ADC-PROTAC Conjugates: Novel Degrader-Antibody Conjugates (DAC)

ADC-PROTACConjugates:Novel Degrader-AntibodyConjugates(DAC)

Degraderantibodyconjugates(DACs)arenewentitiesthatcombineproteolysis targetingchimera(PROTAC)tomonoclonalantibodiesviasomekindofchemical linker.Althoughthisfieldisstillinitsinfancy,severaldifferenttypesofDACshave demonstratedmeaningfulinvitroandinvivobiologicalactivityinpreclinicalstudies

AdvantagesofDACs

Targetedproteindegraders,representedbyPROTACmolecules,areahottopicinthe fieldofnewdrugdevelopmentTakingPROTACmoleculesasanexample,these heterobifunctionalmoleculescanbindtotargetproteinsatoneendandtoE3ligasesat theotherend,directingthetargetproteinstotheproteasomeofthecellfordegradation However,duetothenatureoftheirchimeras,thephysicochemicalpropertiesofthese heterobifunctionaldegradersresultinpoordrugmetabolismandpharmacokinetic(DMPK) properties,suchasloworalbioavailabilityand/orrapidinvivoclearance.

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Figure1GeneralPROTACstructurePOI=proteinofinterestSource:Reference[1]

withmonoclonalantibodies.Antibodyconjugatetechnologyhasbeenclinicallyvalidated forthedeliveryofcytotoxicpayloadsDegraderantibodyconjugates(DACs)mayhave thefollowingadvantagesoverunconjugatedPROTACmolecules

AntibodyDrugConjugates(ADCs)Mechanism ofAction TraditionalADCconsistsofthreecomponents,amonoclonalantibodytargetingaspecific antigen,acytotoxicpayload,andachemicallinkerthatconnectsthetwoWhenan antibodytoanADCbindstoanantigenexpressedonthesurfaceofatumorcellortarget tissue,theADCisinternalizedandtransportedtothelysosome,wherethepayloadcanbe releasedbyavarietyofmechanisms,andthenthepayloadisreleasedfromthelysosome toexertitsbiologicaleffects

BiopharmaPEG https://wwwbiochempegcom Onestrategytoimprovetheinvivodeliveryofchimericdegradantsistoconjugatethem

 (1)Theabilityofmonoclonalantibodiestorecognizespecificantigensanddeliver degradermoleculestospecifictumorsortissues  (2)Enhancedinvivodeliveryofchimericdegradantswithpoorphysicochemicalor DMPKcharacteristics.  (3)Avoidanceofcomplexandnonstandardformulationswhichareoftenrequired toenableunconjugatedPROTACstoachievemeaningfulinvivoexposures

Currently,antibodyconjugationtechnologyhasundergonemultipleiterations,allowing

Degrader-antibodyconjugate(DAC)design

considerations WhilesomeofthestrategiesusedtomanufacturetraditionalADCscanbeusedto manufactureanddeliverDACs,thedesignofDACsoftenrequiresmorechallengesto overcome Forexample,thetoxicpayloadoftraditionalADCsisbroadlytoxictomanycells,whereas DACstypicallyexhibitmoretargetedbiologicalactivityassociatedwithspecificcancersor tissuetypesThus,anantigenselectedforDACgenerationmustbehighly expressedontumors,tissues,orothercellsthataresensitivetomodulationofthe biologicalpathwaytargetedbythedegrader

BiopharmaPEG https://wwwbiochempegcom Figure2DetailsofADCconstructionSource:Reference[1]

researcherstonotonlypreciselycontrolthedrugantibodyratio(DAR),butalsoto preciselylocatethesitewherethepayloadisconjugatedtotheantibodyby introducingunnaturalaminoacidsintotheantibody.

Chimericdegraderstypicallyexhibitlesspotencyininvitrodegradationthancytotoxic drugs,meaningthatmoredegraders(DARsover4)mayneedtobeconjugatedto eachmonoclonalantibodytoachievethedesiredpotency

Moreover,themolecularpropertiesofchimericdegradersmayresultinafinalDACthatis largerandmorelipophilicthantraditionalADCsThesedifferencesmayenhance molecularaggregationandaffectpharmacokineticsTheymayrequirenovelconjugation strategiesorlinkerdesigns

StrategiesfortheDesignofDegrader-antibody conjugate(DAC)

OneofthefirstDACspublishedinapeerreviewedscientificjournalisapotentDAC (GNE-987)thatusesacleavablelinkercontainingadisulfidebondtolinka BRD4-targeteddegradertoaCLL1-targetedmonoclonalantibody.Itconjugates6 degradantmolecules(DAR=6)on1monoclonalantibodybyaddingcysteinetothe specificpositionoftheantibody

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Figure3GNE987Structure,Source:Reference[1]

ThisDACexhibitedpotentdosedependentinvivoactivityinaxenograftmodelofacute myeloidleukemia(AML),whereasneitherantibodiestargetingCLL1nordeconjugated proteindegradersexhibitedinvivoactivityTheseresultsprovidethefirstproofof conceptthatDACcaneffectivelyaccomplishtargeteddeliveryandovercomethe poorpharmacokineticprofileofdegraders.

