title: The human Müllerian inhibiting substance type II receptor as immunotherapy target for ovarian cancer. Validation using the mAb 12G4.
abstract: Ovarian cancer has the highest mortality rate among gynecologic malignancies. The monoclonal antibody 12G4 specifically recognizes the human Müllerian 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.
authors.affiliation: a IRCM; Institut de Recherche en Cancérologie de Montpellier ; Montpellier ; France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Kersual
authors.forename: Véronique
authors.initials: V
authors.lastname: Garambois
authors.forename: Thierry
authors.initials: T
authors.lastname: Chardès
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pouget
authors.forename: Imed
authors.initials: I
authors.lastname: Salhi
authors.forename: Caroline
authors.initials: C
authors.lastname: Bascoul-Mollevi
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bibeau
authors.forename: Muriel
authors.initials: M
authors.lastname: Busson
authors.forename: Henri
authors.initials: H
authors.lastname: Vié
authors.forename: Béatrice
authors.initials: B
authors.lastname: Clémenceau
authors.forename: Christian K
authors.initials: CK
authors.lastname: Behrens
authors.forename: Pauline
authors.initials: P
authors.lastname: Estupina
authors.forename: André
authors.initials: A
authors.lastname: Pèlegrin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Navarro-Teulon
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D005260:Female; D006106:Granulosa Cell Tumor / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009375:Neoplasms, Glandular and Epithelial / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; C084621:anti-Mullerian hormone receptor
keywords: ADCC, Antibody-Dependent Cell Cytotoxicity; EOC, epithelial ovarian cancer; GCT; GCT, granulosa cell tumors; MIS, Müllerian inhibiting substance; MISRII; MISRII, Müllerian inhibiting substance type II receptor; immunotherapy; mAb, monoclonal antibody; ovarian carcinoma; therapeutic antibodies