Intoxication of CD22⁺ B cells by moxetumomab pasudotox. The recombinant immunotoxin is composed of VH and VL (green), which are disulfide bonded together by cysteines replacing Arg44 of VH and Gly100 of VL. The carboxy terminus of VH is fused to the toxin. VH contains a mutation of SSY to THW at positions 100, 100a, and 100b, respectively. The toxin PE38 is composed of domain 2 (amino acids 253-364, yellow), 1a (amino acids 381-399, not shown), and the catalytic domain 3 (amino acids 400-613, red). After the variable domains bind to CD22, the immunotoxin internalizes into a coated pit by endocytosis, domain 2 is proteolytically cleaved between Arg279 and Gly280 by Furin, the carboxy terminus of the toxin traffics to the endoplasmic reticulum using the KDEL receptor (light green), and then, once in the cytosol, the enzymatic domain within domain III ADP ribosylates EF2, leading to protein synthesis inhibition and apoptotic cell death.