Abstract
Recent studies indicate that abnormalities of the alpha-chain of the interleukin-3 receptor (IL-3RA or CD123) are frequently observed in some leukemic disorders and may contribute to the proliferative advantage of leukemic cells. This review analyzes the studies indicating that CD123 is overexpressed in various hematologic malignancies, including a part of acute myeloid and B-lymphoid leukemias, blastic plasmocytoid dendritic neoplasms (BPDCN) and hairy cell leukemia.Given the low/absent CD123 expression on normal hematopoietic stem cells, attempts have been made at preclinical first, and then at clinical level to target this receptor. Since the IL-3R is a membrane receptor there are two relatively simple means to target this molecule, either using its natural ligand or neutralizing monoclonal antibodies. Recent reports using a fusion molecule composed by human IL-3 coupled to a truncated diphteria toxin have shown promising antitumor activity in BPDCN and AML patients.
Highlights
The Interleukin (IL)-3, IL-5 and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) Receptor, form a subfamily of membrane receptors, known as the Beta Common family of cytokines because these three receptors share the common signaling subunit βc
Targeting of IL-3R in acute leukemias All these findings have suggested that IL-3R may represent a potentially important target for the development of new antileukemic drugs [40]
Conclusions and future directions In conclusion, the strudies carried out during the last two decades have clearly shown that CD123 is overexpressed in many hematologic malignancies, including blastic plasmocytoid dendritic neoplasms (BPDCN), Acute Myeloblastic Leukemia (AML), B-ALLs, Hairy Cell Leukemia
Summary
The Interleukin (IL)-3, IL-5 and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) Receptor, form a subfamily of membrane receptors, known as the Beta Common (βc) family of cytokines because these three receptors share the common signaling subunit βc. These studies provided evidence for that it concerns pharmacokinetics about a pharmacokinetic profile similar to that previously reported for other humanised antibodies and for that concerns pharmacodynamics about a marked dose-dependent depletion of peripheral blood basophils and plasmacellular dendritic cells, associated with a transient decrease of NK lymphocytes and with virtually no effects at the level of monocytes and pluripotent bone marrow progenitor/stem cells [63] These pharmacodynamic studies were completed by the observation that CSL362 administration to NSG mice xenografted with human primary AML cells considerably potentiated the antileukemic effect elicited by the administration of the drug combination cytabarine/daunorubicin [64]. Advances in patient selection and drug design should establish a role for CD123 targeted therapy in hematologic malignancies
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