswiththeselectivityofmonoclonalantibodiesanda favorablepharmacokineticprofileCurrently,14therapeuticADCsreceived marketingapproval.Theytargetavarietyofdiseasemarkers,ofwhichHER2 andTrop2arethemostwidelyusedtargetsforADCdrugs
HottestADCTarget-HER2
Humanepidermalgrowthfactorreceptor2(HER2)isatransmembrane receptorfortyrosinekinasesandamemberoftheepidermalgrowthfactor receptor(EGFR)family,whichalsoincludesHer1(EGFR),HER3andHER4. Allfourmembersregulatecellproliferationanddifferentiationthrough ligand-dependentorindependentformsofhomo-orheterodimerizationactivity. Unliketheotherthreemembers,HER2istheonlyreceptorthatcanforma dimerwithanyoftheothermembers,therebytriggeringasignalingpathway thatregulatescellproliferationandsurvivalHER2targetedtherapyhas significantlyimprovedtheprognosisofHER2positivebreastandgastric cancers
Figure1.MechanismofactionofHER2,source:reference1
HuatengPharma https://ushuatengscicom Therearecurrentlymorethan30ADCdrugstargetingHER2intheclinical phaseworldwide,withthreealreadyapprovedformarketing.
▶T-DM1(Kadcyla)wasthefirstFDA-approvedHER2-targetedADC drugforthetreatmentofadvancedHER2+breastcancerandwasalso approvedforuseinearlystage,highriskpatientswithresidualdiseaseafter neoadjuvanttherapy.
▶In2019,T-DXd(DS-8201;ENHERTU)becamethesecondapproved HER2-targetedADCdrugthatshowedsignificantantitumoractivityinpatients withtreatment-refractoryHER2+metastaticbreastcancer.
▶In2021,RC48(DisitamabVedotin)wasapprovedinChinaforthe treatmentofpatientswithlocallyadvancedormetastaticHER2overexpressing gastriccancerwhohavereceivedatleasttwoformsofsystemic chemotherapy
Figure2ListofantiHer2ADCsinclinicaltrialsoronthemarket,source: reference1
Severalanti-HER2-targetedADCsattheforefrontofdevelopmenthave demonstratedexcellentantitumoractivityinthetreatmentofbreastcancer,
HuatengPharma https://ushuatengscicom andinaddition,someofthemhaveshownsignificantclinicalbenefitinother HER2positivecancers.
▶DS-8201achievedsignificantimprovementsinthetreatmentofpatients withmetastaticbreastcancerandHER2positivegastriccancer.Inthephase IIclinicaltrial,patientswithmetastaticbreastcancerachievedanobjective responserate(ORR)of60.9%,progression-freesurvival(PFS)of16.4months andoverallsurvival(OS)of12monthsPatientswithHER2positivegastric canceralsoexperiencedsignificantclinicalbenefitfromDS-8201,withanORR of432%,diseasecontrolrate(DCR)of795%andPFSof56monthsIn HER2-mutantnon-smallcelllungcancer,theORRwas72.7%andthemedian PFSwas113months
▶RC48alsodemonstratedsuperiorclinicalefficacyinthetreatmentof uroepithelialcarcinoma(ORR51.2%,OS13.9months,PFS6.9months), gastriccancer(ORR181%,PFS38months,OS76months)andbreast cancer(ORR36.7%,SD60.0%).
▶DS8201andRC48havealsoshownsignificantefficacyintreatingpatients withlowHer2expressionIntheHER2IHC1+orIHC2+breastcancerstaging trial,DS8201ahadanORRof37%andaDCRof87%Inamulticenterphase IItrialofHER2negativeuroepithelialcarcinoma(IHC0orIHC1+),RC48had anORRof25%andaDCRof75%
▶ARX788hasshownsignificantefficacyintreatingpatientswith HER2-positivegastriccancer:9outof20patients(45.5%)receivedaPR.And inMarch2021,theFDAhasgrantedanorphandrugdesignation toARX788forthetreatmentofpatientswithHER2-positivegastriccancer.
NovelADCTarget-Trop2
Tumorassociatedcalciumsignaltransducer2(TROP2)isaglycoproteinthat inhumansisencodedbytheTACSTD2geneItisa36kDatransmembrane proteinconsistingof323aminoacidsandfourNlinkedglycosylationsites HighexpressionofTrop2playsakeyroleinthegrowthoftumorcellsandis associatedwithaggressivediseaseandpoorprognosisTROP2wasfirst describedin1981asaproteinhighlyexpressedonthesurfaceoftrophoblast cellsbutlateronrevealedtoplaycomplicatedrolesincancercellgrowth, proliferation,migration,invasionandsurvival.Itsoverexpressionwas demonstratedinvarioustumortypesandcorrelatedwithunfavorable prognosisandincreasedriskofmetastasis,includingbreast,lung,urothelial, gastric,colorectal,pancreatic,prostatic,cervical,headandneck,andovarian carcinomas.
