(A) The fusion of IL3 at the C terminus of the truncated diphtheria toxin. The binding domain of diphtheria toxin, located at the C terminus, is deleted and replaced by IL3. Thus, the cytotoxicity of the fusion protein is targeted to cells expressing IL3 receptors (CD123). The domain names are as follows: A, active enzyme domain; T, translocation domain; B, binding domain. The binding domain is removed and replaced by IL3 to form DT-IL3, which is called SL-401 in Frankel et al.1 (B) The pathway of binding, entry, and killing by DT-IL3. DT-IL3 binds CD123 and is internalized, and the A chain is processed proteolytically to release the A chain. The A chain translocates from acidic endosomes to the cytosol. In the cytosol, the A chain ADP-ribosylates EF2 and inhibits protein synthesis. Cells die because they cannot make new protein.
