IMGN853 Induces Autophagic Cell Death in Combination Therapy for Ovarian Cancer.

ABSTRACT: Antibodies targeting folate receptor 1 (FOLR1) induce autophagic cell death in addition to antibody-dependent cytotoxicity, but the biological relevance of anti-FOLR1 antibody–induced autophagy for clinical applications remains unclear. In this study, we investigated the role of autophagic cell death triggered by IMGN853 (mirvetuximab soravtansine), an FOLR1-targeted antibody–drug conjugate, and explored potential combinations of IMGN853 with chemotherapeutic drugs used for ovarian cancer treatment. We discovered that FOLR1 was predominantly expressed in epithelial ovarian cancer cells, with similar expression levels observed in both primary ovarian tumors and metastatic omental tumors from patients with high-grade serous ovarian cancer (HGSC). Treatment with IMGN853 improved survival in mice bearing patient-derived xenografts of HGSC, enhanced autophagic flux, and induced cell death in HGSC cells. Additionally, it increased expression of the autophagy-related marker LC3B-II and cell death as marked by cleaved caspase-3, in a manner dependent on beclin-1, in HGSC models. Notably, combinations of IMGN853 with topotecan or the anti–VEGF-A antibody (B20) significantly reduced tumor growth compared with IMGN853 alone, whereas no significant effect was observed with olaparib. Our findings indicate that IMGN853 induces autophagic cell death, which contributes to its tumor-inhibiting effects. The identification of these effective combination therapies and the mechanisms behind FOLR1-mediated autophagic cell death could facilitate further clinical development of IMGN853. SIGNIFICANCE: FOLR1 is heterogeneously overexpressed in epithelial ovarian cancer. We examined the combined effects of the anti-FOLR1 antibody-drug conjugate (IMGN853) with other drugs, including topotecan, anti-VEGF-A antibody, and olaparib. These findings could contribute to the continued development of IMGN853 in the treatment of ovarian cancer.