ADC Therapies: Current Development & Future Prospects

ADCTherapies:CurrentDevelopment&Future Prospects

TheconceptofADC(Antibody-DrugConjugates)hasbeenaroundforalongtime,butthe ADCindustryhasstruggledinthepastduetothehightechnicalthresholdrequiredfor theirsynthesis,thelong-termoff-target,thediscoveryofspecificantigensandother technicalproblemsItwasnotuntilrecentyearsthattherapiddevelopmentofADCdrugs began,aftermanyyearsofexperimentsanditerationsbyscientistsonhowtosynthesize ADCdrugs,improvesafety,andreduceoff-targetandtoxicsideeffects

ADCdrugshaveboththetumortargetingofantibodydrugsandthepowerfulkillingeffect ofsmallmoleculedrugs,showingexcellentclinicalefficacyinbreastcancer,urothelial carcinoma,gastriccancer,hemomaandotherfields,bringingmoretreatmentoptionsfor tumorpatientswhohavefailedmulti-linetreatmentWiththeintensivemarketingof variousADCdrugsinrecentyears,especiallytheapprovalofthethird-generationADC drugsrepresentedbyEnhertuandTrodelvy,moreandmoreinnovativepharmaceutical companieshaveincreasedtheirlayoutinthisfieldADCtherapieshavebecomeoneof thehotresearchdirectionsinthefieldoftumortherapytodayHerewewillintroducethe currentdevelopmentandfutureprospectsofADCtherapies

TheConceptofADCDrugs

ADCdrugsarecalled"biologicalmissiles",whichconsistofthreeparts:antibodies, payloads,andlinkersAmongthem,theantibodyactsasa"guidancesystem"andis responsibleforselectivelyrecognizingantigensonthesurfaceofcancercells.The payload(thatis,smallmoleculecytotoxicdrugs)actsasa"warhead"andisresponsible forkillingcancercellsThelinkerisresponsibleforconnectingtheantibodyandthe payload

TimelineofimportanteventsforADCdrugs

(Source:Antibodydrugconjugate:the“biologicalmissile”fortargetedcancertherapy)

FiveElementsofADCDrugDesign

ADCisacomplexstructurecomposedofthreeparts:antibody,linkerandpayload,which determinesthatitspreparationprocesswillbemorecomplicatedDuringthepreparation andproductionprocess,smallmoleculartoxinsneedtoundergomultiplesyntheticsteps, dissolveinavarietyofsolvents,andmaintaintheirchemicalstructureandproperties duringtheseprocesses.InordertoenableADCdrugstofunctioneffectivelyandachieve theexpectedefficacyandsafety,thetarget,antibody,linker,payload,conjugation methodsandreasonablecombinationamongthemshouldbefocusedoninthedesign anddevelopmentofADCThesuccessofADCdrugsoftendependsonthedesignof thesefiveelements.

1.Target

TargetselectionisakeypartofADCdrugdesignandtheprimaryconsiderationinADC developmentAnidealtargetshouldhavethefollowingcharacteristics:Thefirstistissue specificity,thetargetantigenshouldbeexpressedatahighlevelintumorcells,andnotor lowlyexpressedinnormaltissues.Thensecondisthestability.Thatis,thetargetantigen

isnoteasytofallofffromthetargettissue,soastopreventthecombinationofantigens withADCdrugsintheinternalcirculationsystem,therebyreducingtheamountof aggregationtothetargetsite,affectingtheefficacyandsafetyofthedrugThethirdis efficientinductionofinternalizationAftertheantibodybindstothesurfaceantigenof tumorcells,theADC-antigencomplexmustbeabletoeffectivelyinducethe internalizationprocessandenterthetumorcellstoachieverapidreleaseofthepayload.

Intheory,ADCdrugscanreleasetoxinsoutsidetumorcells,killingtumorcellsthroughthe "bystandereffect"withoutinternalizingthecellsInfact,mostoftheeffectivenessofADC drugsisbasedoninternalizeddrugrelease.Therefore,aftertheantibodyinanADCdrug bindstothesurfaceantigenofatumorcell,theADc-antigencomplexmustbeableto effectivelyinducetheinternalizationprocess,enterthetumorcell,andachievethe effectivereleaseofsmallmoleculedrugsthroughappropriateintracellulartransportand degradationprocesses.

HER2hasbecomeahottargetforresearchanddevelopmentworldwideAmongthe15 drugsonthemarket,thedrugtargetsforsolidtumorsincludeHER2,trop2,nectin4,EGFR, andthetargetsforhematomaincludeCD19,CD22,CD33,CD30,etc.Amongthem,there are3drugstargetingHER2,followedbyCD22,atotalof2drugsAsofDecember2022, therearemorethan60ADCdrugstargetingHER2intheworld,accountingfornearly 40%.

