Abstract Background: Ly6E, a glycosylphosphatidylinositol (GPI)-anchored protein, is involved in fetal-placenta fusion, immune regulation, and virus-host interaction. It promotes tumor growth, vascularization, and immune evasion. Ly6E is highly expressed across several tumor types including breast cancer, non-small cell lung cancer (NSCLC), ovarian, pancreatic, gastric, and head and neck cancers, and its expression is reported to be correlated with poor survival. M7437 is a novel, highly stable anti-Ly6E ADC with a potent TOP1i payload (exatecan) site-specifically conjugated via an enzyme-cleavable linker. Methods: The binding of M7437 to cancer cells was assessed using flow cytometry. M7437 potency and bystander effect were tested in viability assays using cancer cell lines. Antitumor activity was evaluated in patient-derived xenograft (PDX) mouse models. In a GLP repeat-dose toxicity study, cynomolgus monkeys were treated 3 times in a Q3W schedule with M7437. Results: M7437 demonstrated specific binding to and selective killing of Ly6E-positive cancer cells with sub-nanomolar potencies. A potent bystander effect of M7437 was demonstrated in co-culture experiments. Treatment with 7-9 mg/kg M7437 caused strong and long-lasting antitumor activity in PDX models across several indications (triple-negative breast cancer, squamous cell carcinoma of the head and neck, NSCLC, ovarian, pancreatic, and gastric cancer), including models where published TOP1i ADCs showed limited activity. In a pivotal repeat-dose toxicity study in cynomolgus monkeys, the pharmacologically relevant species, M7437 was well-tolerated. M7437 demonstrated favorable pharmacokinetic properties and linker-payload stability in cynomolgus monkey. Conclusions: M7437 demonstrated strong antitumor activity in PDX models, including a broad range of indications and a potent bystander effect indicating the potential to treat tumors with heterogeneous target expression. Together with an acceptable toxicity profile and favorable pharmacokinetic properties, the observed preclinical data support the clinical development of M7437. Citation Format: Simon Krah, Felix Hart, Jan Anderl, David Huels, Christine Knuehl, Susanne Brandstetter, Joao N. Pereira, Stanley Sweeney-Lasch, Nicolas Rasche, Stephan Dickgiesser, Julia Jabs, Richard Schneider, Christiane Amendt, J. Christoph Vahl, Paul D. Lyne. M7437, a novel anti-Ly6E antibody-drug conjugate (ADC) with topoisomerase 1 (TOP1) inhibitor payload: Preclinical antitumor activity and safety 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 1322.
Krah et al. (Fri,) studied this question.