IAR025, a novel anti-DLL3 x CD3-bispecific antibody, displays high antitumor efficacy in preclinical models of small-cell lung cancer.

Small-cell lung cancer (SCLC) is one of the most aggressive subtype of lung carcinoma with limited treatment options. Delta-like ligand 3 (DLL3), a Notch ligand protein, has been an attractive target for SCLC due to its high expression on SCLC but limited expression on normal tissues. Here, we developed a bispecific T cell engager, IAR025, and investigated its antitumor efficacy against SCLC. IAR025 has a CD3 arm for T cell activation and a DLL3 arm for recognizing tumor cells with optimal affinity and binding domain. IAR025 resulted in a dose-dependent eradication of DLL3-positive SCLC cells, without nonspecific cell destruction in DLL3-negative cells in vitro. Administration of IAR025 in DMS79 and SHP-77 humanized mouse models significantly inhibited tumor growth. The mechanism study revealed that IAR025 treatment led to increased T-cell recruitment in tumors. IAR025 activity was further enhanced when combined with chemotherapy or anti-PD-1 treatment. In cynomolgus monkeys, IAR025 was well-tolerated at a dose up to 10 mg/kg and exhibited linear pharmacokinetics with a half-life of 90 h. Collectively, these preclinical results demonstrate that IAR025 is a highly potent therapeutic strategy for treating SCLC.