Abstract
Recent work by our team has shown the therapeutic value of targeting anti-mülllerian hormone type II receptor (AMHRII) in gynaecological cancers, particularly in ovarian cancers where therapies are often limited due to a high recurrence rate (70%). AMHRII is overexpressed in cancers and restricted in healthy tissues. Our laboratory developed the first anti-AMHRII antibody which is currently in clinical development by Gamamabs under the name Murlentamab. The first results are encouraging, with, in particular, significant recruitment of the immune system at the tumor level. The AMHRII can be heterodimerized with 3 type I receptors, ALK2, ALK3 and ALK6. However, in oncology, no study has shown the precise involvement of these type I receptors, which are essential for AMH signaling. In order to improve our anti-AMHRII therapies, we have focused on the roles of ALK receptors associated with the AMHRII receptor in the signaling of AMH. The observation that ALK2 and ALK3 are involved differently has led us to develop a new therapeutic strategy using bispecific antibodies targeting AMHRII-ALK receptors to direct AMH signaling towards an apoptotic pathway.In embryology, AMH is known to induce regression of the Müllerian ducts by apoptosis. On the basis of this pro-apoptotic physiological effect, many authors have proposed AMH as a therapeutic agent for gynaecological cancers. The common feature of these studies is the use of AMH at high doses compared to physiological concentrations found in men and women. In our work, we showed that low-dose AMH has a paradoxical effect that promotes proliferation. These results led us to develop a second antibody therapeutic strategy to suppress the proliferative effect of AMH, instead of administering high doses of AMH to induce apoptosis of cancer cells.