MCE 抗体药物偶联物 (ADC) Antibody-Drug Conjugates (ADCs).docx

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MedChemExpress

Antibody-DrugConjugates(ADCs)Handbook

ToimprovetheSpecificityofBioactiveMoleculestoTumorCells

MCE

MasterofBioactiveMolecules

Antibody-DrugConjugates(ADCs)

Antibody-DrugConjugate(ADC)isapotentbiopharmaceuticalcancer-targeteddrugscomprisedofahumanizedorhumanmonoclonalantibodyconjugatedwithcytotoxicdrugs(payloads)viaachemicallinker[1].

ADCsexhibithighselectivityandtoxicitytothetumor,andbecomeoneofthefastest-growingclassesoftherapeutics.TheADCsaremulticomponentmolecules.Theselectionoftargetantigen,antibody,payload,linker,andconjugationstrategiesisofvitalimportanceinthedesignofADCs.

Exceptforspecificantigensandantibodies,linkersandpayloadsarealsoveryimportantfactorsfortheefficacyofADCs.

ADCCytotoxin

Destroyscancercells

ADCLinker

Joinsantibodyanddrug

Antibody

Targetscancercells

Figure1.SchematicstructureofADCs.

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Inhibitors ? ScreeningLibraries ? Proteins

ADCsExpandtheTherapeuticWindow

ADCscanincreaseefficacyandreducethetoxicityofpayloadscomparedwithtraditionalcytotoxicdrugs.Theselectivedeliveryofcytotoxicdrugstotumorcellsincreasesthepercentageofcytotoxicmoleculesthatreachthetumor,thusbroadeningthetherapeuticwindow.Nevertheless,thetherapeuticwindowremainednarrowforsecond-generationADCs.Thisisduetooff-targettoxicity,competitionwithunconjugatedantibodiesandaggregationorfastclearance.

Withthecomingofnewtechnology,thediscoveryofthepayloads,theoptimizationoftheantibody,thelinkerandconjugationchemistryplaysakeyroleinimprovingthetherapeuticwindowofthird-generationADCs[2].

Chemotherapies Second-generationADCs Third-generationADCs

Drugdose

Maximumtolerateddose

Minimumeffectivedose

TherapeuticWindow

Maximumtolerateddose

MMAEorMMAF;DM1orDM4

ConjugatedvialysineonmAb

Reducedhingecysteineconjugation

Minimumeff