2.Antibody

ADCantibodiescanspecificallybindtothetargetantigenonthesurfaceoftumorcells andbehighlyinternalizedintocells,whichrequiresthefollowingcharacteristics:Thefirst istargetspecificityandhighendocytosisAntibodiesshouldhavehighantigenspecificity andaffinity,andachieveeffectiveinternalizationtoreleasethepayloadincellsThe secondislowimmunogenicity,whichneedstoachievetheminimumimmunogenicity throughtheselectionofhumanizedorwholehumanantibodiesThethirdislong

circulationhalf-life,ADCdrugsinthebloodshouldhavealongcirculationtimetosmoothly enterthetumorcells.

IgG1iscurrentlythemostmainstreamADCantibodyTheantibodiesofADCdrugsare mainlyimmunoglobulinG(IgG)antibodies,includingfoursubtypesofIgG1,IgG2,IgG3 andIgG4Afterbindingtotargetcells,IgG1caninducevariousimmuneresponsessuch asADCCandCDCIthasexcellentcharacteristicssuchasstrongstabilityandlong half-life,andhasbecomethemainstreamchoiceofADCdrugsOfthe15drugsalready onthemarket,13useIgG1astheantibody,andtheremainingtwouseIgG4(bothfrom Pfizer).

Theemergenceofantibody-baseddrugshasenabledsubstantialprogressinthe treatmentofavarietyofdiseases,includingcancer,autoimmunediseases,cardiovascular diseases,benignblooddiseasesandbonediseases.Antibodyfragmentsandbispecific antibodiesofferpromisingtherapeuticprospectsforinnovativetherapiesAntibodiesneed tomeethighspecificity,strongtargetbindingability,lowimmunogenicity,andlow cross-reactivitytoachievemoreefficientuptakeofADCdrugsbytumorcellsandlonger half-lifeofADCdrugsinserum.

3.Linker

Thelinkerisusedtoconnectthemonoclonalantibodyandthepayload,anditschemical propertiesandconjugationsitesarecrucialtothestabilityoftheADCdrugandthe releaseofthepayloadThelinkerneedstohavethefollowingthreecharacteristics:(1) Thelinkerhasstabilityintheblood;(2)Thelinkercanaccuratelyreleasethewarheadat thetargetlocation;(3)Thelinkershouldhavecertainhydrophilicity

ADChasundergonethreegenerationsofupgradesAccordingtothereleasemechanism oftheload,thelinkersgraduallydifferentiatesintocleavablelinkersandnon-cleavable linkersCleavablelinkershavebecomethemainstreamtrendCleavablelinkerscanbe dividedintotwocategories:enzyme-dependentandchemical-dependentTheyhave

abystandereffectandcankillcellswithlowantigenexpressioninheterogeneous tumors.Theyarethemainstreamdirectionofcurrentdrugdevelopment.Twelveofthe15 marketeddrugsusedegradablelinkersAmongthem,drugssuchasEnhertuandAidixi arecleavablelinkers,andtheircatabolitescanpassthroughthecellmembranetoexerta bystandereffect

4.Payload

PayloadisoneofthemostcriticalcomponentsofADCdrugs,anditisthedecisivefactor forADCdrugstoplaytheroleoftargetcellkilling.Thepayloadshouldhavethefollowing characteristics:first,itishighlycytotoxicTheamountoftoxiningestedatthetumorsiteis verylowToxinmoleculesshouldplaythehighestcytotoxiceffectatalowconcentration andkilltumorcellsefficiently.Thesecondismodifiability,thestructureofthedrugcanbe modifiedtoensurethatitcanbecoupledwithalinkerThethirdishighstability,thetarget ofthetoxinmoleculeismainlylocatedinthecell,andthetoxincannotbedegradedand inactivatedinthebiochemicalenvironmentafterbeingreleasedintothecellFourth, hydrophobicandmembrane-permeable,toxinswiththesecharacteristicscanpenetrate thecellmembranetoplayabystandereffectandkillcellswithlowexpressionof surroundingantigenafterbeingreleasedinthecell

5.ConjugationMethods

Conjugationtechnologyconnectsantibodiesandsmallmoleculetoxinsthroughlinkers, involvingchemicalreactions,antibodymodificationandtransformationandotherrelated technologies.TheconjugationtechnologyadoptedbyADCdrugsiscloselyrelatedtoits finaldrug-to-antibodyratio(DAR),andthevalueanddistributionofDARwill significantlyaffectthepropertiesofADCdrugsToolargeaDARmayleadtothe accumulationofADCdrugsandthenbeclearedinthecirculatorysystem.Toosmalla DARmaycauseADCdrugstofailtoachievethebesttherapeuticeffectDARbetween2 and4isthebestchoiceforADCdrugs

PopularTargetsForADCDrugs

15marketedADCdrugscorrespondto11targets,whichareCD33,CD30,HER2,CD22, CD79b,Nectin-4,BCMA,EGFR,CD19,TissueFactorandFRα.

