PeptideDrugConjugates(PDCs):Novel
TargetedTherapeuticsForCancer
Peptidesplaymultiplefunctionsintheprocessofhumanlife,suchasrepairing cells,improvingcellmetabolism,preventingcelldegeneration,etc.Peptides arebiologicallyactiveandhaveexcellenttargetedtransportcapabilitiesThis capabilityisapplicablenotonlytooncology,butalsototargetedtherapiesfor COVID-19,diabetes,rheumatism,andrheumatoidarthritis
Peptide-drugconjugates(PDCs)arethenextgenerationoftargeted therapeuticsafterADCs,andtheircoreadvantagesareenhancedcell permeabilityandimproveddrugselectivityPeptide-drugconjugates(PDCs)of comparablepotencyhavebroaderapplicationsthancurrentantibody-drug conjugates(ADCs)Inrecentyears,pharmaceuticalcompanieshavebeen developingPDCsastargetedtherapeuticcandidatesforcancer,COVID-19, metabolicdiseases,etc.
TargetedTherapyStrategies
Canceristhesecondleadingcauseofdeathworldwide.Dependingonthe patient'sstageandtumortype,thepatientisgivenoneormoreofthefollowing treatments:surgery,radiation,orchemotherapy.Drugtherapyhasdifferent levelsoftoxicityandsideeffects,andsomeserioussideeffectsarethedirect causeoflimitingdrugdosageoruse.Incancertherapy,threetargetedtherapy modalitiesareusedtoenhancethenonspecificandantitumoractivityof cancertherapy.First,targetedtherapeuticdrugscaninhibittheexpressionof theprotein,suchasproteinkinasesorenzymesAnotherapproachistofuse aneffectivemolecularstructure(suchasADC,toxinsmallmoleculeorCAR-T) toanoverexpressedproteinonthesurfaceoftumorcellsandsynergistically inhibittumorcelldivisionwhiledeliveringacytotoxicpayloadorstimulatinga tumor-directedimmuneresponseThethirdapproachistheapplicationofPDC, whichdrivestheaccumulationoftoxicpayloadsintumorcells
Thebiggestchallengefortransportingproteinsandpeptidesinthebodyis theirinstability.Considerationshouldbegiventomolecularsize,molecular charge,proteininternalstructure,solventeffects,lipidmembrane accumulationandhydration,stability,affinityforreceptors,etc.InADCs, specificmonoclonalantibodies(mAbs)thatexpressantigensoncancer cellscanbeusedtotransportcytotoxicsubstanceswhilereducingdamageto normalcells,resultinginbettertherapeuticoutcomesandenhanceddrug metabolism.However,mAbcancauseimmunogenicity.PDCsandADCsare similarinconceptbuthavedistinctstructuresand
HuatengPharma https://ushuatengscicom characteristics.Antibodieshavehigherspecificityandlongerhalf-life,while targetingpeptideshavebetterdrug-loadingabilityandtissuepenetrationability. Inaddition,multipurposelinearorcyclicpeptidesaremorepronetostructural changesThecomparisonbetweenPDCsandADCsisshowninTable1
GeneralConsiderationsForPDCAndItsClinicalTrials
Peptide-drugconjugate(PDC)isakindoftargetedtherapydrug,itsfunctionis similartothatofADC.PDCusedfortumortherapygenerallyconsistsof threecomponents:homingpeptide,linkerandpayload.Allthree componentscoordinatethedeliveryofchemotherapydrugsbytargeting receptorsontumorcellstoamplifytheirtherapeuticeffects
Table1ThecomparisonofPDCandADCHomingpeptidesareanimportantcomponentofPDC.Bicyclictoxinpeptides (BTPs),dendriticpeptides,andself-assemblyenhancingpeptideshavebeen demonstratedasdrugdeliverysystems.PDCshaveseveraladvantagessuch asdeepertumorpenetration,lessimmunogenicityandfasterrenalclearance ThedrugislinkedtoBTPtoensureconformationalstability.In2021,Bicycle Therapeutics(Nasdaq:BCYC)announcedthreeexperimentalBTC(Bicycle ToxinConjugate)drugs:BT1718,BT5528andBT8009.Allpatientsarein PhaseI/IIclinicaldevelopmentBT1718isanovelbicyclicpeptideanticancer drugthattargetsmembranetypeImatrixmetalloproteinasestoreleaseits toxicpayload,DM1BT5528showedpreliminaryantitumoractivityasadrug targetingEphA239.BT8009isaBTCtargetingNectin-4,whichhasshown excellentanti-tumoractivityinpreclinicalstudiesNectin-4isatypeI membraneproteinthatisoverexpressedinmosttumors,includingurothelial, breast,pancreaticandtriple-negativebreastcancer(TNBC),andcanaffect cellproliferation,differentiation,migrationandinvasion
