Résumé
Asymptomatic in early stages, ovarian cancer is a “silent killer” corresponding to the 5th cause of female deaths in US. In 2010 it is estimated that 21,880 women in US will be diagnosed with ovarian cancer. Due to the limitations of the current therapeutic approaches, there is a strong need for novel, more efficient, therapies. We describe here a humanized monoclonal antibody 3C23K targeting the human Müllerian Inhibiting Substance type II Receptor (MISRII), expressed on most ovarian cancer subtypes, including epithelial ovarian cancer (EOC) representing more than 90% of ovarian cancers. Starting from murine monoclonal antibody 12G4, 3C23K was obtained following chimerization, humanization by CDR grafting and affinity maturation. Moreover, 3C23K displays a particular glycosylation profile known to favor effector recruitment in vitro and in vivo (EMABling®). Assessed on MISRII transfected cells (cov434-MISRII), 3C23K was characterized by an affinity constant to the antigen increased by 3 fold as compared to murine 12G4. In order to evaluate 3C23K efficacy in vitro and in vivo, we have established several MISRII expressing cell lines derived from patient primary EOC tumors. Functional characterization of 3C23K has been carried out in vitro, including antibody-dependent cell-mediated cytotoxicity (ADCC), complement dependent cytotoxicity, apoptosis and intracellular signaling. In particular, 3C23K was found to display a higher ADCC activity on MISRII expressing cell lines as compared to the same sequence expressed in CHO cells. In vivo, 3C23K exhibited a significant effect on tumor growth against several ovarian tumor xenografted models derived from patient primary EOC tumors. Altogether these data strongly suggest that humanized monoclonal antibody 3C23K may represent a promising candidate for ovarian cancer immunotherapy. 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 4574. doi:10.1158/1538-7445.AM2011-4574