Homocamptothecin Payloads with Enhanced Potency for Antibody-Drug Conjugates

Abstract Camptothecin derivatives, exemplified by DXd, are a dominant class of payloads for antibody-drug conjugates (ADCs). Herein, we describe the design and synthesis of H2, a novel homocamptothecin featuring a simplified hydroxybutyl structure that circumvents the complex assembly of the F-ring. H2 exhibits superior hydrolytic stability, while maintaining potent intrinsic cytotoxicity. In vitro, the H2-conjugated ADC candidates, Tras-L-H2 and Tras-TL-H2, demonstrated robust bystander killing effect and potent antiproliferative activity, similar to that observed with T-DXd. Importantly, these candidates exhibited noninferior antitumor efficacy to that of T-DXd in JIMT-1 xenograft model. These findings demonstrate the therapeutic utility of the seven-membered homocamptothecin scaffold and identify H2 as a promising candidate for next-generation ADC payloads.