Angewandte Chemie International Edition · 2016 · 77 citations · 23 references
PharmacyMedicinal ChemistryPharmaceuticsAntibody EngineeringDrug DeliveryDrug DiscoveryAntibody CharacterizationAntibody ConjugatesAntibody ConjugationAntibody Specificity EngineeringAntibody StabilityAntibody-drug ConjugatesAntibody-drug Conjugate AntibodiesAntibody-drug Conjugate LinkersAntibody-drug LinkersConjugate CharacterizationConjugation Chemistry For AntibodiesPhysiological Ph EffectsTargeted DeliveryTargeted Delivery Systems
A strategy for the conjugation of alcohol-containing payloads to antibodies has been developed and involves the methylene alkoxy carbamate (MAC) self-immolative unit. A series of MAC β-glucuronide model constructs were prepared to evaluate stability and enzymatic release, and the results demonstrated high stability at physiological pH in a substitution-dependent manner. All the MAC model compounds efficiently released alcohol drug surrogates under the action of β-glucuronidase. To assess the MAC technology for ADCs, the potent microtubule-disrupting agent auristatin E (AE) was incorporated through the norephedrine alcohol. Conjugation of the MAC β-glucuronide AE drug linker to the anti-CD30 antibody cAC10, and an IgG control antibody, gave potent and immunologically specific activities in vitro and in vivo. These studies validate the MAC self-immolative unit for alcohol-containing payloads within ADCs, a class that has not been widely exploited.
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Development of potent monoclonal antibody auristatin conjugates for cancer therapy
Svetlana O. Doronina, Brian E. Toki, Michael Torgov et al. · Nature Biotechnology · 2003 · 1.2K citations
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