Targeting AML Stem Cells with CSL362: Enhancing NK Cell-Mediated Cytotoxicity through Monoclonal Antibody Therapy

The CD123 antigen is present in several blood-related cancers, such as AML, MDS, B-ALL, and others. Notably, in AML, CD123 is predominantly found on AML cells, particularly on stem cells that are more primitive, suggesting a potential therapeutic target. A mouse antibody, 7G3, which inhibits IL-3 binding to CD123, was found to be effective against human AML stem cells in mice, leveraging both innate immune system engagement and other mechanisms.

Further development led to the creation of CSL362, a humanized and enhanced antibody. This antibody not only neutralizes IL-3 but also has a stronger binding affinity to the FcγRIIIa receptor on NK cells, which is linked to improved cell-killing efficacy. In vitro tests have shown that CSL362 is more effective at eliminating CD123-positive cell lines compared to a non-engineered version. Importantly, it can also target primary AML cells and stem cells, even those resistant to non-engineered antibodies.

In a mouse model of AML, CSL362 demonstrated superior efficacy in slowing down cancer growth. NK cells were identified as the primary mediators of CSL362's cytotoxic effects. Clinical samples also showed that CSL362 can deplete AML cells when combined with patient-derived immune cells, indicating that the NK cells' function is preserved enough for targeted cell killing.

The accumulated pre-clinical evidence supports advancing CSL362 into clinical trials for AML treatment, particularly for patients with functional NK cells. A Phase 1 clinical trial for CD123-positive AML patients in remission is currently in progress, as registered on Clinical Trials.gov.