Novel therapeutic approach to improve hematopoiesis in low risk MDS by targeting MDSCs with the Fc-engineered CD33 antibody BI 836858

• Published in: Leukemia Vol. 31; no. 10; pp. 2172 - 2180
• Main Authors: Eksioglu, E A, Chen, X, Heider, K-H, Rueter, B, McGraw, K L, Basiorka, A A, Wei, M, Burnette, A, Cheng, P, Lancet, J, Komrokji, R, Djeu, J, List, A, Wei, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2017; Nature Publishing Group
• Subjects: 13/21; 13/31; 38/77; 631/136/232; 631/1647/338; 631/67/1990/1673; 692/308/575; 692/699/67/1059/2325; Activation; Adducts; Aged; Aged, 80 and over; Antibodies; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antibody-Dependent Cell Cytotoxicity; Bioassays; Blocking; Bone marrow; Bone Marrow - pathology; Cancer Research; Care and treatment; Cell death; Cellular proteins; Colonies; Comet assay; Critical Care Medicine; Cytokines; Cytotoxicity; Damage detection; Development and progression; Female; Genetic aspects; Genetic Engineering; Genomic Instability; Group dynamics; Health aspects; Hematology; Hematopoiesis; Hematopoiesis - drug effects; Histocompatibility antigen HLA; Humans; Immunoglobulin Fc Fragments - therapeutic use; Intensive; Internal Medicine; Male; Medicine; Medicine & Public Health; Microenvironments; Middle Aged; Molecular Targeted Therapy; Monoclonal antibodies; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelodysplastic Syndromes - blood; Myelodysplastic Syndromes - immunology; Myelodysplastic Syndromes - pathology; Myelodysplastic Syndromes - therapy; Myeloid-Derived Suppressor Cells - drug effects; Myeloid-Derived Suppressor Cells - immunology; Oncology; original-article; Pathogenesis; Patients; Reactive Oxygen Species; Sialic Acid Binding Ig-like Lectin 3 - immunology; Signal transduction; Signal Transduction - drug effects; Signal Transduction - immunology; Stability; Stem Cell Niche; Suppressor cells; Toxicity
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2017.21

We recently reported that the accumulation of myeloid-derived suppressor cells (MDSC), defined as CD33 + HLA-DR − Lin − , has a direct role in the pathogenesis of myelodysplastic syndrome (MDS). In particular, CD33 is strongly expressed in MDSC isolated from patients with MDS where it has an important role in MDSC-mediated hematopoietic suppressive function through its activation by S100A9. Therefore, we tested whether blocking this interaction with a fully human, Fc-engineered monoclonal antibody against CD33 (BI 836858) suppresses CD33-mediated signal transduction and improves the bone marrow microenvironment in MDS. We observed that BI 836858 can reduce MDSC by antibody-dependent cellular cytotoxicity, which correlated with increases in granule mobilization and cell death. BI 836858 can also block CD33 downstream signaling preventing immune-suppressive cytokine secretion, which correlates with a significant increase in the formation of CFU-GM and BFU-E colonies. Activation of the CD33 pathway can cause reactive oxygen species (ROS)-induced genomic instability but BI 836858 reduced both ROS and the levels of double strand breaks and adducts (measured by comet assay and γH2AX). This work provides the ground for the development of a novel group of therapies for MDS aimed at MDSC and their disease-promoting properties with the goal of improving hematopoiesis in patients.