IMGN853 Induces Autophagic Cell Death in Combination Therapy for Ovarian Cancer
Anca Chelariu-Raicu1,2,3, Thanh Chung Vu1, Sujanitha Umamaheswaran1,4
1Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Research Communications
|March 3, 2025
Summary
The antibody-drug conjugate IMGN853 triggers autophagic cell death in ovarian cancer cells, improving survival. Combinations with topotecan or anti-VEGF-A antibody show enhanced tumor reduction, supporting further clinical development.
Area of Science:
- Oncology
- Cell Biology
- Immunotherapy
Background:
- Folate receptor 1 (FOLR1) is overexpressed in epithelial ovarian cancer.
- Antibodies targeting FOLR1 can induce autophagic cell death, but clinical relevance is unclear.
- IMGN853 (mirvetuximab soravtansine) is an FOLR1-targeted antibody-drug conjugate.
Purpose of the Study:
- Investigate the role of autophagic cell death induced by IMGN853 in ovarian cancer.
- Explore combinations of IMGN853 with existing chemotherapeutic drugs for ovarian cancer treatment.
Main Methods:
- Assessed FOLR1 expression in ovarian tumors.
- Treated mice bearing patient-derived high-grade serous ovarian cancer (HGSC) xenografts with IMGN853.
- Evaluated autophagic flux, cell death markers (LC3B-II, cleaved caspase-3), and beclin-1 dependency.
- Tested combinations of IMGN853 with topotecan, anti-VEGF-A antibody (B20), and olaparib.
Main Results:
- FOLR1 expression was predominant in epithelial ovarian cancer cells, including metastatic sites.
- IMGN853 treatment improved survival in HGSC xenografts, enhanced autophagic flux, and induced cell death.
- IMGN853 increased LC3B-II and cleaved caspase-3 expression, dependent on beclin-1.
- Combinations of IMGN853 with topotecan or anti-VEGF-A antibody significantly reduced tumor growth compared to IMGN853 alone.
Conclusions:
- IMGN853 induces autophagic cell death, contributing to its anti-tumor effects in ovarian cancer.
- Effective combination therapies include IMGN853 with topotecan or anti-VEGF-A antibody.
- Understanding FOLR1-mediated autophagy mechanisms can advance IMGN853's clinical development.
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