Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha-Targeting Antibody-Drug Conjugate, Potentiates the Activity of Standard of Care Therapeutics in Ovarian Cancer Models
Autor: | Jan Pinkas, Jenny Lee, Jennifer A. Coccia, Yinghui Zhou, Laura M. Bartle, Jose F. Ponte, Rodrigo Ruiz-Soto, Olga Ab, Marian Themeles, Leanne Lanieri |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Cancer Research Immunoconjugates endocrine system diseases Pharmacology Carboplatin chemistry.chemical_compound Mice 0302 clinical medicine Ovarian Neoplasms Neovascularization Pathologic Cell Cycle Drug Synergism FRα folate receptor alpha Cell cycle female genital diseases and pregnancy complications Bevacizumab 030220 oncology & carcinogenesis CR complete response Female medicine.drug Folate Receptor Alpha Antibody-drug conjugate Original article Antineoplastic Agents Antibodies Monoclonal Humanized ADC antibody-drug conjugate 03 medical and health sciences In vivo Cell Line Tumor medicine Animals Humans PLD pegylated liposomal doxorubicin Doxorubicin Folate Receptor 1 Maytansine EOC epithelial ovarian cancer Platinum business.industry CI combination index medicine.disease Xenograft Model Antitumor Assays Disease Models Animal 030104 developmental biology chemistry Drug Resistance Neoplasm Ovarian cancer business |
Zdroj: | Neoplasia (New York, N.Y.) |
ISSN: | 1476-5586 |
Popis: | Elevated folate receptor alpha (FRα) expression is characteristic of epithelial ovarian cancer (EOC), thus establishing this receptor as a candidate target for the development of novel therapeutics to treat this disease. Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate (ADC) that targets FRα for tumor-directed delivery of the maytansinoid DM4, a potent agent that induces mitotic arrest by suppressing microtubule dynamics. Here, combinations of IMGN853 with approved therapeutics were evaluated in preclinical models of EOC. Combinations of IMGN853 with carboplatin or doxorubicin resulted in synergistic antiproliferative effects in the IGROV-1 ovarian cancer cell line in vitro. IMGN853 potentiated the cytotoxic activity of carboplatin via growth arrest and augmented DNA damage; cell cycle perturbations were also observed in cells treated with the IMGN853/doxorubicin combination. These benefits translated into improved antitumor activity in patient-derived xenograft models in vivo in both the platinum-sensitive (IMGN853/carboplatin) and platinum-resistant (IMGN853/pegylated liposomal doxorubicin) settings. IMGN853 co-treatment also improved the in vivo efficacy of bevacizumab in platinum-resistant EOC models, with combination regimens causing significant regressions and complete responses in the majority of tumor-bearing mice. Histological analysis of OV-90 ovarian xenograft tumors revealed that concurrent administration of IMGN853 and bevacizumab caused rapid disruption of tumor microvasculature and extensive necrosis, underscoring the superior bioactivity profile of the combination regimen. Overall, these demonstrations of combinatorial benefit conferred by the addition of the first FRα-targeting ADC to established therapies provide a compelling framework for the potential application of IMGN853 in the treatment of patients with advanced ovarian cancer. |
Databáze: | OpenAIRE |
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