Exploring the Synergy of MGD024 with Conventional Agents in Acute Myeloid Leukemia: Insights from Preclinical Studies

Acute myeloid leukemia (AML) continues to be a challenging condition, especially for patients who relapse or are unable to undergo intensive therapies. A new approach using bispecific molecules that engage CD3 has shown promise in treating aggressive AML or those unfit for standard treatment. Flotetuzumab, a bispecific DART molecule targeting CD123 and CD3, has demonstrated efficacy in patients resistant to initial therapy. CD123 is a potential therapeutic target expressed by AML cells and stem cells.

MGD024 is a modified version of this DART molecule, designed for a longer half-life and less frequent dosing. It features a lower affinity for CD3 to reduce the risk of cytokine release, which could improve tolerability and make it suitable for early-stage AML or unfit patients. A study was conducted to evaluate the potential of MGD024 in combination with the standard of care (SOC) for AML.

The study compared MGD024 with flotetuzumab and a modified version of flotetuzumab with an Fc domain, RES234M1.1, in mouse models of AML. Both human AML cell lines with varying CD123 expression levels were used to test the efficacy of the treatments. The results showed that MGD024 had lower in vitro potency but still achieved similar cytolytic activity to the other molecules at higher concentrations. In vivo, MGD024 also showed reduced potency but was able to achieve comparable tumor growth reduction at higher doses.

Furthermore, MGD024 was tested in combination with sub-active doses of cytarabine, venetoclax, or azacitidine. The combination with cytarabine or venetoclax resulted in complete or near-complete tumor elimination, while azacitidine did not enhance the effect of MGD024. Importantly, the SOC agents did not negatively impact the activity of MGD024 at the tested doses, and all treatments were well tolerated.

The findings suggest that MGD024 could be a viable option for combination therapy with SOC in AML patients. An IND application for MGD024 is planned for patients with specific relapsed or refractory hematologic malignancies.