ADCtargetsapprovedbyFDA

Intermsofcurrenttargettrends,themostpopulartargetintheADCfieldisHER2, followedbythepopularTrop-2Atthesametime,Claudin182,apopulartargetinthe fieldofgastriccancer,isalsoanotherpopulartargetincurrentresearchanddevelopment.

InthecompetitionforthedevelopmentofClaudin182target,inadditiontoADC,many newattemptshavealsoemerged,suchasCAR-T.However,underthecurrentsituation thatthereisnoobviousadvantageinthedevelopmentofefficacy,itisspeculatedthatthe marketwillbemoreinclinedtocheaperADCdrugs,anditmaybemoredifficultto commercializeCAR-Tforthetreatmentofsolidtumors

1.HER2

HER2,shortforhumanepidermalgrowthfactorreceptor-2,isareceptortyrosine kinaseonthesurfaceofcellmembranesthatcanregulatecellproliferationand differentiationAtpresent,abnormalexpressionofHER2hasbeenfoundinbreastcancer, ovariancancer,gastrointestinalcancer,lungcancerandnon-smallcellcancerTumors withhighexpressionofHER2showstrongabilitytometastasizeandinfiltrate,areless sensitivetochemotherapy,andarepronetorelapse

ThereareseveralHER2AdCsonthemarket,includingKadcyla,Enhertuanddisitamab vedotin.KadcylaisthefirstHER2ADCdrug,whichcansignificantlyreducetheriskof recurrenceby50%afterbreastcancersurgery.Ithasasignificanteffectinthetreatment ofbreastcancer,butitisnoteffectiveinthetreatmentofgastriccancerEnhertuis currentlythemosteffectiveHER2ADCdrug,anditsclinicaltrialsforbreastcancerand gastriccancerhaveallbeensuccessful.Inparticular,EnhertubeatKadcylainthePhase IIIhead-to-headclinicaltrial(DESTINY-Breast03)forthetreatmentofbreastcancer Disitamabvedotinhasbeenapprovedformarketing,anditsefficacydataiscomparableto thatofKadcyla

2.TROP-2

TROP-2,shortfortrophoblastcellsurfaceantigen2,promotesthegrowth, proliferationandmetastasisoftumorcellsmainlybyregulatingcalciumionsignaling pathway,theexpressionofcyclinandreducingfibrinadhesionTROP-2ishighly expressedinavarietyoftumors,suchaspancreaticcancer,breastcancer,coloncancer,

bladdercancer,oralsquamouscellcarcinomaandovariancancer,anditshigh expressioniscloselyassociatedwithshortenedsurvivalandpoorprognosisoftumor patientsTrodelvy,amarketedTROP-2ADCdrug,reducedtheriskofdiseaseordeathby 59%andextendedoverallsurvivalto109months

3.Claudin18.2

Claudin18.2belongstoafamilyofClaudinintegrinmembraneproteinsthatexistinthe tightjunctionbetweenepithelialandendothelialClaudin182isusuallyburiedinthe gastricmucosaandcannotbecontactedandboundbyantibodiesinnormaltissues. However,theoccurrenceofmalignanttumorswillleadtothedestructionofthetight junctionTheClaudin182epitopeonthesurfaceoftumorcellswasexposedandbecame aspecifictarget.Claudin18.2ishighlyexpressedingastriccancer,aswellaspancreatic, esophageal,andlungcancersThecurrentlayoutofCladin182ADCdrugs,thefast progressingonesareCMG901andSHR-A1904

MarketedDrugsAndMarketSizeForADCDrugs

1.MarketingADCDrugs

AsofDecember2022,15ADCdrugshavebeenapprovedworldwideTheworld'sfirst ADCdrug,Mylotarg,wasapprovedin2000,butitwaswithdrawnin2010duetofatalliver injury,anditwasre-launchedin2017afteroptimizingthedrugregimentoimprove efficacyandsafetyFrom2001to2010,noADCdrugwasapprovedformarketinginthe world,andthedevelopmentoftheindustryenteredalowperiodWiththecontinuous advancementoftechnology,thesecond-generationADCdrugrepresentedbyAdcetris waslaunchedin2011,andatotalof4productswerelaunchedfrom2011to2018Since 2019,ADCdrugshaveusheredinaconcentratedperiodofmarketing,andatotalof10 drugshavebeenapprovedsofar.Fromtheperspectiveofindications,thedistributionof hematologicaltumorsandsolidtumorsinthemarketeddrugsisrelativelyeven,8are

usedforthetreatmentofsolidtumors,and7areusedforhematologicaltumorsSolid tumorsaremainlyconcentratedinbreastcancerandurothelialcarcinoma.

