241P Development and characterization of a novel DLL3-targeting antibody drug conjugate (ADC) for the treatment of solid tumors

DLL3, a type I transmembrane protein that serves as an inhibitor in the Notch pathway, is a validated target for direct therapy. It exhibits significant upregulation and abnormal expression on the cell surface in small cell lung cancer (SCLC) and other high-grade neuroendocrine tumors, promoting SCLC migration and invasion. ZL-1310, an innovative ADC targeting DLL3, was developed by leveraging the tumor microenvironment activable linker-payload (TMALIN) platform platform). This ADC comprises a humanized anti-DLL3 antibody, a linker susceptible to protease cleavage, and a novel camptothecin derivative as its payload. It achieves a high drug-to-antibody ratio (DAR 8) with homogeneously conjugated, hydrophilic linker-payload combinations. ZL-1310 demonstrated strong and specific binding to DLL3 from various species but not to other Delta family members. Its high affinity and specificity for DLL3 on the cell surface led to internalization, cell cycle arrest, and the induction of apoptosis in tumor cells. In vivo, ZL-1310 was well-tolerated and effectively suppressed the growth of established human tumors in a dose-dependent manner in both cancer cell-derived and SCLC patient sample-derived xenograft models. Additionally, the cytotoxic payload significantly accumulated in the tumors compared to mouse plasma. ZL-1310 exhibited a stable pharmacokinetic (PK) profile with overlapping ADC and total antibody (TAb) curves in both GLP rat and NHP pharmacology and toxicology studies. Importantly, the well-characterized nonclinical pharmacology, PK, and safety profile of ZL-1310 support its progression into clinical trials. ZL-1310, a high-affinity humanized IgG1 mAb specific for DLL3, is conjugated with a novel payload and developed for the treatment of SCLC and other DLL3+solid tumors. Zai Lab has completed IND-enabling studies and received FDA clearance of its IND application for evaluating ZL-1310 in subjects with small cell lung cancer.