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Calicheamicin in Antibody-Drug Conjugates: Experim
Calicheamicin in Antibody-Drug Conjugates: Experim
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mindyhausler
10 posts
Dec 11, 2025
5:54 PM
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Calicheamicin, an enediyne antibiotic with extreme cytotoxicity, is a validated payload in antibody-drug conjugates (ADCs). The preclinical evaluation of ABBV-011, an SEZ6-targeted calicheamicin ADC, focused on experimental characterization of catabolic stability. Researchers employed in vitro plasma incubation assays combined with HPLC-MS analytical profiling to identify circulating metabolites and catabolites. Comparative metabolic studies against gemtuzumab ozogamicin and inotuzumab ozogamicin revealed a novel liability: disulfide bond cleavage in the N-acetyl-?-calicheamicin payload, compromising linker stability. This was further supported by in vivo pharmacokinetic experiments, which confirmed similar degradation pathways. These experimental insights emphasize the importance of systematic catabolic pathway analysis to optimize linker design and predict ADC performance. ABBV-011 exemplifies how targeted metabolism studies of calicheamicin conjugates inform rational ADC development.
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