SincetheFDAapprovedthefirstmonoclonalantibodyin1986,antibodydrugshave emergedinavarietyofinnovativeanddiverseforms,includingAntibodyDrugConjugates (ADCs),bispecificantibodies,nanobodies,andotherforms ADCsareknownasbiologicalmissiles,andtherearecurrently14drugsapproved worldwide.TheprimarymechanismofactionisinternalizationoftheADC,withthe releaseofthepayloadintothecytoplasmaftercleavageofthelinkerThismakestheADC drugsverydemandingintermsofthetargetstowhichtheantibodiesbind BispecificantibodieshavelongbeenhighlyanticipatedUnlikemonoclonalantibodies, bispecificantibodiescanrecognizetwoepitopesofatargetortwodifferenttargetsatthe sametime,thusproducingbetterefficacythroughmultipledifferentmolecular mechanisms.However,thedesignprinciplesrequireahighlevelofimmunological understanding,andthechallengesoflightandheavychainmismatches,lackofpurity, andlackofthermalstabilityatthemanufacturinglevelhaveresultedinfewapproved bispecificantibodiesTherearecurrentlyonlyfivebispecificantibodiesapproved worldwide. Therapiddevelopmentofbispecificantibody(BsAb)technologycontributestomore choicesofantibodiesasapartnerofADCsConjugatingpayloadintoBsAbtoimprove specificityandinternalization,calledbispecificADCs(BsADCs),hasbeenstudiedin recentyears,whichmaybeasolutiontotheexistingproblemsofendocytosis,toxicityand drugresistanceofADCdrugs
WhatAreTheFeaturesOfBispecificADCs?
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BispecificAntibodyDrugConjugates(ADCs): EmergingTrends
ThedualantiADCscurrentlyunderinvestigationcanbedividedintotwomain categories:bispecificADCstargetingdualtumorassociatedantigens(TAA)(e.g., MUC1/EGFRADC),andbispecificADCstargetingdualepitopes(eg, HER2/HER2-ADC) Tumorassociatedantigen(TAA)isanimportantclassofdruggabletargetsthatarehighly expressedspecificallyontumorcellsWiththerapiddevelopmentoflinkerandpayload technologies,significantprogresshasbeenmadeinthedevelopmentofTAA-based antibodycoupleddrugs(ADCs),with14ADCstargeting11TAAtargetsapprovedtodate BispecificADCdrugstargetingdualTAAareabrandnewformofescalatingontopofthe advantagesofADC (i)Twotargetscanenhancetumortargetingandreducethetoxicitytonormaltissues. (ii)CertaindualepitopebispecificADCsordualtargetbispecificADCscanproducebetter internalizationandenhancethekillingeffect (iii)Overcometheproblemofdrugresistancecausedbydecreasedsingletarget expression.However,whiledualtargetingbringsbetterefficacy,itmayalsohavethe problemofatoonarrowtherapeuticwindowEspeciallyinTAA,theexpressionofthis targetalsoexistsinnontumortissues,andthetoxicityofthetwocombinationstogether mayexceedthesimplesumofthetwo
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Fig1Schematicrepresentationoffragmentexpression,thesplitinteintranssplicing, anddrugconjugationprocessusedtogeneratereactivatedBsADC.Source:reference1 Intermsofglobaldrugdevelopment,theresearchanddevelopmentofthebispecificADC pipelinearestillinitsearlystageandtherearefewpreclinicalproductsindevelopment Therearethreemajorchallengesahead
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BispecificADCsUnderInvestigation M1231 M1231isanEGFR/MUC1bispecificADCdevelopedbySUTROthatusesthecompany's proprietaryfixedpointcouplingtechnologytoattachHemiasterlinderivativestospecific aminoacidsitesoftheantibodyviaacleavablelinkerwithaDARvalueofabout4.
•Secondly,mostofthecurrentantibodiesagainstthesemoleculesarescreened byblockingactivity,anditisnotyetknownwhethertheirendocytosisactivitymeetsthe demandandwhethertheycanbethebestcandidateantibodymoleculesforADCdrugs
•Fromtheperspectiveoftheproductionprocess,bispecificantibodyproduction suffersfromlowefficiencyduetomismatch,ontopofwhichthecouplingreactionis performed,furtherincreasingthedifficultyandchallengeoftheproductionprocess
•First,therearefewantibodybackbonemoleculesthatcanbeusedforbispecific antibodyconstruction,andthetargetsareveryconcentrated,withonlyafewtargetssuch asHER2,HER3,EGFR,MUC1,etc.Thereisalackofsufficient"backbone"fortherapid constructionofstablyexpressedbispecificADCmolecules
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Figure3StrongantitumoractivityinpatientderivedxenograftmodelsofM1231,source: reference[2] InJanuary2021,anopenlabel,nonrandomized,parallel,doseescalating, doseexpandingPhaseIclinicaltrial(NCT04695847)wasinitiatedintheUnitedStates andCanadatoevaluatethesafety,pharmacokinetics,tolerateddoseandclinicalefficacy ofM1231asasingleagentinthetreatmentofpatientswithadvancedsolidtumors (expectedn=84).
Figure2StructureofM1231,source:reference1
EMDSeronopresentedpreclinicaldataofM1231at2020AACRTheresultsshowedthat asingledoseofM1231exhibitedsometumorcurativeeffectinNSCLCandsqCC EsophagealPDXmodels,andtherewasacorrelationbetweentumorremissioneffectand targetexpression.
