Coibamide Analogue as a Novel-Class Payload for Antibody-Drug Conjugate

Although antibody-drug conjugates (ADCs) have made substantial
progress as targeted therapies, the range of suitable ADC payloads
remains limited. In this study, the highly N-methylated
cyclodepsipeptide [MeAla3-MeAla6]-coibamide (CA) was selected as a
novel toxin for ADC construction due to its potent toxicity and unique
mechanism of action. Using a quaternary ammonium salt approach, two
linker-payload variants, MC-VA-PAB-CA and MC-GGFG-PAB-CA, with distinct
cathepsin B (CTB)-cleavable linkers, were synthesized and assessed.
Among them, MC-GGFG-PAB-CA demonstrated higher enzyme-responsive cleavage
efficiency and superior plasma stability and was selected for conjugation
with the epidermal growth factor receptor (EGFR) antibody cetuximab
(Ctx), resulting in the formation of Ctx-CA. This conjugate exhibited
EGFR-dependent antitumor activity, a pronounced “bystander
killing effect”, and a significant tumor suppression effect
in mouse models. Furthermore, the applicability of this conjugation
strategy was confirmed through validation with the HER2 antibody.
These findings suggest that CA is a promising weapon for next-generation
ADCs.