P4.01 - In vivo synergism between chemotherapy and the 3C23K monoclonal antibody targeting the AMH-type II receptor in ovarian cancer PDX models

Abstract

ABSTRACT Background: Mullerian inhibiting substance, also called anti-Mullerian hormone (AMH), belongs to the TGF-alpha family and plays a key role during sexual development. Various reports have underlined expression of AMHRII in human gynecologic cancers including ovarian cancers (OC). Based on these considerations, a humanized glyco-engineered monoclonal antibody (3C23K) specific to AMHRII has been developed. In this study, we have assessed AMHRII expression in a panel of OC patient-derived xenografts (PDXs) and evaluated in vivo efficacy of 3C23K. Materials and Methods: AMHRII expression was studied in 14 OC PDXs, using flow cytometry (FC), immunohistochemistry (IHC) and immunofluorescence (IF). In vivo efficacy of 3C23K alone (20 mg/kg twice a week, IP) or in combination with standard chemotherapy (CT) (carboplatin 66 mg/kg IP days 1-22 + paclitaxel 30 mg/kg IP days 1-22) has been evaluated in 4 AMHRII-positive undifferentiated, mucinous or serous adenocarcinoma OC PDXs. On these 4 models, expression of AMHRII was studied before and after treatments, as well as tumor-associated macrophages (TAMs) infiltrate. Results: Using FC analyses, 6 over the 14 PDX tested (43%) were positive with at least 25% of tumor cells expressing AMHR2. Data obtained with IHC and IF analyses were in concordance with FC results. In vivo experiments showed an intermediate efficacy of the 3C23K when administered alone and a synergistic effect when associated with CT. In particular, 3C23K was found to consistently increase the proportion of complete response (CR) on any of the models tested, namely OV54 (188 cumulated days of CR vs 47), OV25 (30 vs 10), OV21 (12 vs 0) and OV16 (67 vs 37). 3C23K administration did not modify tumor AMHRII expression. Stromal FC analyses showed a high TAMs infiltrate of M2 type compatible with induction of Antibody Dependent Cell Phagocytosis by the glyco-engineered 3C23K antibody. Conclusions: Using a panel of OC PDXs, we confirmed the expression of AMHRII in human OC. Targeting this receptor by 3C23K, dramatically increases the efficacy of a standard CT. Our results therefore suggest that such combination could be further developed in OC patients whose prognosis remains dismal. 3C23K is planned to enter in early clinical phase this year.