Challenges for Therapeutic Application of Pseudomonas Exotoxin-Based Immunotoxins

Abstract

Immunotoxins are therapeutic molecules that belong to a class of biopharmaceuticals called “Armed antibodies”. Immunotoxins are based on very potent toxins of bacterial or plant origin that lack target-cell specificity. To make them target-cell-specific, the non-specific cell binding domains of the original toxins are replaced with a target-cell-specific binding protein, in most cases a monoclonal antibody or a recombinant antibody fragment. The most clinically-advanced immunotoxins are currently being evaluated in phase II and III clinical studies. Like other targeted and non-targeted therapeutics, immunotoxins too suffer from several limitations that may hinder their therapeutic efficacy. Such limitations include, but are not limited to immunogenicity, modification of the extracellular target to which the targeting antibody binds, modification of the intracellular target upon which the toxin acts to cause cell growth inhibition, and insufficient potency as single agents and off-target toxicity, where non-target cells and organs are affected by the immunotoxin, severely impairing its therapeutic index. This chapter is devoted to a group of immunotoxins in which the toxic moiety is derived from exotoxin A (PE) of the bacterium Pseudomonas aeruginosa. The limitations to the efficacy of PE-based immunotoxins, as well as potential solutions for overcoming such limitations, will be presented. Chapter 2 of this book: “Resistance of tumor cells against antibody-targeted protein toxins” by Ulrich Brinkmann et al. is focused on factors that influence the sensitivity or potential resistances of cancer cells towards recombinant immunotoxins which carry truncated and/or mutated derivatives of Pseudomonas exotoxin as cytotoxic payloads.