Tagraxofusp

Interleukin 3 (IL-3) is a cytokine and hematopoietic growth factor that promotes the differentiation of hematopoietic cells into various myeloid cells. It mediates its biological actions by binding to the IL-3 receptor, which is made up of two subunits: the alpha (α) subunit - also known as CD123 - is the site of ligand attachment and confers receptor specificity, while the beta (β) subunit, also known as CDw131 - plays a role in signal transduction, internalization of the ligand-receptor complexes, and activation of the Ras signalling pathway. The expression of the IL-3 receptor is prevalent in CD34+ hematopoietic cells as well as on granulocytes and monocyte precursors. CD123, the subunit of the IL-3 receptor, has also been implicated in the pathophysiology of BPDCN, as transformed plasmacytoid dendritic cells that overexpress CD123 are frequently observed.

Tagraxofusp targets leukemic stem cells that express CD123. It is a fusion protein made up of diphtheria toxin (DT) and IL-3; therefore, it binds to the IL-3 receptor with high affinity. Upon binding to the IL-3 receptor on CD123-expressing cells, tagraxofusp is internalized via receptor-mediated endocytosis. The catalytic domain of DT is then cleaved and translocates from the endosome into the cytosol. The catalytic domain of DT irreversibly inhibits protein synthesis by inactivating elongation factor 2 (EF2), eventually inducing apoptosis.