BiopharmaPEG https://wwwbiochempegcom ZW-49
Inpreclinicalstudies,ZW49hasshownexcellentdruggability.Accordingtodatafromthe company'spreclinicalanimalmodelstudypublishedin2020,ZW-49showedsuperior anticancereffectsinbothlowandhighHER2expressingbreastcancermodelsand showedsomeefficacyinaHER2highexpressingbreastcancerbrainmetastasismodel.
Figure4StructureofZW49,anditsadvantages,source:reference[3]
ZW49isabispecificADCdrugdevelopedbyZymeworksthatspecificallybindsboth nonoverlappingepitopesoftheHER2receptor(ECD4/trastuzumaband ECD2/pertuzumab)ThebispecificADCisbasedonZW25coupledtoAuristatintoxinA viaaproteasecleavagelinker.
Figure5.PreclinicalefficacyofZW49,source:Zymeworkswebsite
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REGN5093-M114
ComparedwiththemarketedTrastuzumabemtansine(Rocheanti-HER2-ADC,launched in2013)andTrastuzumabderuxtecan(AstraZenecaandDaiichiSankyoantiHER2ADC, launchedin2019),ZW49hasamoresuperiorperformanceinshrinkingtumorvolume andimprovingsurvivalrates InJanuary2021,ZymeworkspublishedselecteddatafromthePhaseIclinicaltrialof ZW49.TheresultsshowedthatZW49demonstratedantitumoractivityacrossall treatmentregimensanddoselevelsPartialremission(PR)andstabledisease(SD)were observedinbothQ2WandQ3WdosingregimensAndinall35patientstreatedwith ZW49,notreatmentrelatedhematotoxicity,pulmonarytoxicityandhepatotoxicitywere observed.Morethan90%oftheadversereactionsweremildormoderate.
REGN5093M114hasbeeninitiatedinPhaseI/IIclinicaltrial(NCT04982224)intheU.S. inJuly2021,withanexpectedcompletiondateofDecember2026.
REGN5093M114nakedantibodyitselfalsohassometumorsuppressiveeffectandhas demonstratedgoodefficacyinavarietyofpreclinicalmodelsInvariousanimaltumor models,REGN5093M114at10mg/kgcouldcompletelyinhibittumorcellsorevenclear them,whileMETxMETbispecificantibodywithouttoxincouplingcouldonlyinhibittumor growthatdosesupto25mg/kg,andcouldnotcleartumorcellsAndcomparedwiththe METADCdrugsalreadyintheclinic,thebispecificADCREGN5093M114couldnotonly inhibittumorgrowthbutevenremovetumorcellsatthesamedose(Figure7below),soits efficacyismuchbetterthantheADCsintheclinic
REGN5093M114isabispecificADCdevelopedbyRegenrontargetingtwodifferent epitopesofMET.Theantibodyisa1+1asymmetricbispecificantibodythatlinksthe antibodytothetoxinM24(maytansinederivative)throughtheM114linkerwithaDAR valueofabout32
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Figure6Structureofregn5093-m114
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Figure8StructureofBLB01D1 ADCdrugshavebeendevelopedoverseveraldecadesbeforetheyhavebeguntoshow resultsTheemergenceofbispecificADCsisanoutgrowthofthetrendtowardantibody engineeringandcouplingtechnologyAlthoughtherearestillafewprojectscarriedout
Figure7.METxMETM114comparesfavorablytoaclinicalstageMETADC.Source: reference[4] BL-B01D1 BLB01D1isanEGFR/HER3bispecificADCdevelopedbyBailiPharmaceuticals,which adoptsitsuniqueAClinkertolinkthecamptothecinderivativeED04tothecysteinesiteof theantibodywithaDARvalueofabout75Theresultsofthepreclinicalstudyshowed thatBLB01D1wasabletoexertgoodantitumoreffectsatanadministereddoseof10 mg/kgOnOctober19,2021,BailiPharma'sclinicaltrialapplicationforBLB01D1 receivedimpliedpermissionfromtheNMPAforthetreatmentofadvancedormetastatic epithelialtumors
4DaSilvaJO,YangK,SurrigaO,etalABiparatopicAntibodyDrugConjugatetoTreat METExpressingCancers,IncludingThosethatAreUnresponsivetoMETPathwayBlockadeMol CancerTher2021;20(10):19661976doi:101158/15357163MCT210009 RelatedArticles: DevelopmentofPDL1AntibodyDrugConjugates(ADC)
https://wwwmerckgroupcom/investors/eventsandpresentations/conferencesandroadshows/2021/en/ 211122RDUpdateCallFinalENpdf
BiopharmaPEG https://wwwbiochempegcom andfailureshaveoccurred,thisisjustthegeneralruleofdrugdevelopmentItisbelieved thattheconceptofbispecificantibodiescanprovidemoreideasinthecurrentcontextof multiplefactorsthatemphasizedifferentiationandtemporarytarget"depletion"
3https://wwwzymeworkscom/publications/1282018PRESENTATIONpdf
References: 1.Zong,HuiFang&Zhang,BaoHong&Zhu,Jianwei.(2022).GeneratingaBispecificAntibodyDrug ConjugateTargetingPRLRandHER2withImprovingtheInternalizationPharmaceuticalFronts04 e113e120101055/s00421749334
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BispecificAntibodiesCurrentStatusandProspects
EmergingMultipleMyelomaTherapies:mAbs,ADCs,CAR-TCells&Bispecific Antibodies RecentAdvancesInHematology2022:ADCs,BispecificAntibodies,CARTCells…
2R&Dupdatecall2021,MerckKgaA
GlobalAntibodydrugConjugates(ADCs):Approvals&ClinicalTrailsReview