Diphtheria toxin fused to variant human interleukin-3 induces cytotoxicity of blasts from patients with acute myeloid leukemia according to the level of interleukin-3 receptor expression

Leukemic blasts from patients with acute myeloid leukemia (AML) frequently express high levels of the interleukin-3 receptor α chain (IL-3Rα). In the present study, we have explored the sensitivity of primary leukemic blasts obtained from 34 patients with AML to a diphtheria toxin (DT) composed of the catalytic and translocation domains of DT (DT₃₈₈) fused to IL-3 (DT₃₈₈IL-3) and to DT₃₈₈ fused to a variant IL-3 with increased binding affinity (DT₃₈₈IL-3[K116W]). On a molar basis, DT₃₈₈IL-3[K116W] was significantly more active than DT ₃₈₈IL-3 in mediating leukemic cell killing. The rate of cell killing induced by the 2 DT/IL-3 fusion proteins was significantly correlated with the level of IL-3Rα/IL-3Rβ expressed on leukemic blasts. These observations support a potential use of DT₃₈₈IL-3[K116W] in the treatment of refractory AMLs and provide a simple biochemical parameter for the selection of eligible patients.