InclinicaltrialsofPDCs,twotherapeuticPDCsarecurrentlyapprovedon themarket:177Lu-dotatate(lutathera)andmelflufen.ThefirstPDCdrug 177Lu-dotatateapprovedbytheU.S.FoodandDrugAdministration(FDA)is forthetreatmentofgastroenteropancreaticneuroendocrinetumors
HuatengPharma https://ushuatengscicom (GEP-NETs)Melflufenisindicatedfortheearlytreatmentofrefractory multiplemyeloma(MM)byrapidlyreleasingthealkylatingagentintothetumor viaaminopeptidaseinthecellHowever,inOctober2021,thecompany oncopeptidesABannounceditsdecisiontowithdrawmelflufenfromtheUS marketduetothefailureofaPhaseIIIclinicaltrialtosuccessfullyreducethe riskofdeathinpatientswithrelapsedrefractorymultiplemyeloma(HR=1104)
Table2PDCinclinicaltrials
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HomingPeptideinPDC
TheselectionofpeptidesaffectstheefficiencyofdrugendocytosisinPDCs Oncethetargethasbeenselected,itisalsoimportanttoselecttheappropriate peptideforPDC,whichhassignificanteffectsonefficacy, pharmacokinetic/pharmacodynamiccharacteristics,andtherapeuticindices TheidealpeptidesofPDCsshouldhavestrongtarget-bindingaffinity,high stability,lowimmunogenicity,highefficiencyinternalizationandlongplasma half-life.
Homingpeptidesarespecificallytargetedoverexpressedproteinreceptorsin tumortissuesItdirectlydeliverstheloadeddrugtotargetcells,limiting off-targetdeliveryofchemotherapydrugs.Thesehomingpeptideshavebeen previouslyreportedtohavehighbindingaffinitytotargetsitesatnanomolar concentrations.Todeterminetheirtarget-bindingaffinity,avarietyof techniquescanbeused,includingsurface-enhancedramanscattering(SERS), bio-layerinterferometry(BLI),isothermaltitrationcalorimetry(ITC),anddrug affinityresponsivetargetstability(DARTS)
Thesepeptidesarealsohydrophobic,amphiphilic,andfavorablefornegative chargesacrosscellmembranesCell-penetratingpeptidesnotonlydeliverthe
Figure2HomingPeptideandTargetBindingAffinityAssayTechnique (Imagesource:References[1])
HuatengPharma https://ushuatengscicom drugtothetargettissue,butalsoallowforcellularinternalizationPositively chargedCPPshavesomedisadvantages,suchasunstabletargetselectivity, leadingtonon-specificcellularuptakeTherefore,anionCPPsareoftenused inPDCtoimprovetumorcellspecificity
Peptidesareidealcarriermoleculesbecausetheyhavethesamecapabilities asmonoclonalantibodies.Theyhaveahighaffinityforoverexpressed receptorsonthesurfaceoftumorcells,withoutthedrawbacksofmAb However,thebindingofthepayloadtothepeptidemoleculeisparticularly criticalbecausethespatialstructureofthepayloadaffectsreceptorbinding andselectivity,thusinterferingwithreceptorrecognition.Therefore, understandingpeptidereceptorinteractionsisessentialforrationaldrug selection.
PharmacokineticsofPeptides
Whendesigningdrugs,itisimportanttostudypharmacokinetics(PK)and pharmacodynamics(PD)Peptidesandsmallmoleculeshavedifferent pharmacokineticcharacteristics.LikeADCs,peptidesarenoteasytotake orallyHowever,oraladministrationisoneofthemostconvenientmethods andpatientshavebettermedicationcompliance
Figure3Peptidepropertiesinvivoandinvitro (Imagesource:References[1])HuatengPharma
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Thehalf-lifeandinvivocirculationtimeofpeptidesareshorterthanthoseof biomacromolecules,andthefrequencyofadministrationisslightlyhigher, resultinginslowresearchonADCsandPDCsThehalf-lifeofhydrophilic peptidesisdeterminedbyseveralsolubleenzymesinbloodandcell membranes.Exopeptidaseisoneofthemostimportantsolubleenzymes.This isrelatedtothecatabolismofthepeptideandthechemicalinstabilityofthe plasma.