Insomecases,proteindegradermoleculesdonotcontaingroupssuitablefor conjugatingtomonoclonalantibodies,anditmaybenecessarytoaddgroupsto thedegradermoleculethatcangeneratecovalentbonds.Forexample,thefigure belowdepictstheintroductionofanamineoranilinechemicalgroup(bluecirclesinthe picture)intoaproteindegradermoleculetoprovideasiteforcovalentlinkerattachment Inthisexample,amineoranilinegroupsareintroducedintodifferentpositionsofthe chemicalstructureofthedegradermoleculeThesepositionsdonotleadtoadecreasein theactivityofthedegradermoleculeitself.Inthisexample,thegeneratedprotein degraderisconjugatedtoanantibodytargetingSTEAP1viaanenzymaticallycleavable peptidelinker

Figure4BRD4targetingDACs,enzymecleavablelinkersSource:Reference[1]

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DACsoptimizedtotargetSTEAP1basedonthisstrategyexhibitedlowertoxicitythan unconjugatedproteindegradersininvitroexperiments,indicatingthatthetherapeutic indexofchimericproteindegradersmaybeimprovedusingantibodyconjugation techniques. InadditiontotargetingBRD4fordegradation,DACshavealsobeenusedtodegrade estrogenreceptoralpha(ERα),TGFβR2,BRM,andothertargetsCurrentlypublished studiesshowthatPROTACmoleculesbasedondifferentE3ligasescanbe conjugatedtoantibodies,andresearchershavealsodevelopedavarietyoflinkers toconjugatethemtomonoclonalantibodiestargetingdifferentantigens.These DACstypicallyhaveahigherratioofdrugantibodies(DAR=6)comparedtomost traditionalADCs(DAR=2to4)

OutlookandConclusion

Currently,severalbiotechcompaniesarealreadyoptimizingthistechnologyandseeking todevelopinnovativetherapiesForexample,OrumTherapeuticsclosedan$84 millionSeriesBroundoffundinglastyeartodevelopadegraderantibodyconjugate (DAC).Atthisyear'sAACRAnnualMeeting,Orumpresentedpreclinicalresultsfor

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Figure5Summaryofdegraderantibodyconjugates(DACs)describedinthiswork Source:Reference[1]

ORM5029,whichconjugatesadegradertargetingthedegradationofGSPT1witha monoclonalantibodytargetingHER2andshowssimilaractivitytoEnhertuina HER2lowexpressionmodel

Figure6.ORM5029exhibitsinvivoactivityinaHER2lowexpressionmodel,source: OrumTherapeuticsofficialwebsite

AlthoughthefieldofDACsisstillintheearlystages,severalDACshavedemonstratedin vitroandinvivoactivity,demonstratingtheabilityofthistherapeuticmodalitytotarget proteindegradationpayloadstospecifictumorsorcellsBasedonthesepromising preliminaryresults,furtherdevelopmentandapplicationofDACsisexpected

However,challengesremainindeterminingwhichPROTACsaresuitableforconjugation, andhowthatconjugationtechnologycanbestpreserve,orevenenhancethebiological

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activityoftheselectedchimericdegradersFurtherproofofconceptforthistechnologyis expectedinmorestudieswithcloserassociationtodisease.

BiopharmaPEG,asaleadingPEGderivativesupplier,canprovidehighpurityPEG linkersinGMPornonGMPgradesforyourADC&PROTACresearchanddevelopment

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References:

[1]DragovichPSDegraderantibodyconjugatesChemSocRev2022May23;51(10):38863897doi: 101039/d2cs00141aPMID:35506708

[2]PillowTH,AdhikariP,BlakeRA,etalAntibodyConjugationofaChimericBETDegraderEnables invivoActivity.ChemMedChem.2020;15(1):1725.doi:10.1002/cmdc.201900497

[3]ManeiroMA,ForteN,ShchepinovaMM,etalAntibodyPROTACConjugatesEnable

HER2DependentTargetedProteinDegradationofBRD4ACSChemBiol2020;15(6):13061312 doi:101021/acschembio0c00285

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