Abstract 1170: MEN1112/OBT357, a first-in-class humanized de-fucosylated monoclonal antibody targeting CD157 positive cells in acute myeloid leukemia and myelodysplastic syndrome

Abstract

Abstract Bst1/CD157 is a GPI-anchored transmembrane protein encoded by a member of the CD38 NADase/ADP-ribosyl cyclase gene family, which is expressed on some blood cells of the myeloid lineage, such as monocytes and neutrophils. The antigen is found to be highly expressed, at diagnosis and relapse, in primary samples derived from Acute Myeloid Leukemia (AML) patients, showing the brightest expression in monocyte-oriented blasts. Moreover, CD157 is expressed in high and low-risk Myelodysplastic Syndrome (MDS) patients. MEN1112/OBT357, is a humanized de-fucosylated monoclonal antibody, in clinical development (clinicaltrials.gov identifier: NCT02353143), that is characterized by high affinity and specificity against CD157, inducing potent in vitro Antibody-Dependent Cell-mediated Cytotoxicity (ADCC). The de-fucosylation improved the binding of MEN1112/OBT357 to both high and low-affinity alleles of FcγRIIIa/CD16a, allowing stronger recognition by NK cells. Since no Complement-Dependent Cytotoxicity (CDC) activity was detected, the MEN1112/OBT357 mechanism of action should mainly rely on immune effector cells. Indeed, in an in vitro reporter assay, MEN1112/OBT357 significantly triggered ADCC activity against AML target cell lines with different expression of CD157. Since the ex vivo sensitivity assay is considered a pharmacologically and clinically relevant model to evaluate the preclinical efficacy of therapeutic antibodies in AML (1), MEN1112/OBT357 activity was tested in 38 AML primary samples, demonstrating promising efficacy in an autologous setting, both in peripheral blood and bone marrow samples, in comparison to healthy donor blood samples and independently from FcγRIIIa polymorphisms. A similar activity was also observed in CD157 positive MDS primary samples. Since Myeloid-Derived Suppressor Cells (MDSCs) have been described to be increased in the bone marrow of both AML and MDS patients and their presence to be associated with resistance to chemotherapy (2, 3), we investigated CD157 expression in MDSCs, demonstrating a high expression of the antigen in the bone marrow and peripheral blood of AML patients. Importantly, we confirmed in ex vivo experiments, the depletion of these immunosuppressive cells by MEN1112/OBT357. Overall, our data demonstrate that MEN1112/OBT357 is a novel antibody with potent ex vivo activity against blast cells in AML and MDS patients, suggesting a potential contribution of MEN1112/OBT357 in altering the immunosuppressive environment in the bone marrow niche.