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

Autor:	Bougherara H; Inserm, U1016, Institut Cochin, Paris, France.; Cnrs, UMR8104, Paris, France.; Université Paris Descartes, Sorbonne Paris Cité, Paris, France., Némati F; Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, PSL University, Paris, France., Nicolas A; Department of Tumor Biology, Institut Curie, Paris, France., Massonnet G; Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, PSL University, Paris, France., Pugnière M; INSERM U896, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France., Ngô C; Department of Gynaecological and Oncological Surgery, Hôpital Européen Georges Pompidou, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, Paris, France., Le Frère-Belda MA; Department of Pathology, Hôpital Européen Georges Pompidou, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, Paris, France., Leary A; Gustave Roussy Hospital, Inserm U981, Villejuif, France., Alexandre J; Inserm, U1016, Institut Cochin, Paris, France.; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.; Department of Medical Oncology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France., Meseure D; Department of Tumor Biology, Institut Curie, Paris, France., Barret JM; GammaMabs Pharma, Centre Pierre Potier, Toulouse, France., Navarro-Teulon I; INSERM U896, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France., Pèlegrin A; INSERM U896, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France., Roman-Roman S; Department of Translational Research, Institut Curie, PSL University, Paris, France., Prost JF; GammaMabs Pharma, Centre Pierre Potier, Toulouse, France., Donnadieu E; Inserm, U1016, Institut Cochin, Paris, France.; Cnrs, UMR8104, Paris, France.; Université Paris Descartes, Sorbonne Paris Cité, Paris, France., Decaudin D; Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, PSL University, Paris, France.; Department of Medical Oncology, Institut Curie, Paris, France.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2017 Oct 07; Vol. 8 (59), pp. 99950-99965. Date of Electronic Publication: 2017 Oct 07 (Print Publication: 2017).
DOI:	10.18632/oncotarget.21556
Abstrakt:	Müllerian inhibiting substance, also called anti-Müllerian 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. Competing Interests: CONFLICTS OF INTEREST This study was supported by grants from GamaMabs Pharma, in which belong two authors, Jean-Marc Barret and Jean-François Prost.
Databáze:	MEDLINE
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