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

Abstract

Key Points• 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.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-cellmediated 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.

Immunological effects of hypomethylating agents

“…As a notable example from a recent clinical trial, patients treated with decitabine for a 10-day course demonstrated significantly higher antibody-dependent cell-mediated cytotoxicity (ADCC) in response to an investigational anti-CD33 monoclonal antibody[37]. Expression of NKG2D ligand was significantly increased at 28 days following decitabine treatment compared to pre-treatment control samples.…”

The Broad Spectrum of Human Natural Killer Cell Diversity

“…In this scenario, the MHC class I-binding receptor-mediated inhibitory signal is absent allowing the uninhibited donor NK cell to kill its AML target. NK cell killing can be further promoted in the presence of AML-directed monoclonal antibodies and/or if the leukemic blasts express stress-induced ligands that can engage surface NK cell activating receptors such as NKG2D (Vasu et al, 2016). …”

Interferon-γ Promotes Antibody-mediated Fratricide of Acute Myeloid Leukemia Cells

“…However, it was withdrawn from the market due to toxicity issues (13,14). Today, other CD33-targeting drug-antibody conjugates, such as SGN-CD33A and Fc-engineered anti-CD33 antibodies, are being studied in AML (1,12,15). The targeting of Fc␥RI has similarly been proposed, especially after the finding that IFN␥ could increase the expression of the high affinity Fc␥ receptor, Fc␥RI (16 -19).…”