title: Decitabine enhances anti-CD33 monoclonal antibody BI 836858-mediated natural killer ADCC against AML blasts.
abstract: Acute myeloid leukemia (AML) is the most common type of acute leukemia, affecting older individuals at a median age of 67 years. Resistance to intensive induction chemotherapy is the major cause of death in elderly AML; hence, novel treatment strategies are warranted. CD33-directed antibody-drug conjugates (gemtuzumab ozogamicin) have been shown to improve overall survival, validating CD33 as a target for antibody-based therapy of AML. Here, we report the in vitro efficacy of BI 836858, a fully human, Fc-engineered, anti-CD33 antibody using AML cell lines and primary AML blasts as targets. BI 836858-opsonized AML cells significantly induced both autologous and allogeneic natural killer (NK)-cell degranulation and NK-cell-mediated antibody-dependent cellular cytotoxicity (ADCC). In vitro treatment of AML blasts with decitabine (DAC) or 5-azacytidine, 2 hypomethylating agents that show efficacy in older patients, did not compromise BI 836858-induced NK-cell-mediated ADCC. Evaluation of BI 836858-mediated ADCC in serial marrow AML aspirates in patients who received a 10-day course of DAC (pre-DAC, days 4, 11, and 28 post-DAC) revealed significantly higher ADCC in samples at day 28 post-DAC when compared with pre-DAC treatment. Analysis of ligands to activating receptors (NKG2D) showed significantly increased NKG2D ligand [NKG2DL] expression in day 28 post-DAC samples compared with pre-DAC samples; when NKG2DL receptor was blocked using antibodies, BI 836858-mediated ADCC was significantly decreased, suggesting that DAC enhances AML blast susceptibility to BI 836858 by upregulating NKG2DL. These data provide a rationale for combination therapy of Fc-engineered antibodies such as BI 836858 with azanucleosides in elderly patients with AML.
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, and.
authors.forename: Sumithira
authors.identifier: 0000-0002-5374-5888
authors.initials: S
authors.lastname: Vasu
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, and.
authors.forename: Shun
authors.identifier: 0000-0002-8389-9001
authors.initials: S
authors.lastname: He
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, and.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Cheney
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, and.
authors.forename: Bhavani
authors.initials: B
authors.lastname: Gopalakrishnan
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, and.
authors.forename: Rajeswaran
authors.initials: R
authors.lastname: Mani
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, and.
authors.forename: Gerard
authors.initials: G
authors.lastname: Lozanski
authors.affiliation: Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH;
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA;
authors.forename: Veronica
authors.initials: V
authors.lastname: Groh
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, and.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Whitman
authors.affiliation: Research Oncology, Boehringer Ingelheim RCV, Vienna, Austria;
authors.forename: Renate
authors.initials: R
authors.lastname: Konopitzky
authors.affiliation: Research Oncology, Boehringer Ingelheim RCV, Vienna, Austria;
authors.forename: Christian
authors.initials: C
authors.lastname: Kössl
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, and.
authors.forename: Donna
authors.initials: D
authors.lastname: Bucci
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, and.
authors.forename: David M
authors.initials: DM
authors.lastname: Lucas
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, and.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, and.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, and.
authors.forename: William
authors.initials: W
authors.lastname: Blum
authors.affiliation: Research Oncology, Boehringer Ingelheim RCV, Vienna, Austria;
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Adam
authors.affiliation: Research Oncology, Boehringer Ingelheim RCV, Vienna, Austria;
authors.forename: Eric
authors.initials: E
authors.lastname: Borges
authors.affiliation: Medicine Oncology, Boehringer Ingelheim Pharma GmbH, Biberach/Riss, Germany; and.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Rueter
authors.affiliation: Research Oncology, Boehringer Ingelheim RCV, Vienna, Austria;
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Heider
authors.affiliation: Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope, Duarte, CA.
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, and.
authors.forename: Natarajan
authors.initials: N
authors.lastname: Muthusamy
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D000077209:Decitabine; D004357:Drug Synergism; D018922:HL-60 Cells; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D015470:Leukemia, Myeloid, Acute / Q000628:therapy*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C000621731:BI 836858; C571163:CD33 protein, human; D007141:Immunoglobulin Fc Fragments; D011994:Recombinant Proteins; D063268:Sialic Acid Binding Ig-like Lectin 3; D000077209:Decitabine; D001374:Azacitidine