Targeting AML Stem Cells with CSL362: Enhancing NK Cell-Mediated Cytotoxicity through IL-3Rα/CD123

The interleukin-3 receptor alpha chain (IL-3Rα/CD123) is commonly found in various hematological malignancies, including AML, and is particularly overexpressed on leukemic stem cells (LSC). This overexpression suggests a potential therapeutic target. A mouse monoclonal antibody, 7G3, which inhibits IL-3 binding to CD123, has been shown to eliminate human LSC in a mouse model of AML.

The antibody has been humanized and affinity-matured to create CSL362, which has an enhanced affinity for the FcγRIIIa (CD16) receptor on NK cells. In vitro studies indicate that CSL362 has improved antibody-dependent cell-mediated cytotoxicity (ADCC) against CD123-expressing cell lines compared to a non Fc-engineered anti-CD123 monoclonal antibody. This enhanced activity is observed in both primary AML blasts and CD34+CD38?CD123+LSC, even in samples resistant to non Fc-engineered anti-CD123 mAb-mediated ADCC.

In an AML xenograft mouse model, CSL362 demonstrated greater efficacy in reducing leukemic growth than the non Fc-engineered anti-CD123 mAb. NK cells have been identified as the primary effector cells responsible for CSL362-mediated cytotoxicity in human peripheral blood. Clinical samples have shown the potential for autologous depletion of target AML blasts following incubation with CSL362, suggesting that NK cell function is preserved enough in patients for targeted killing of leukemic cells.

Pre-clinical data supports the advancement of CSL362 into clinical development for the treatment of AML, particularly in patients with adequate NK cell function. A Phase 1 clinical trial for CSL362 in patients with CD123 positive AML in remission is currently in progress.