The humanized anti-human AMHRII mAb 3C23K exerts an anti-tumor activity against human ovarian cancer through tumor-associated macrophages

// Houcine Bougherara 1, 2, 3, * , Fariba Nemati 4, * , Andre Nicolas 5 , Gerald Massonnet 4 , Martine Pugniere 6 , Charlotte Ngo 7 , Marie-Aude Le Frere-Belda 8 , Alexandra Leary 9 , Jerome Alexandre 1, 3, 10 , Didier Meseure 5 , Jean-Marc Barret 11 , Isabelle Navarro-Teulon 6 , Andre Pelegrin 6 , Sergio Roman-Roman 12 , Jean-Francois Prost 11 , Emmanuel Donnadieu 1, 2, 3, * and Didier Decaudin 4, 13, * 1 Inserm, U1016, Institut Cochin, Paris, France 2 Cnrs, UMR8104, Paris, France 3 Universite Paris Descartes, Sorbonne Paris Cite, Paris, France 4 Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, PSL University, Paris, France 5 Department of Tumor Biology, Institut Curie, Paris, France 6 INSERM U896, Institut de Recherche en Cancerologie de Montpellier, Montpellier, France 7 Department of Gynaecological and Oncological Surgery, Hopital Europeen Georges Pompidou, Universite Paris Descartes, Assistance Publique-Hopitaux de Paris, Paris, France 8 Department of Pathology, Hopital Europeen Georges Pompidou, Universite Paris Descartes, Assistance Publique-Hopitaux de Paris, Paris, France 9 Gustave Roussy Hospital, Inserm U981, Villejuif, France 10 Department of Medical Oncology, Cochin Hospital, Assistance Publique-Hopitaux de Paris, Paris, France 11 GammaMabs Pharma, Centre Pierre Potier, Toulouse, France 12 Department of Translational Research, Institut Curie, PSL University, Paris, France 13 Department of Medical Oncology, Institut Curie, Paris, France * These authors have contributed equally to this work Correspondence to: Didier Decaudin, email: didier.decaudin@curie.fr Emmanuel Donnadieu, email: emmanuel.donnadieu@inserm.fr Keywords: human ovarian cancers; Mullerian hormone type II receptor; patient-derived xenografts (PDXs); chemotherapy; tumor-associated macrophages Received: November 08, 2016     Accepted: May 31, 2017     Published: October 07, 2017 ABSTRACT Mullerian inhibiting substance, also called anti-Mullerian hormone (AMH), inhibits proliferation and induces apoptosis of AMH type II receptor-positive tumor cells, such as human ovarian cancers (OCs). On this basis, a humanized glyco-engineered monoclonal antibody (3C23K) has been developed. The aim of this study was therefore to experimentally confirm the therapeutic potential of 3C23K in human OCs. We first determined by immunofluorescence, immunohistochemistry and cytofluorometry analyses the expression of AMHRII in patient’s tumors and found that a majority (60 to 80% depending on the detection technique) of OCs were positive for this marker. We then provided evidence that the tumor stroma of OC is enriched in tumor-associated macrophages and that these cells are responsible for 3C23K-induced killing of tumor cells through ADCP and ADCC mechanisms. In addition, we showed that 3C23K reduced macrophages induced-T cells immunosuppression. Finally, we evaluated the therapeutic efficacy of 3C23K alone and in combination with a carboplatin-paclitaxel chemotherapy in a panel of OC Patient-Derived Xenografts. In those experiments, we showed that 3C23K significantly increased the proportion and the quality of chemotherapy-based in vivo responses. Altogether, our data support the potential interest of AMHRII targeting in human ovarian cancers and the evaluation of 3C23K in further clinical trials.