Abstract 2662: MGT-1141, an antibody-drug-conjugate targeting DLL3 positive cancers

Abstract Background: Delta-like ligand 3 (DLL3) is highly expressed on the cell surface of small cell lung cancer (SCLC) and neuroendocrine cancers (NECs)—among the most lethal malignancies—but is minimally or not expressed in normal tissues, making it an attractive target for DLL3-positive cancers. Here, we describe the preclinical activity of MGT-1141, an anti-DLL3 antibody-drug conjugate (ADC) that delivers a topoisomerase I inhibitor (exatecan) payload via Marigold’s proprietary linker platform. The IND-enabling study of MGT-1141 is currently ongoing. Methods: Comprehensive in vitro and in vivo evaluations were performed to characterize MGT-1141. Binding affinity, internalization, and cytotoxicity were examined across multiple DLL3-expressing cell lines. Anti-tumor efficacy was assessed in both cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Pharmacokinetic (PK) and pilot dose-range-finding (DRF) studies were conducted in cynomolgus monkeys to determine systemic exposure, half-life, and tolerability. Results: The MGT-1141 antibody exhibited high target specificity with no detectable cross-reactivity toward other Delta-like ligand family proteins. MGT-1141 demonstrated strong binding affinity and rapid internalization in DLL3-expressing cells. In vivo, MGT-1141 showed potent and dose-dependent tumor growth inhibition across multiple CDX and PDX models, with a minimal efficacious dose (MED) of 0.5 mg/kg. Pharmacokinetic studies in cynomolgus monkeys revealed linear, dose-proportional exposure and a favorable terminal half-life. Dose-range finding (DRF) studies indicated good tolerability and a wide therapeutic window. Conclusion: Preclinical evaluations of MGT-1141 have shown potent and selective anti-tumor activity, favorable pharmacokinetic properties, and a well-tolerated safety profile, supporting its further development toward clinical investigation. Collectively, these findings support MGT-1141 as a promising and potential best-in-class DLL3-targeting ADC for the treatment of SCLC and NECs. Citation Format: Mei-Hsuan Tsai, Maomao He, Su-Yu Tsai, Ju-Mei Li, Ping Chao, Ting-Chun Hung, Charng-Sheng Tsai. MGT-1141, an antibody-drug-conjugate targeting DLL3 positive cancers 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 2662.