Altogether, these data indicate that this opsonization of ovarian tumor cells with murlentamab promotes the activation of an effective anti-tumor T cell immune response. 2.5. association with checkpoint inhibitors and other immuno-modulators. Abstract AMHRII, the anti-Mllerian hormone receptor, is usually selectively expressed in normal sexual organs but is also re-expressed in gynecologic cancers. Hence, we developed murlentamab, a humanized glyco-engineered anti-AMHRII monoclonal antibody currently in clinical trial. Low-fucosylated antibodies are known to increase SB225002 the antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) potency of effector cells, but some preliminary results suggest a more global murlentamab-dependent activation of the immune system. In this context, we demonstrate here that this murlentamab opsonization of AMHRII-expressing ovarian tumor cells, in the presence of unstimulated- or tumor-associated macrophage (TAM)-like macrophages, significantly promotes macrophage-mediated ADCC and shifts the whole microenvironment towards a pro-inflammatory and anti-tumoral status, thus triggering anti-tumor activity. We also statement that murlentamab orients both unstimulated- and TAM-like macrophages to an M1-like phenotype characterized by a strong expression of co-stimulation markers, pro-inflammatory cytokines and chemokines, favoring T cell recruitment and activation. Moreover, we show that murlentamab treatment shifts CD4+ Th1/Th2 balance towards a Th1 response and activates CD8+ T cells. Altogether, these results suggest that murlentamab, through na?ve macrophage orientation and TAM reprogrammation, stimulates the anti-tumor adaptive immune response. Those mechanisms might contribute to the sustained clinical benefit observed in advanced malignancy patients treated with murlentamab. Finally, the enhanced murlentamab activity in combination with pembrolizumab opens new therapeutic perspectives. Keywords: murlentamab, glyco-engineered antibody, tumor-associated macrophages, ovarian malignancy, adaptive immunity, immunotherapy 1. Introduction The Anti-Mllerian hormone type II receptor (AMHRII), also known as MIS type II receptor (MISRII or MISIIR), is usually a member of the transforming growth factor beta (TGF-) receptor superfamily [1,2]. AMHRII plays a major role in male fetus sexual differentiation by inducing, SB225002 as a consequence of AMH activation, the regression of Mllerian ducts, precursors of female reproductive organs SB225002 (uterus, fallopian tubes and upper vagina) [3]. In adults, AMHRII seems to have a restricted expression profile, being mainly expressed in granulosa cells in women from birth to menopause, acting in follicular growth modulation [4] and expressed in Sertoli and Leydig cells of males with involvement in androgen biosynthesis regulation [5]. Several studies have confirmed the expression of AMHRII in gynecological malignancy tissues [6,7,8,9,10] and, more recently, AMHRII was found expressed by certain non-gynecological malignancy such as non-small cell lung malignancy and colorectal malignancy [11,12]. This set of consistent evidence led to the development of murlentamab, also named GM102 or 3C23K, a humanized glyco-engineered anti-AMHRII monoclonal antibody. Following an extensive pharmacological SB225002 profiling as well as toxicological studies in cynomolgus monkeys [12,13,14], a phase I study of murlentamab in gynecological cancers (www.clinicaltrial.gov/”type”:”clinical-trial”,”attrs”:”text”:”NCT02978755″,”term_id”:”NCT02978755″NCT02978755, accessed SB225002 on: 20 June 2016) and a phase IIa in colorectal malignancy (www.clinicaltrial.gov/”type”:”clinical-trial”,”attrs”:”text”:”NCT03799731″,”term_id”:”NCT03799731″NCT03799731, accessed on: 11 July 2018) are currently ongoing. Effector functions mediated by the Fc a part of immunoglobulins have been reported to be strongly related to their = 20) were analyzed before (baseline) and during cycle 1 (at D15) and cycle Rabbit Polyclonal to NF1 2 (at D43) of murlentamab treatment. Murlentamab infusion induced both an increase in the proportion of blood monocytes positives for the CD69, an early activation marker, and a decrease in CD69+ activated-regulatory T cells (Tregs), whilst no significant variance was noticed regarding CD69+ CD8+ T cells at these times of blood sampling (Physique 1A). Blood samples from ovarian malignancy patients were not centralized but tested in each clinical site, using site-specific markers. Therefore, analysis of blood samples from patients treated at Gustave Roussy (Paris, France) (= 4) also showed signs of immune activation characterized by an increased proportion of CD8+.
