Preclinical Characterization of Catabolic Pathways and Metabolism of ABBV-011, a Novel Calicheamicin-Based SEZ6 Targeting Antibody Drug Conjugate.

Antibody-drug conjugates (ADC) have gained momentum for treatment of cancers, with 14 ADCs currently approved for commercial use worldwide. (Fu, Li, Han, Shi, & Zhang, 2022) Calicheamicin is one of the payloads contributing to this trend, being utilized for both gemtuzumab ozogamicin (GO, trade name: Mylotarg) and inotuzumab ozogamicin (IO, trade name: Besponsa). Here, we discuss the catabolic pathway and metabolism of ABBV-011, a novel SEZ6-targeted, calicheamicin-based ADC being investigated for the treatment of small cell lung cancer (SCLC). Specifically, our investigation has found that disulfide bond cleavage in calicheamicin payload is a key liability that potentially impacts overall stability of the ADC. To our knowledge, there have been no reported observations of disulfide bond cleavage of calicheamicin ADCs. ABBV-011 utilizes a novel linker structure, leading to a distinct metabolic profile when compared to GO and IO. Despite this difference in linker structures, we propose that this liability may also be relevant for other calicheamicin ADCs. Multiple data sets supporting our investigation were acquired as part of the preclinical development of ABBV-011 and demonstrate the utility of in vitro experiments to characterize potential ADC candidates prior to clinical trials.

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