Targeting of acute myeloid leukemia in vitro and in vivo with an anti-CD123 mAb engineered for optimal ADCC

Abstract

Acute myeloid leukemia (AML) is a biologically heterogeneous group of related diseases in urgent need of better therapeutic options. Despite this heterogeneity, overexpression of the interleukin (IL)-3 receptor α-chain (IL-3 Rα/CD123) on both the blast and leukemic stem cell (LSC) populations is a common occurrence, a finding that has generated wide interest in devising new therapeutic approaches that target CD123 in AML patients. We report here the development of CSL362, a monoclonal antibody to CD123 that has been humanized, affinity-matured and Fc-engineered for increased affinity for human CD16 (FcγRIIIa). In vitro studies demonstrated that CSL362 potently induces antibody-dependent cell-mediated cytotoxicity of both AML blasts and CD34(+)CD38(-)CD123(+) LSC by NK cells. Importantly, CSL362 was highly effective in vivo reducing leukemic cell growth in AML xenograft mouse models and potently depleting plasmacytoid dendritic cells and basophils in cynomolgus monkeys. Significantly, we demonstrated CSL362-dependent autologous depletion of AML blasts ex vivo, indicating that CSL362 enables the efficient killing of AML cells by the patient's own NK cells. These studies offer a new therapeutic option for AML patients with adequate NK-cell function and warrant the clinical development of CSL362 for the treatment of AML.

Dual-targeting triplebody 33-16-123 (SPM-2) mediates effective redirected lysis of primary blasts from patients with a broad range of AML subtypes in combination with natural killer cells

“…A loose correlation between these two properties was observed for bulk AML cells (Figure 3), and similar correlations have been reported for the CD33-specific BiTE AMG330, 9 the CD123 antibody Talacotuzumab (CSL 362), 48,49 and the CD3 x CD123 DART agent MGD006. 56 While the target antigen density likely dictates the strength of binding of these agents to the target cells and the subsequent engagement of killer cells, it is unlikely that binding strength alone will translate 1:1 into an enhanced lytic activity.…”

IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells

“…Recently, there have been increasing efforts to identify molecular aberrations that could serve as pharmacologic targets within AML and MDS stem cell compartments. [10][11][12][13][14][15][16] Resulting therapies have shown promising effects in preclinical studies, 17,18 but further work will be necessary to identify therapeutic targets against preleukemic stem cells that would lead to long-term remission and prevention of relapse in AML and MDS.…”

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

“…IFN␥-mediated CD38 Up-regulation Requires p38, NF-B, and JAK/STAT-Previous studies have shown increased expression of CD38 by IFN␥ in chronic lymphocytic leukemia to be JAK/STAT and T-bet-dependent (20). To determine which downstream signaling pathways were required for the up-regulation of CD38 seen with IFN␥ treatment, primary AML apheresis samples were pretreated with inhibitors for ERK, PI3K, p38 MAPK, JAK/STAT, and NF-B.…”

“…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). Recently, a study was completed using a monoclonal antibody to CD123 that has been humanized, affinity-matured, and Fc-engineered for increased affinity toward CD16 (Fc␥RIIIa), which showed an effect against AML both in vitro and in vivo in an environment with adequate NK cell function (20).…”