HuatengPharma
Figure3.TROP2promotestumorinvasionandmetastasis,source: https://wwwcusabiocom/
Currently,onlyoneTrop2ADChasbeenapprovedformarketing worldwide,butseveralpreclinicalproductsarealreadyadvancing,and internationaltransactionsaroundTrop2ADCsareinfullswing.Thefuture competitivelandscapeoftheTrop2ADCmarketisworthlookingforwardto
SacituzumabGovitecan/Trodelvy(Gilead/Immunomedics)
SacituzumabGovitecan(Trodelvy),theonlyTrop2targetedADCdrug currentlyapprovedforthetreatmentoftriplenegativebreastcancer(TNBC) andlocallyadvancedormetastaticuroepithelialcarcinoma(UC). TrodelvyComposition
▶AnantiTrop2humanizedIgG1κmAbSacituzumab
▶Ahydrolyzablelinker,withashortPEGylatedunit
▶AtopoisomeraseIinhibitor,SN38,DAR=74Amongthem,SN38isthe bioactivemetaboliteofIrinotecan,whichcaneffectivelyinhibitDNAsynthesis andcauseDNAsingle-strandbreakage.Comparedwithmicrotubuleinhibitors, SN38hasashorterhalflifeandislesslikelytoaccumulateinvivo;atthe sametime,sincethenumberofintracellulartargetsofmicrotubuleinhibitors farexceedsthatofDNAinhibitors,DNAinhibitorsareexpectedtoexertbetter cellkillingeffectswiththesamenumberofwarheadsenteringthecell.
Note:PEGderivativesareonekindofthemostwidelyusedlinkersintargeted
HuatengPharma https://ushuatengscicom therapywithmanyfeatures,suchashighusagerate,targeting,regulatingPH value,etc.HuatengPharmaoffersavarietyofPEGlinkerstofacilitate antibodydrugconjugate(ADC)developmentprojectsAllPEGlinkersare of>95%purityandtheyarethebasicbuildingblocksforasuccessfulADC
Figure4Trodelvystructure
DS-1062(DaiichiSankyo/AstraZeneca) DS1062(Datopotamabderuxtecan,datoDXd)isaTrop2ADCcodeveloped byDaiichiSankyoandAstraZeneca. DS1062composition
▶AnantiTrop2humanizedIgG1mAbDatopotamab;
▶Cleavablecysteinelinker;
▶AtopoisomeraseIinhibitor,DXd，DAR=4DXdisaninnovativeDNA topoisomeraseinhibitorthatis10timesmoreactivethanIrinotecan(SN38) andinterfereswithDNAreplication,recombinationandgeneexpression However,DS1062isdesignedwithonlyaDARof4,whichissignificantly lowerthantheDARof8ofDS8201Trop2isalsoexpressedinhealthycells, sothetherapeuticwindowisrelativelynarrowandthepayloadrationeedsto bereduced.
Figure5DS1062structure,source:DaiichiSankyowebsite
DS1062iscurrentlybeingdevelopedfornonsmallcelllungcancerandtriple negativebreastcancer.
Advancednon-smallcelllungcancer:the6mg/kgdosegroupofDS-1062 achievedanobjectiveremissionrateof21%,withadiseasecontrolrateof 67%andaPFSof8.2months.
Advancedtriplenegativebreastcancer:initialobjectiveremissionrate(ORR) of43%anddiseasecontrolrate(DCR)of95%in21evaluablepatientstreated withDS1062inablinded,independentcenterevaluation.
BasedonAstraZeneca/DaiichiSankyo'sexclusiveadvancedADCtechnology, DS1062haspromisingclinicaldataandisexpectedtobealeaderamong Trop2ADCs.
Conclusion
Decadesofeffortsfromtheacademiaandtheindustryhaveledtosuccessful developmentofavarietyofADCtherapiesthatbenefittensofthousands
HuatengPharma https://ushuatengscicom cancerpatientsNowtherearedozensoftargetsforADCresearchExcept HER2andTrop2,therearemanyotherpromosingADCtargets.Itisbelieved that,moreandmoretargetswillbediscoeveredforADCresearch
References:
[1]ZhangX,HuangAC,ChenF,ChenH,LiL,KongN,LuoW,FangJ.Novel developmentstrategiesandchallengesforantiHer2antibodydrugconjugates AntibTher.2022Jan27;5(1):18-29.doi:10.1093/abt/tbac001.PMID: 35146330;PMCID:PMC8826051
[2]BardiaA,HurvitzSA,TolaneySM,etal.SacituzumabGovitecanin MetastaticTripleNegativeBreastCancerNEnglJMed 2021;384(16):1529-1541.doi:10.1056/NEJMoa2028485 [3]https://wwwdaiichisankyocom/
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