title: Novel therapeutic approach to improve hematopoiesis in low risk MDS by targeting MDSCs with the Fc-engineered CD33 antibody BI 836858.
abstract: 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.
authors.affiliation: Immunology Program and Malignant Hematology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Eksioglu
authors.affiliation: Immunology Program and Malignant Hematology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: Boehringer Ingelheim RCV, Vienna, Austria.
authors.forename: K-H
authors.initials: KH
authors.lastname: Heider
authors.affiliation: Boehringer Ingelheim Pharma GmbH &Co. KG, Biberach/Riss, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Rueter
authors.affiliation: Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: McGraw
authors.affiliation: Department of Malignant Hematology, H. Lee Moffitt Cancer Center and the Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Basiorka
authors.affiliation: Immunology Program and Malignant Hematology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Wei
authors.affiliation: Immunology Program and Malignant Hematology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Burnette
authors.affiliation: Immunology Program and Malignant Hematology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: P
authors.initials: P
authors.lastname: Cheng
authors.affiliation: Immunology Program and Malignant Hematology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lancet
authors.affiliation: Immunology Program and Malignant Hematology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: R
authors.initials: R
authors.lastname: Komrokji
authors.affiliation: Immunology Program and Malignant Hematology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Djeu
authors.affiliation: Immunology Program and Malignant Hematology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: A
authors.initials: A
authors.lastname: List
authors.affiliation: Immunology Program and Malignant Hematology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Wei
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity; D001853:Bone Marrow / Q000473:pathology; D005260:Female; D005818:Genetic Engineering; D042822:Genomic Instability; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects* / Q000276:immunology; D017382:Reactive Oxygen Species; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D055153:Stem Cell Niche
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C000621731:BI 836858; C571163:CD33 protein, human; D007141:Immunoglobulin Fc Fragments; D017382:Reactive Oxygen Species; D063268:Sialic Acid Binding Ig-like Lectin 3