2.GlobalMarketSize

TheADCdrugmarketisgrowingstronglyandhasbroadprospectsfordevelopment. Accordingtorelevantstatistics,theglobalADCdrugmarketreachedUS$531billionin 2021,anincreaseof875%over2019Andin2022,thetotalsalesoftheseADCdrugs arenearly$7billionAccordingtoNatrue'smarketforecast,theglobalADCdrugmarket willreachUS$16.4billionin2026,andthemarketwillmaintainrapidgrowth.

KadcylaandAdcetrishaveobviousadvantages,whileEnhertuhasthegreatestmarket potentialIntermsofindividualdrugsales,Kadcyla,asecond-generationdrug,ranked firstgloballyin2021with$2.178billioninrevenue,makingitthemostcommercially successfulADCdrugtodateAdcetrisrankedsecondwithsalesof$1306billionThese twodrugshavebeenonthemarketearlier,occupyingabsolutemarketadvantagesThe salesofstardrugEnhertuexceeded400millionUSdollars,rankingthird.Accordingtothe relevantestimationpublishedbyNature,Enhertusaleswillexceed6billionyuanin2026 tojumptothefirstplacebyvirtueofitsremarkableclinicalefficacyandrichindications

ProspectsForANewGenerationofADCDrugs

1.Findingnewtargetsandexpandingindicationshasbecomean importanttrend

Thecurrentglobalmarketeddrugsandresearchpipelinesaremainlyconcentratedon maturetargetssuchasHER2andCD22,andthecompetitionfortargethomogeneityis relativelyserious,especiallythelaunchoftheblockbusterdrugEnhertuTheresearch anddevelopmentofnewdrugshasbroughtgreatpressure,andthesearchfornew targetshasbecometheresearchanddevelopmentfocusofpharmaceuticalcompanies Atpresent,pipelinesofemergingtargetssuchasHER3,TIM1,andSEZ6haveemerged,

andtheindicationshavealsobeenexpandedtonon-smallcelllungcancer,kidneycancer, gastriccancer,ovariancancer,metastaticrectalcancer,andothertypesofcancer.

2.Bispecificantibody-drugconjugatesbecomeanewdirection ofexploration

Bispecificantibodiescansimultaneouslyrecognizetwoepitopesofatargetortwo differenttargets,andtheirclinicaleffectisbetterthanthatofmonoclonalantibodiesThe rapiddevelopmentofbispecificantibodytechnologyhasprovidedanewdirectionforthe developmentofADCdrugsDual-antibodyADCdrugshavethedualadvantagesof dual-antibodyandADCdrugs,whichmayeffectivelysolvetheproblemsoflow endocytosisefficiency,off-targettoxicityandsideeffectsanddrugresistancefacedby ADCdrugs.

3.Newdrugconjugates(XDC)havebroaddevelopmentspace

Withthecontinuousadvancementoftechnology,scientistsandR&Dcompanieshaveput forwardmoreideasbasedontheADCstructure,andhavedevelopedavarietyofnew conjugationtechnologyconcepts,includingpeptidedrugconjugates(PDC),small molecule-drugconjugates(SMDC),immune-stimulatingantibodyconjugate(ISAC), antibody-oligonucleotideconjugates(AOC),radionuclidedrugconjugates(RDC), antibodyfragment-drugconjugates(FDC),aptamerdrugconjugates(ApDC),antibodycell drugconjugates(ACC),etcTheindicationsofthesenewdrugsarenolongerlimitedto tumortreatment,buthavealsobeguntoexpandtoautoimmunediseases,bringinghope tomorepatients

Conclusion

Globally,avarietyofADCtherapieshavebeensuccessfullydeveloped,benefitingtensof thousandsofcancerpatientsTheapprovalof15ADCdrugsandtheexcellentclinical performanceofmultipleADCshavealsoattractedmoreattentiontothefield,whichisvery

importantforthisrelativelyyoungbuthighlycomplexfieldTheincreasingnumberofADC drugapprovalshasstimulatedtheenthusiasmofresearchersforADCresearchand developmentWiththeongoingeffortsofresearchersintheseareas,itishopedthatmore ADCdrugswithgreaterefficacyandfewersideeffectswillbeapprovedandmarketed, ultimatelyhavingatransformativeimpactonthetreatmentofcancerpatients

Relatedarticles:

[1]ADCDrugsGlobalSalesof2021andFutureProspects

[2]TheBystanderEffectofADCs

[3]9TypesofDrugConjugatesOverview:ADC,RDC,ISAC,SMDC,AOC

[4].Peptide-DrugConjugate(PDC)VSImmuneStimulatingAntibodyConjugate(ISAC)