Pharmacology

The immunotoxin-conjugated MoAbs, or ITs, are fusion proteins that consist of MoAbs covalently linked to protein toxins. These highly potent toxins are typically derived from plant, bacterial, or fungal sources and possess the ability to disrupt protein synthesis through a series of catalytic enzymatic reactions at very small concentrations.1 The most technically challenging of all MoAbs to design and deliver, immuno-toxins are genetically engineered to retain their cyto-toxic potency, while their tissue-binding domains are truncated in order to allow for MoAb-directed targeting of specific cell surface proteins. This minimizes binding of the toxin to healthy cells, while selectively targeting malignant clones.29 In order for the toxin to exert its effect, it must undergo internalization by the cell, rather than remaining on the cell surface as with unconjugated MoAbs. This allows the toxin to gain access to critical intracellular functions located within the cytosol. Receptor-mediated endocytosis occurs once the compound binds to the cell surface. Upon entering a cell, the toxin is carried by clathrin-coated vesicles to either acidic endosomes (bacterial toxins) or neutral trans-Golgi (plant toxins), where interruption of protein synthesis occurs. Both plant and bacterial toxins disrupt the elongation step of protein synthesis, through enzymatic alteration of either elongation factor 2 or its binding site.30 Toxins that have been used in this manner include ricin, abrin, diphtheriatoxin, and pseudomonas toxin. A variety of compounds are currently in clinical development (Table 103.2).

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