Abstract 4776: Preclinical study of bispecific antibody drug conjugates (bsADCs) targeting DLL3 and SEZ6 demonstrated potent anti-tumor activity in small cell lung cancer (SCLC) xenograft models

Abstract 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. Citation Format: Ting Yi, Liu Yang, Kunying Hao, Wenpeng Cao, Yu Qi, Jushi Gai, Luheng Du, Gao An, Chengzhang Shang, Yi Yang, Frank An. Preclinical study of bispecific antibody drug conjugates (bsADCs) targeting DLL3 and SEZ6 demonstrated potent anti-tumor activity in small cell lung cancer (SCLC) xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4776.