MGT-1142, an antibody-drug conjugate targeting a novel glycan for small-cell lung cancer

Background: Aberrant glycosylation is a hallmark of many malignancies, driving tumor growth, immune evasion, and metastasis. Certain tumor-associated glycans are highly expressed in small-cell lung cancer (SCLC) but minimally present in normal tissues, making them attractive yet underexplored targets for antibody-drug conjugates (ADCs). MGT-1142 is an exatecan-based ADC engineered with an optimized Fc domain to recognize a tumor-specific glycosylation pattern and selectively deliver a potent topoisomerase I inhibitor payload. Methods: Comprehensive in vitro and in vivo evaluations were performed to characterize MGT-1142. Binding affinity, internalization, and cytotoxicity were examined across multiple SCLC cell lines. Anti-tumor efficacy was assessed in both cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Pharmacokinetic (PK) and dose-range-finding (DRF) studies were conducted in cynomolgus monkeys to determine systemic exposure, half-life, and tolerability. Results: MGT-1142 exhibited high target specificity with no detectable cross-reactivity to structurally related glycans. It demonstrated strong binding and rapid internalization in glycan-positive cells, resulting in potent inhibition of antigen-positive tumor cell proliferation. In vivo, MGT-1142 achieved dose-dependent tumor growth inhibition across multiple CDX and PDX models. Cynomolgus PK studies revealed linear, dose-proportional exposure and a favorable terminal half-life. Dose range finding studies indicated good tolerability and a wide therapeutic window. Conclusions: MGT-1142 shows potent and selective anti-tumor activity, favorable pharmacokinetics, and an encouraging safety profile in preclinical studies. These findings support MGT-1142 as a potential first-in-class glycan-targeting ADC for the treatment of small-cell lung cancer.