Toxin-Based Therapeutic Approaches

Shapira, Assaf; Benhar, Itai

Three generations of immunotoxins. First generation immunotoxins were prepared by chemically conjugating antibodies/ligands to intact toxin units or to toxins with attenuated cell binding capability. Reducible or non-reducible chemical bonds/linkers were used for that purpose; the first was generally applied when the conjugation site was positioned on part of the toxin that translocates to the cytosol. In second generation immunotoxins, truncated toxins that lack a cell binding domain were chemically conjugated to a targeting moiety. In third generation immunotoxins, mostly produced in the bacterium Escherichia coli, the cell binding domain of the toxin is genetically replaced with a ligand or with the Fv portion of an antibody in which the light and heavy chain variable fragments are either genetically linked (scFv) or held together by a disulfide bond (dsFv). In the next chapter, selected immunotoxins will be classified by their toxic moiety (diphtheria toxin, pseudomonas exotoxin A or RIPs derivatives), and a short review on the mechanism of action of their coupled toxins will be followed by a brief description of their disease-causing target, targeting antibody/ligand, and current status of clinical trials. Information about these and other clinically evaluated immunotoxins is summarized in Table 1 . For ligand targeted toxins, we provide detailed examples of toxin based therapies that were evaluated in patients and do not detail the hundreds of examples of molecules that were evaluated pre-clinically.