Rapidrenalclearanceandshorthalf-lifehindertheresearchofpeptidesinvivo andaffecttheirdruggabilityTheFDArecentlyapprovedtheoralpeptide N-[8-(2-hydroxybenzyl)alanine](SNAC)asanadjuncttoalbiglutideforthe treatmentoftype2diabetesSNACactsasabufferinthestomachand reducestheactivityofproteolyticenzymes.Althoughsemaglutidehasbeen approvedforusebytheFDA,oralpeptidesstillhavealongwaytogobefore clinicalapplication.
ThereareseveralwaystoimprovetheADMEpropertiesofpeptides,suchas increasingcellpermeability,enhancingchemicalstability,anti-proteolytic ability,andreducingrenalclearance,therebyprolongingtheinvivocirculatory half-lifeProlonginghalf-lifeisbeneficialforeconomicjustificationandpatient complianceBasedonthischaracteristic,PDCadministrationcanhaveawide rangeofdoseadjustment.
LinkersinPDC
TheselectionoflinkersisoneofthekeyfactorsinthedesignofPDC,andthe microenvironmentofPDCsneedstobeconsideredsoasnottointerferewith thebindingaffinityofpeptidestotheirreceptorsanddrugefficacy.Thetypesof linkersusedinPDCsvary,dependingontheirlength,stability,release mechanism,functionalgroup,hydrophilicity/hydrophobicity,andother characteristicsLinkersusedinPDCsmustexhibitstabilitytoprevent prematureandnonspecificdrugrelease.
Thelinkerneedstohaveacertainlevelofstability,sothatitcanensurethe integrityofthecirculationprocessbeforethePDCreachesthetumorcells, avoidingtheearlyreleaseoftoxindrugsandcausingoff-targettoxicity,which affectsthetherapeuticwindowofPDCAfterenteringthetargetcell,thelinker mustensuretheeffectivereleaseofthetoxindrugtoexertitskillingeffect Linkerscanbedividedintocleavablelinkersandnon-cleavablelinkers.A cleavablelinkercanbecleavedenzymaticallyorchemicallyNon-cleavable linkerscannotbeactivatedbyexternalstimuli.Whilecleavablelinkersare betterfordevelopingtargetedtherapeutics,non-cleavablelinkersaremore stableinmetaboliccyclesinvivo.Thechoiceofcleavableornon-cleavable
HuatengPharma https://ushuatengscicom linkerdependsonthedesignandmodeofactionofthetargetedtherapeutic drug.
(Imagesource:References[1])
DrugToxinsinPDC
DrugtoxinsareanintegralpartoftheprocessofkillingtumorsAfterPDCs enterthecells,drugtoxinsarethemaincauseofthefinaldeathofthetarget cellsTherefore,thetoxicityandphysicochemicalpropertiesofdrugtoxinscan directlyaffecttheabilityofdrugstokilltumors,thusaffectingitsefficacy. Conjugatedcytotoxinsmusthavethefollowingfourrequirements:clear mechanismofaction,smallmolecularweight,highcytotoxicity,andretention ofantitumoractivityafterchemicalconjugationwithpeptides
Eachdrugtoxinhasitslimitations,suchaspoorpharmacokineticproperties However,thedrug'snon-selectivityisthebiggestdisadvantage,causing serioussideeffectsThesepeptidesallowspecifictargeting,thusbroadening thetherapeuticfield.Duetotheattachmentofchemotherapydrugstopeptides, increaseddosesareoftenrequiredtoreducethecytotoxicdosereduction TherearemanycriteriafordeterminingthecytotoxicityofPDCs,suchasin vivocirculationstability,highefficiencyofdrugeffect,andthepresenceof linker-linkablesitesChemotherapeuticagentsinPDCincludedoxorubicin, paclitaxel,etc.Inaddition,italsoincludesradionuclides,suchas177Lu dotatate
StabilityofPDC
Similartopeptides,themajordisadvantagesofPDCarepoorcirculatory stabilityandrapidrenalclearancePDCshouldremainstableincirculationto
