Fig. 11

Iluzanebart Proposed Mechanism of Action. A Healthy CSF1R signaling. Under normal conditions, ligand binding to CSF1R induces homodimerization and triggers transphosphorylation and activation of the CSF1R intracellular kinase domains, recruiting Src kinase and triggers downstream mediators such as SYK and transmembrane adapter protein DAP12, promoting microglia survival, proliferation, phagocytosis, and motility. Ligand binding to and activation of TREM2 also triggers the same intracellular signaling pathways through pSYK and through the DAP12 adapter protein. B Dysfunctional CSF1R in CSF1R-ALSP. When CSF1R receptors are dysfunctional due to genetic mutations, signaling through microglia health-promoting pathways is reduced (C) Treatment of CSF1R-ALSP with iluzanebart. Iluzanebart binds with high affinity to the extracellular domain of two TREM2 molecules, sequestering them in an active, dimerized state and activating microglia health-promoting downstream signaling to compensate for lost CSF1R signaling as well as increasing signaling through an increase in the amount of CSF1 receptors at the cell surface