Purpose of the study: Müllerian inhibiting substance, also called anti-Müllerian hormone (AMH), belongs to the TGF-β family and plays a key role during sexual development. It has been shown that AMH inhibits proliferation and induces apoptosis of AMH type II receptor-positive tumor cells, and particularly progenitor cancer cells. Moreover, various reports have underlined expression of AMHRII in human gynecologic cancers including ovarian tumors. Based on these considerations, a humanized glyco-engineered monoclonal antibody (3C23K) capable of increasing effector cells engagement has been developed and tested in AMHR2 transfected xenografted cell lines. In order to document its activity in naturalistic models, we have initiated a preclinical study to assess AMHRII expression in a panel of ovarian cancer patient-derived xenografts (PDXs) and evaluate in vivo efficacy of 3C23K.
Experimental procedures: AMHRII expression was studied in 14 ovarian cancers PDXs, using both flow cytometry (FC) and immunofluorescence (IF) analyses performed with alexaFluor488-conjugated 3C23K antibody on 300µm slices of xenograft fragments. In vivo efficacy of 3C23K alone (10 or 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 planned to be evaluated in 4 AMHRII-positive ovarian cancers PDXs. One undifferentiated highly proliferative serous ovarian adenocarcinoma PDX, the OV54 model, has already been treated. On these 4 selected models, expression and quantification of AMHRII was or will be performed before and after treatments, as well as tumor-associated macrophages (TAMs) infiltrate.
Summary of the data: Expression studies showed that over the 14 PDX tested, 6 (43%) were positive with at least 25% of tumor cells being positive, among these 3 expressed more than 50% of positive cells. This expression was confirmed by ex vivo IF with a profile comparable to that observed with fresh primary human ovarian tumors resected from stage IV patients.
In vivo experiments (OV54 model) showed an intermediate efficacy of the 3C23K antibody administered alone, as well as a high and significant increase of CT antitumor effect.
Synergistic effects were characterized by 50% of complete response (CR) when 3C23K (20mg/kg/inj.) was added to CT vs 10% CR with CT alone. The cumulative number of days under CR was 110 with 3C23K + CT vs 7 on CT alone. Impact on survival was consistent with a 90% survival at D37 with 3C23K + CT vs 60% survival on CT alone.
We did not observe modification of AMHRII expression in OV54 tumors after 3C23K administration. Stromal FC analyses showed a high TAMs infiltrate of M2 type compatible with induction of Antibody Dependent Cell Phagocytosis by 3C23K.
Conclusions: Using a panel of 14 ovarian cancer PDXs, we confirmed the expression of AMHRII in human ovarian cancers. Targeting this receptor by a specific monoclonal antibody, i.e. 3C23K, dramatically increases the efficacy of a standard chemotherapy. Our results therefore suggest that such combination could be further developed in ovarian cancer patients whose prognosis remains dismal.
Citation Format: Fariba Némati, Jean-Marc Barret, Gérald Massonnet, Houcine Bougherara, Marie-Aude Le Frère-Belda, Jean-François Prost, Didier Decaudin. in vivo synergism between chemotherapy and the 3C23K monoclonal antibody directed against the anti-müllerian hormone type II receptor in ovarian cancer patient-derived xenografts [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1404.