The human Mullerian inhibiting substance type II receptor as immunotherapy target for ovarian cancer. Validation using the mAb 12G4
Résumé
Ovarian cancer has the highest mortality rate among gynecologic malignancies. The monoclonal antibody 12G4 specifically recognizes the human Mullerian inhibiting substance type II receptor (MISRII) that is strongly expressed in human granulosa cell tumors (GCT) and in the majority of human epithelial ovarian cancers (EOC). To determine whether MISRII represents an attractive target for antibody-based tumor therapy, we first confirmed by immunohistochemistry with 12G4 its expression in all tested GCT samples (4/4) and all, but one, EOC human tissue specimens (13/14). We then demonstrated in vitro the internalization of 12G4 in MISRII(high)COV434 cells after binding to MISRII and its ability to increase the apoptosis rate (FACS, DNA fragmentation) in MISRII(high)COV434 (GCT) and MISRII(medium)NIH-OVCAR-3 (EOC) cells that express different levels of MISRII. A standard (51)Cr release assay showed that 12G4 mediates antibody-dependent cell-meditated cytotoxicity. Finally, in vivo assessment of 12G4 anti-tumor effects showed a significant reduction of tumor growth and an increase of the median survival time in mice xenografted with MISRII(high)COV434 or MISRII(medium)NIH-OVCAR-3 cells and treated with 12G4 in comparison to controls treated with an irrelevant antibody. Altogether, our data indicate that MISRII is a new promising target for the control of ovarian GCTs and EOCs. A humanized version of the 12G4 antibody, named 3C23K, is in development for the targeted therapy of MISRII-positive gynecologic cancers.
Mots clés
Cell Line
Tumor
Fluorescence
Microscopy
Animals
Female
Humans
inhibitors/*immunology/metabolism
Immunotherapy/methods
Transforming Growth Factor beta/antagonists &
Peptide/antagonists & inhibitors/*immunology/metabolism
Receptors
Ovarian Neoplasms/*immunology/metabolism/therapy
Glandular and Epithelial/immunology/metabolism/therapy
Neoplasms
Granulosa Cell Tumor/immunology/metabolism/therapy
Equipe
Original
Antibodies
Monoclonal/*immunology/therapeutic use
Antibody-Dependent Cell Cytotoxicity/drug effects/immunology
Apoptosis/drug effects/immunology
Xenograft Model Antitumor Assays
Nude
Mice
Immunohistochemistry
Domaines
Cancer| Origine | Fichiers éditeurs autorisés sur une archive ouverte |
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