Lung cancer is the most common type of cancers and the leading cause of cancer-related mortality worldwide with 2.5 million new cases and 1.8 million deaths in 2022. Small-cell lung cancer (SCLC) accounts for ~15% of all lung tumors, representing the most aggressive high-grade neuroendocrine carcinoma with a five-year survival rate less than 4%. Majority of patients are diagnosed with extensive stage SCLC (ES-SCLC) with brain metastases identified in ~80% of cases and the prognosis is dismal with 5-year survival under 2%. Patients often relapse from front line therapies and current treatments in the second-line setting are very limited.

Delta-like ligand 3 (DLL3) expression is highly restricted to SCLC, neuroendocrine tumors, and glioblastoma with minimally or no expression in normal tissues, making it a very specific and attractive tumor associated target (TAA) for SCLC. Like DLL3, seizure-related homolog protein 6 (SEZ6) is also expressed in SCLC, neuroendocrine tumors, and glioblastoma. Tarlatamab, a T cell engager targeting DLL3, was recently approved for SCLC. ADCs targeting DLL3 have shown robust anti-tumor activities in clinical trials. Similarly, anti-SEZ6 ADCs have also shown promising clinical activities.

We constructed a bispecific ADC (bsADC) that targets both DLL3 and SEZ6 (DLL3xSEZ6) for SCLC and other tumor types where both DLL3 and SEZ6 are co-expressed. We hypothesized that dual targeting of these clinically validated targets would provide more selective and more potent anti-tumor activity, help overcome tumor heterogeneity in tumoral DLL3 and SEZ6 expression levels and allow a broader patient population for treatment. The bispecific antibody (bsAb) moiety of the bsADC was 1+1 format and was conjugated to a novel TOP1 inhibitor payload with potent bystander effect (DAR 8) and a highly hydrophilic, enzyme-cleavable linker. In vitro, the bsAb showed robust internalization capability in multiple double positive SCLC cell lines. In vivo, the bsADC exhibited robust anti-tumor efficacy in SCLC xenograft models. In summary, our DLL3xSEZ6 bsADC showed promising in vitro and in vivo preclinical activities with first-in-class potential for treatment of SCLC.