Targeting Ly75 Antigen with MEN1309: A Promising ADC for Solid Tumor Therapy

The study introduces MEN1309, a humanized antibody drug conjugate (ADC) targeting the Lymphocyte antigen 75 (LY75), which is overexpressed in various tumor types. LY75, a C-type lectin receptor, is implicated in endocytosis and internalization, making it a suitable target for ADC therapy. MEN1309 is designed to attach to LY75 via an IgG1 antibody and is linked to the microtubule disruptor DM4 through a cleavable linker.

The research evaluated MEN1309's efficacy both in vitro and in vivo using xenograft and patient-derived xenograft (PDX) models. Immunohistochemistry (IHC) confirmed the presence of LY75 in cancers such as pancreatic, triple-negative breast, bladder, and diffuse large B-cell lymphoma. MEN1309 demonstrated potent cytotoxicity against multiple cancer cell lines, including those with varying levels of antigen expression.

In vivo studies revealed that MEN1309, administered at dosages of 2.5-5 mg/kg, induced significant antitumor effects and complete, durable responses in most tumor models tested. Importantly, the treatment did not cause weight loss or death in the animals. Comparative treatments with isotype control-DM4, non-conjugate antibody IgG1, and free DM4 showed minimal therapeutic effects.

In a PDX model of triple-negative breast cancer, MEN1309 resulted in complete tumor regression. In a pancreatic cancer xenograft model, the pharmacokinetics of MEN1309 were characterized, and its activity was correlated with a pharmacodynamic marker of DM4's effect on microtubules, showing an initial high exposure followed by a rapid decline and subsequent increase in cells showing mitotic arrest.

The findings suggest that MEN1309 is a selective and potent ADC with potential for treating various LY75-positive tumor types and warrants further investigation in Phase I clinical trials.