Abstract Background: Delta-like ligand 3 (DLL3) is a single transmembrane protein that is a member of the Notch ligand family and an inhibitor of the Notch signaling pathway involved in cell signaling. DLL3 has low cytoplasmic expression in normal tissue but is selectively overexpressed and trafficked to the membrane in small cell lung cancer (SCLC) as well as some other neuroendocrine cancers, where its expression is correlated with aggressive disease. XB773 is an antibody-drug conjugate comprising a humanized VHH Fc antibody with high affinity for DLL3 that is conjugated to a topoisomerase 1 inhibitor using site-specific AJICAP® technology. Here, we describe the preclinical characterization of XB773, including its in vitro cytotoxicity and internalization and in vivo efficacy in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Methods: In vitro cytotoxicity, internalization, and bystander activity of XB773 were evaluated in DLL3-overexpressing cell lines using luminescence and fluorescence assays. In vivo tumor growth inhibition was evaluated in the SHP77 CDX model of SCLC and the NCI-H660 model of neuroendocrine prostate cancer (NEPC) using 1, 3, and 6 mg/kg dose levels in a single or repeat dose schedule. Tumor growth inhibition was additionally assessed in a PDX model of SCLC at 5 and 10 mg/kg (single dose). Results: XB773 displayed in vitro cytotoxic activity at nanomolar concentrations and demonstrated internalization properties. Bystander effect was illustrated through the cytotoxic activity of XB773 against non-DLL3-expressing Jurkat cells when cocultured with DLL3-overexpressing cells compared with monoculture where no cytotoxicity was observed. In vivo, XB773 demonstrated significant dose-dependent antitumor activity in PDX and CDX models of SCLC as well as in a model of NEPC expressing DLL3. Tumor regression was observed in the SHP77 model. Conclusions: XB773 demonstrated target-mediated tumor cell cytotoxicity and in vivo efficacy across several xenograft cell lines and PDX models of SCLC and neuroendocrine cancers. Taken together, these preclinical results support further development of XB773. Investigational New Drug-enabling studies are ongoing. Citation Format: Marlene Hennessy, Ganapathy Sarma, Yutaka Matsuda, Jenny Chang, Suprit Deol, Zhenzhen Mo, Yan Hu, Maoyin Li, Rajesh Kumar, Hui Zhao, Brian A. Mendelsohn, Minjong Park, Summer Park, Janice Kim, Ragadeepthi Tunduguru, Kathleen R. Gogas, Seema Kantak, . Preclinical characterization of XB773, a novel anti-DLL3 antibody-drug conjugate abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1661.
Hennessy et al. (2026) studied this question.