SDP-LIV1, a Novel and Optimized LIV-1 Antibody–Drug Conjugate Demonstrating Superior Antitumor Efficacy and a Favorable Safety Profile for the Treatment of Solid Tumors

LIV-1 is a transmembrane protein belonging to the zinc transporter family and represents a promising target for antibody-drug conjugate (ADC) therapy because of its broad expression in tumors and limited normal tissue expression. Ladiratuzumab vedotin (SGN-LIV1A), a LIV-1-targeting ADC with a payload of monomethyl auristatin E, has been discontinued from clinical development. The preliminary clinical results demonstrated promising efficacy in triple-negative breast cancer but no response in hormone receptor-positive/HER2-negative breast cancer, along with typical monomethyl auristatin E-related adverse events. In this study, we demonstrated a novel LIV-1-directed ADC, SDP-LIV1, consisting of an in-house developed anti-LIV-1 antibody conjugated to a proprietary topoisomerase I inhibitor via a cleavable glycine-glycine-phenylalanine-glycine linker, with an optimized average drug-to-antibody ratio of 6. Preclinical studies revealed that SDP-LIV1 showed promising in vitro and in vivo efficacy in breast and gastric cancers with favorable preclinical pharmacokinetics and safety profiles, suggesting that SDP-LIV1 has great potential for the clinical treatment of patients with solid tumors expressing LIV-1.