IGM-2537: A CD123-Targeted IgM TCE with Enhanced Anti-AML Activity and Reduced Cytokine Release

IGM-2537 is a novel bispecific antibody designed to target CD123, a protein found in high levels on AML cells, with the aim of improving treatment outcomes for this disease, particularly in cases of relapse or resistance to standard therapies. The antibody is constructed with 10 binding sites for CD123 and a single binding site for CD3, allowing for high affinity binding to cancer cells and activation of T cells to destroy them. It has been shown to have a high binding affinity and specificity for CD123, targeting a unique site that does not interfere with IL-3 binding.

In vitro and ex vivo studies have demonstrated IGM-2537's ability to effectively engage both CD123 and CD3, leading to the activation of T cells and the destruction of AML cell lines. Notably, IGM-2537 has shown a significant reduction in cytokine release compared to other CD123-targeting therapies, which is a crucial factor in reducing the risk of cytokine release syndrome, a potentially serious side effect.

In vivo studies using a humanized mouse model have confirmed the drug's anti-tumor efficacy, with tumor growth inhibition observed at doses ranging from 1 to 10 mg/kg. Furthermore, when compared to an IgG-based TCE molecule, IGM-2537 has been found to have a better safety profile, with a 100-fold greater tolerability in cynomolgus monkeys. The IgM format of the TCE molecule has also shown to deplete CD123-positive basophils and reduce plasmacytoid dendritic cells with minimal cytokine induction.

Overall, IGM-2537 has exhibited potent activity against AML both in vitro and in vivo, with a favorable safety profile and an improved therapeutic window, suggesting its potential as a novel treatment for AML.