SDP-LIV1, a Novel and Optimized LIV-1 Antibody-drug Conjugate Demonstrating Superior Anti-Tumor Efficacy and Favorable Safety Profile for Treatment of Solid Tumors.

Abstract

LIV-1 is a transmembrane protein belonging to the zinc transporter family and a promising target for antibody-drug conjugate therapy due to its broad expression in tumors and limited normal tissue expression. Ladiratuzumab vedotin (SGN-LIV1A), a LIV-1 targeting ADC with 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/human epidermal growth factor receptor 2 negative breast cancer, and typical monomethyl auristatin E-related adverse events were observed. Here, 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 GGFG (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 tumor expressing LIV-1.