Résumé
Often diagnosed at an advanced stage, ovarian cancer is responsible for the highest mortality rate among patients with gynecologic malignancies. Due to the limitations of the current therapeutic approaches, there is a strong need for novel, more efficient, therapies, among which targeted immunotherapy. The monoclonal antibody 12G4 specifically recognizes the human Müllerian Inhibiting Substance type II Receptor (MISRII). Expressed at high levels on most human Granulosa Cell Tumors (GCT) as well as on a majority of human epithelial ovarian cancer (EOC) cells, MISRII represents a good target for antibody-based tumor targeting.
Characterization of murine antibody 12G4 has been previously reported, in particular epitope mapping and in vitro assays showing that 12G4 binding does not affect MIS interaction with MISRII. In the present study we further assess 12G4 activity in vitro and in vivo. 12G4 was shown to induce 37% and 30% apoptosis in vitro (FACS, DNA fragmentation) on the two MISRII expressing cell lines cov434-MISRII and OVCAR3, respectively. Internalization of the antibody-MISRII complex was also observed in vitro on cov434-MISRII. Using 12G4 antibody we confirmed by immunohistochemistry the expression of the MISRII target in all GTC samples and all but one EOC tissue sections (13/14). Furthermore, we have developed several immunodeficient Nude mouse models of ovarian tumor xenografts expressing human MISRII. In these models the efficacy of 12G4 could be clearly demonstrated with a significant effect on tumor growth.
According to our data, MISRII, expressed on a majority of EOCs appears as a good target for ovarian cancer immunotherapy. Furthermore, based on the good efficacy observed in vivo for 12G4, the development of a humanized anti-MISRII antibody, derived from 12G4, has been initiated and represents a new promising targeted therapeutic approach.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4568. doi:10.1158/1538-7445.AM2011-4568