Abstract
AbstractAcute 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.
Highlights
Acute myeloid leukemia (AML) is the most common acute leukemia in adults, causing .10 000 deaths per year in the United States.[1,2,3] Antibody-based therapeutics in AML have targeted CD33 which is expressed in over 80% of leukemic cells.[4,5,6,7] Gemtuzumab ozogamicin (GO), an anti-CD33 immunoconjugate, is composed of a humanized immunoglobulin G4 (IgG4) antibody conjugated to the powerful antimitotic calicheamicin which mediates cell death following rapid internalization of the antibody-antigen complex formation.[5]
BI 836858 is a fully human anti-CD33 antibody which was derived by Fc engineering of BI 836854, a standard IgG1-type antibody derived from human antibody-producing transgenic mice
BI 836858 showed a higher degree of retained cell surface CD33 compared with HuM195 (Figure 1B), whereas the non–Fc-engineered version BI 836854 showed similar levels as BI 836858; in addition, the non–FC-engineered antibody BI 836854 had higher surface expression of CD33 in comparison with lintuzumab
Summary
Acute myeloid leukemia (AML) is the most common acute leukemia in adults, causing .10 000 deaths per year in the United States.[1,2,3] Antibody-based therapeutics in AML have targeted CD33 (sialic acid–binding immunoglobulin-like lectin 3) which is expressed in over 80% of leukemic cells.[4,5,6,7] Gemtuzumab ozogamicin (GO), an anti-CD33 immunoconjugate, is composed of a humanized immunoglobulin G4 (IgG4) antibody conjugated to the powerful antimitotic calicheamicin which mediates cell death following rapid internalization of the antibody-antigen complex formation.[5]. Data from phase 3 trials and a meta-analysis have shown an advantage in overall survival in patients treated with GO combined with standard induction chemotherapy in older AML patients.[9,10] An unconjugated humanized anti-CD33 antibody, lintuzumab (HuM195), has resulted in complete remissions in elderly patients,[11] randomized studies have not shown improvement in overall survival.[12]
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