Figure4ThechemicalstructureofdifferentlinkersHuatengPharma https://ushuatengscicom preventpre-releasechemotherapyandsystemicexposureIthasbeen confirmedthatnanoparticlescanenhancethestabilityofPDC.Oneapproach toovercomethepoorcyclingstabilityistocombinePDCswithgold nanoparticles(AuNPs)Theoverallstabilitycanbeimprovedduetoits desirablephysicochemicalproperties,safety,relativeeaseofsynthesis,and longcirculatinghalf-lifeWhenPDCusedtotreatlymphomacellsinmicewas combinedwithPEG-coatedAuNPtogenerateselectivePEG-AuNP-PDC,the PDCcirculatinghalf-lifewasincreased90-foldNanoparticlesenhancethe stabilityofPDCsthroughabifunctionalapproach.Thedesignprincipleis basedonnear-infraredlightnon-invasiveanti-tumortherapyphotothermal therapy(PTT),andnanomaterial-enhancedPKpropertiesofPDCsisan ongoingresearcharea,makingPDCshavegreatpotentialforclinicaltrials
AdministrationRouteofPDC
PDCmustbeadministeredintravenously,similartoADCMoreresearchis neededonthedeliverysystemsofpeptidesandproteins.Recently,anovel methodfororaladministrationofpeptideshasbeenreportedintheliterature, usingthepeptideself-assemblymethodtopreparepectin dihydroartemisinin/hydroxymycinnanoparticles(PDC-H-NPs)Combining PDC-H-NPswithpro-pectinandanticancerdrugsdihydroartemisininor hydroxycamptothecincanincreasedrugloading,improvewatersolubility,and achievedrugrelease(Figure5)However,therouteofadministration,particle size,pharmacokineticproperties,immuneclearance,etc.hindertheclinical applicationofnanomedicineTherearealsoliteraturereportsusinglipid nanoparticlesandcell-producedexosomesasdrugdeliverysystems.Inthe future,oraladministrationmaybeanewstrategyforusingPDCdrug candidatesinclinicaltrials.
Figure5.Thepropertiesofthepeptideinvivoandinvitro (Imagesource:References[1])Conclusion
PDCisacombinationofpeptideandchemotherapeuticdrug,combining theselectivityofpeptidewiththelethalityofchemotherapeuticdrugBy modifyingtheaminoacidsequenceofthepolypeptide,PDCcanchangethe hydrophobicandionizingpropertiesoftheconjugate,whichsolvesthe problemsofpoorwatersolubilityandfastmetabolism.Comparedwithsmall moleculesandbiologics,peptidesarerarelyusedclinicallyHowever,they exhibitexcellentversatility.PDCdrugscanenhancethepermeabilityoftumor cells,reduceimmunogenicityandreducedevelopmentcosts
PDC,asanemergingresearchfieldinthefightagainstcancer,hasits advantagescomparedwithADC,buttherearestillmanydifficultiestobe overcome.Fortunately,basedonADC'sexperience,theremaybesome shortcutsandfewerdetoursinPDCresearch.Atthesametime,withthe innovationoftechnology,PDCresearchwillgraduallybeclinicallyverified, therebypromotingthedevelopmentofthisfieldandbringingmoreoptionsfor treatment
HuatengPharmaisaleadingandprofessionalmanufacturerwhichcan providePEGlinkersfortheR&DofPDCsWearecommittedtopromotingthe progressofyourPDCdiscoveryanddevelopmentprojects.Weofferthefull rangeofPEGderivativedevelopmentservicesandprovidethemost comprehensivemediaforconjugationresearch.
References:
[1]FuC,YuL,MiaoY,LiuX,YuZ,WeiMPeptide-drugconjugates(PDCs):anovel trendofresearchanddevelopmentontargetedtherapy,hypeorhope?ActaPharmSinB. 2023Feb;13(2):498-516doi:101016/japsb202207020Epub2022Aug3PMID: 36873165;PMCID:PMC9978859.
[2]LindbergJ,NilvebrantJ,NygrenPA˚,LehmannFProgressandfuturedirectionswith peptideedrugconjugatesfortargetedcancertherapy.Molecules2021;26:6042.
[3]SiegelRL,MillerKD,FuchsH,JemalACancerstatistics,2022CAACancerJClin 2022;72:7e33.
https://pubmedncbinlmnihgov/36614268/
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