Abstract
Immunotoxins are a class of targeted cancer therapeutics in which a toxin such as Pseudomonas exotoxin A (PE) is linked to an antibody or cytokine to direct the toxin to a target on cancer cells. While a variety of PE-based immunotoxins have been developed and a few have demonstrated promising clinical and preclinical results, cancer cells frequently have or develop resistance to these immunotoxins. This review presents our current understanding of the mechanism of action of PE-based immunotoxins and discusses cellular mechanisms of resistance that interfere with various steps of the pathway. These steps include binding of the immunotoxin to the target antigen, internalization, intracellular processing and trafficking to reach the cytosol, inhibition of protein synthesis through ADP-ribosylation of elongation factor 2 (EF2), and induction of apoptosis. Combination therapies that increase immunotoxin action and overcome specific mechanisms of resistance are also reviewed.
Highlights
Immunotoxins are a promising class of cancer therapeutics that combine the potent cytotoxicity of a toxin such as Pseudomonas exotoxin A (PE) with the selectivity of an antibody fragment or cytokine [1]
Further investigation revealed that reduction of CAS protein levels through expression of the antisense cDNA resulted in resistance to native PE, diphtheria toxin, and tumor necrosis factor (TNF) α and β, though it did not cause resistance to other agents including the protein synthesis inhibitor cycloheximide
Portions of the pathway used by PE-based immunotoxins are still not perfectly understood
Summary
Immunotoxins are a promising class of cancer therapeutics that combine the potent cytotoxicity of a toxin such as Pseudomonas exotoxin A (PE) with the selectivity of an antibody fragment or cytokine [1]. PE-based immunotoxins present several advantages over chemotherapy in that they kill cells by a unique mechanism (inhibition of protein synthesis) and they do not cause mutations by damaging DNA. Immunotoxins have been successful in treating certain cancers, such as drug resistant hairy cell leukemia [13]. This review discusses cellular mechanisms of resistance to PE-based immunotoxins as well as current efforts to overcome them. While factors such as immunogenicity and the challenges of delivery to solid tumors significantly hinder immunotoxin therapy, they are beyond the scope of this review. It should be noted that resistance mechanisms to immunotoxins utilizing toxin domains from sources other than PE would typically vary depending on the cellular itinerary and toxin mechanism involved. When immunotoxin mechanisms overlap ( in the binding and internalization steps), resistance mechanisms may overlap as well
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