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Monoclonal Antibody-Mediated Targeting of CD123, IL-3 Receptor α Chain, Eliminates Human Acute Myeloid Leukemic Stem Cells

Division of Cell and Molecular Biology, University Health Network, Toronto, ON M5G 1L7, Canada.
Cell stem cell (Impact Factor: 22.15). 08/2009; 5(1):31-42. DOI: 10.1016/j.stem.2009.04.018
Source: PubMed

ABSTRACT Leukemia stem cells (LSCs) initiate and sustain the acute myeloid leukemia (AML) clonal hierarchy and possess biological properties rendering them resistant to conventional chemotherapy. The poor survival of AML patients raises expectations that LSC-targeted therapies might achieve durable remissions. We report that an anti-interleukin-3 (IL-3) receptor alpha chain (CD123)-neutralizing antibody (7G3) targeted AML-LSCs, impairing homing to bone marrow (BM) and activating innate immunity of nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice. 7G3 treatment profoundly reduced AML-LSC engraftment and improved mouse survival. Mice with pre-established disease showed reduced AML burden in the BM and periphery and impaired secondary transplantation upon treatment, establishing that AML-LSCs were directly targeted. 7G3 inhibited IL-3-mediated intracellular signaling of isolated AML CD34(+)CD38(-) cells in vitro and reduced their survival. These results provide clear validation for therapeutic monoclonal antibody (mAb) targeting of AML-LSCs and for translation of in vivo preclinical research findings toward a clinical application.

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Available from: Hayley S Ramshaw, Aug 15, 2015
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    • "Paradoxically, monoclonal antibody (mAb) 7G3 recognizes the IL3Ra NTD (Sun et al., 1996; Barry et al., 1997) and completely blocks IL-3 binding and signaling. We recently showed that mAb 7G3 eliminates engrafted human AML stem cells in a mouse model of human AML (Jin et al., 2009). mAb 7G3, now humanized and designated as CSL362 (Busfield et al., 2014), is entering clinical trials for the treatment of patients with AML (ClinicalTrials.gov "
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    ABSTRACT: Interleukin-3 (IL-3) is an activated T cell product that bridges innate and adaptive immunity and contributes to several immunopathologies. Here, we report the crystal structure of the IL-3 receptor α chain (IL3Rα) in complex with the anti-leukemia antibody CSL362 that reveals the N-terminal domain (NTD), a domain also present in the granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-5, and IL-13 receptors, adopting unique "open" and classical "closed" conformations. Although extensive mutational analyses of the NTD epitope of CSL362 show minor overlap with the IL-3 binding site, CSL362 only inhibits IL-3 binding to the closed conformation, indicating alternative mechanisms for blocking IL-3 signaling. Significantly, whereas "open-like" IL3Rα mutants can simultaneously bind IL-3 and CSL362, CSL362 still prevents the assembly of a higher-order IL-3 receptor-signaling complex. The discovery of open forms of cytokine receptors provides the framework for development of potent antibodies that can achieve a "double hit" cytokine receptor blockade.
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    • "Strikingly, CD123 shows a fourfold increased expression on AML-LSCs over normal HSCs (Jin et al, 2009). This finding, together with the clinical observations that elevated expression of CD123 in AML is associated with higher blast counts at diagnosis and a lower complete remission rate resulting in poorer prognosis (Testa et al, 2002, 2004; Graf et al, 2004), make CD123 a particularly interesting target for antibody-derived therapeutics (Jin et al, 2009). AML-LSCs are known to possess several remarkable properties including self-renewal potential and increased resistance against chemotherapeutics and DNA damage (Lapidot et al, 1994; Bonnet & Dick, 1997; Guan & Hogge, 2000; Guzman et al, 2001; Hope et al, 2004; Ishikawa et al, 2007; Dick, 2008). "
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    • "Below is a partial list of potential LSC targets (Table 1). The CD123 antigen (interleukin-3 receptor alpha chain) was the first to be identified in CD34+CD38À AML cells (Jordan et al., 2000); targeting of this receptor with a neutralizing monoclonal antibody (7G3) reduced the AML burden and inhibited the re-populating activity of LSCs in NOD/SCID mice (Jin et al., 2009). Moreover, the delivery of toxic conjugates to LSCs through this receptor is now under investigation (Frankel et al., 2008). "
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    ABSTRACT: Myeloid leukemias are heterogeneous malignancies in morphology, immunophenotype, genetic and epigenetic alterations, and response to therapy. This heterogeneity is thought to depend on the accumulation of secondary mutations enhancing proliferation/survival and/or blocking differentiation in a small subset of leukemia-initiating cells capable of self-renewal. This model of clonal evolution is based on xenotransplantation studies demonstrating that leukemia can be initiated and maintained in immunodeficient mice by a small subset of purified leukemic cells immunophenotypically similar to normal hematopoietic stem cells and is known as the leukemia stem cell model. Since its original formulation, many studies have validated the main conclusion of this model. However, recent data from xenotransplantation studies in more severely immunodeficient mice suggest that imunophenotype and behaviour of leukemic stem cells is more heterogeneous and "plastic" than originally thought. We will discuss here the evolution of the leukemia stem cell model and its impact for the therapy of patients with myeloid malignancies.
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