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

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.