The anti-Müllerian hormone (AMH) belongs to the TGF-β family and plays a key role during fetal sexual development. Its type 2 receptor, AMHRII, is selectively expressed in normal sexual organs in healthy adults but is also re-expressed in gynecologic cancers including ovarian tumors. Recently, AMHRII expression was also demonstrated in major cancers such as colorectal, non-small cell lung cancers and hepatocarcinoma. This set of consistent findings led to the development of GM102, a humanized glyco-engineered anti-AMHRII monoclonal antibody by GamaMabs Pharma. Following an extensive pharmacologic investigation as well as a regulatory toxicologic program in cynomolgus monkeys, clinical trials with GM102 were launched in 2016 and are currently ongoing. In vitro experiments using GM102 were performed to characterize more precisely its effect on human immune system. Macrophages from healthy donors were unstimulated or stimulated by M-CSF/IL-10 for conferring a TAM-like phenotype. These macrophages were co-cultured with SKOV3-AMHRII+ ovarian cancer target cells in the presence of GM102 before adding lymphocytes from the same donors. By this way, we demonstrate that GM102 opsonization of SKOV3-AMHRII+ tumor cells, in presence of unstimulated- or TAM-like macrophages, shifts the microenvironment toward a proinflammatory and antitumoral status (increase of IL-1β, IL- 12, TNF-α, IL-6 and decrease of IL-23, IL-10) and significantly promotes the macrophage-mediated ADCC and triggers antitumor activity. We also report that GM102 treatment orients the unstimulated- and TAM-like macrophages toward a population characterized by a strong expression of adaptive immune response co-stimulation marker, such as CD80, and induces a chemokine profile favorable to the recruitment of Th1 lymphocytes (increase of CCL-4, CCL-5, CXCL-9 and CXCL-10, as well as IL-12). Moreover, we show that GM102 treatment shifts Th1/Th2 balance of T CD4+ cells toward Th1 response and activates CD8+ T cells. Similar results were obtained with a COV434-AMHRII+ granulosa cell tumor cell line. Interestingly, preliminary analysis of blood samples and biopsies from patients treated by GM102 suggest, as well, a more global effect of GM102 on immune system than a sole involvement of ADCC/ADCP activity. In conclusion, all together these results reveal that GM102 antibody is able to trigger the antitumor activity of unstimulated macrophages and to reorient tumor-supporting macrophages to cytotoxic effectors. These macrophages are subsequently able to stimulate the antitumor adaptive immune system by inducing Th1 response of T CD4+ cells and by activating T CD8+ cells. Those mechanisms might participate to the sustained clinical benefit observed in advanced cancer patients treated with GM102.
Citation Format: Thibault Allain, Marie Salon, Jean-Marc Barret, Mélanie Prat, Olivier Dubreuil, Nathalie Van Acker, Lydie Cassard, Bernard Pipy, Jean-François Prost, Agnès Coste. GM102, a low fucosylated anti-Müllerian Hormone type II Receptor (AMHRII) antibody, promotes in vitro antitumoral activities of innate (macrophages) and adaptative (CD4+ and CD8+ T cells) immune cells [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B77.