The human Mullerian inhibiting substance type II receptor as immunotherapy target for ovarian cancer. Validation using the mAb 12G4

Nathalie Kersual (1) , Véronique Garambois , Thierry Chardès (1) , Jean-Pierre Pouget (1) , Imed Salhi (1) , Caroline Bascoul-Mollevi (2) , Fédéric Bibeau (1) , Muriel Busson (1) , H. Vié (3) , B. Clemenceau (3) , C. K. Behrens (4) , Pauline Estupina (1) , Andre Pelegrin (1) , Isabelle Navarro-Teulon (1)

1 IRCM - U896 Inserm - UM1 - Institut de recherche en cancérologie de Montpellier
2 CRLC Val d'Aurelle-Paul Lamarque
3 CRCNA - Centre de Recherche en Cancérologie Nantes-Angers
4 LFB Biotechnologies

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

Nathalie Kersual, Véronique Garambois, Thierry Chardès, Jean-Pierre Pouget, Imed Salhi, et al.. The human Mullerian inhibiting substance type II receptor as immunotherapy target for ovarian cancer. Validation using the mAb 12G4. mAbs, 2014, 6, pp.1314--26. ⟨10.4161/mabs.29316⟩. ⟨hal-02168055⟩