Decitabine enhances anti-CD33 monoclonal antibody BI 836858–mediated natural killer ADCC against AML blasts

• Published in: Blood Vol. 127; no. 23; pp. 2879 - 2889
• Main Authors: Vasu, Sumithira, He, Shun, Cheney, Carolyn, Gopalakrishnan, Bhavani, Mani, Rajeswaran, Lozanski, Gerard, Mo, Xiaokui, Groh, Veronica, Whitman, Susan P., Konopitzky, Renate, Kössl, Christian, Bucci, Donna, Lucas, David M., Yu, Jianhua, Caligiuri, Michael A., Blum, William, Adam, Paul J., Borges, Eric, Rueter, Bjoern, Heider, Karl-Heinz, Marcucci, Guido, Muthusamy, Natarajan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.06.2016; American Society of Hematology
• Subjects: Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Antibody-Dependent Cell Cytotoxicity - drug effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Azacitidine - administration & dosage; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Cells, Cultured; Combined Modality Therapy; Cytotoxicity, Immunologic; Decitabine; Drug Synergism; HL-60 Cells; Humans; Immunoglobulin Fc Fragments - administration & dosage; Immunoglobulin Fc Fragments - pharmacology; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Leukemia, Myeloid, Acute - therapy; Myeloid Neoplasia; Recombinant Proteins - administration & dosage; Recombinant Proteins - pharmacology; Sialic Acid Binding Ig-like Lectin 3 - immunology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2015-11-680546

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. •BI 836858, an Fc-engineered anti-CD33 antibody, mediates autologous and allogeneic NK cell–mediated ADCC.•Decitabine increases ligands for activating NK receptors potentiating BI 836858 activity, providing a rationale for combination therapy.