Targeting IL3RA with BAY-943: A Promising Anti-Tumor Approach in AML Models

Acute Myeloid Leukemia (AML) has seen limited improvement in clinical outcomes over the past 30 years, highlighting the need for new therapeutic agents with a high therapeutic index and good tolerability. The interleukin 3 receptor alpha subunit (IL3RA or CD123) is a potential target for antibody-drug conjugate (ADC) therapy due to its high expression in AML and classical Hodgkin lymphoma (cHL), but not in healthy hematopoietic stem cells.

BAY-943 is an innovative ADC that combines a humanized anti-IL3RA antibody with a potent kinesin spindle protein inhibitor (KSPi), which is crucial for cell division in the G2/M phase and thus primarily affects proliferating cells. In vitro studies on IL3RA-positive AML and HL cell lines demonstrated BAY-943's potency at nano- to subnanomolar concentrations. In vivo, BAY-943 at 10 mg/kg administered every seven days significantly enhanced survival and reduced tumor burden in AML xenograft models. In a cHL model, complete tumor remission was observed in the majority of mice treated with BAY-943.

Safety evaluations in Cynomolgus monkeys showed that BAY-943 was well tolerated at doses up to 20 mg/kg as a single dose or 10 mg/kg repeated doses, with no thrombocytopenia, neutropenia, or liver toxicity. A transient decrease in IL3RA-expressing cells such as basophils and plasmacytoid dendritic cells was noted.

Collectively, BAY-943 has shown efficacy against IL3RA-positive AML and HL in preclinical models and exhibited a favorable safety profile in non-human primates, supporting its further development as a novel treatment for IL3RA-positive AML. The study was presented at the American Association for Cancer Research Annual Meeting in 2019.