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
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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