Résumé
Asymptomatic in early stages, ovarian cancer is a “silent killer” representing the fifth leading cause of female deaths in western countries. Every year 56,967 women in Europe and USA die as a consequence of this disease. The incidence of ovarian cancer is forecast to undergo a 13 % increase in the next eight years in the seven major developed countries to reach about 72,000 annual cases in 2019. Due to the limitations of the current therapeutic approaches, there is a strong need for novel, more efficient, therapies. For this reason, we have produced 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. This monoclonal antibody derives from the murine monoclonal antibody 12G4 and displays a particular glycosylation profile known to favor effector recruitment (EMABling®) as previously demonstrated in vitro. In vivo, we also showed that 3C23K exhibited a significant effect on tumor growth against several ovarian tumor xenografted models derived from patient primary EOC tumors. In this study, we first confirmed by peptide microarray that the epitope of 3C23K antibody was strictly identical to that of 12G4 antibody and a 3D-model of the full MISRII molecule was generated in order to better localize the 3C23K epitope. Furthermore, SPR studies demonstrated cross-reactivity of 3C23K with MISRII of rabbit, dog, pig, cow and primate. In vivo, antitumor activity of 3C23K against xenografted EOC tumor models was confirmed with various concentrations and treatment schedules. Moreover, interestingly, we constructed a mutant form of 3C23K harboring two mutations in the Fc region (G236R/L328R) in order to prevent binding to both murine and human FcαRs, and demonstrated that such a modification abolished antitumor activity. This data confirmed in vivo that recruitment of effectors is essential for 3C23K efficacy. Finally, in order to anticipate clinical treatment of ovarian cancers, 3C23K was tested in vivo in combination with carboplatin. Combination, when compared with treatment of each product alone, resulted in more than additive antitumor activity. Altogether these data showed that humanized monoclonal antibody 3C23K represents a promising candidate for ovarian cancer immunotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2528. doi:1538-7445.AM2012-2528