Immunotoxins: is there a clinical value?

Drug targeting is an attractive new approach to killing malignant cells, thereby leaving normal tissue unharmed. A decisive breakthrough was the advent of hybridoma technology, making monoclonal antibodies (MoAb) available in limitless supply. To construct reagents with selectivity for certain tumor cells, MoAbs or Fab' fragments were chemically linked to ribosome-damaging toxins derived from plants or bacteria like ricin, abrin, saporin, Pseudomonas exotoxin (PE), and diphtheria toxin (DT) to form immunotoxins, which combined the selectivity of the carrier moiety with the potency of the toxin moiety. The first generation of these immunotoxins showed impressive results in vitro but in most cases disappointing antitumour effects in animals or humans. By contrast, the second generation of immunotoxins, consisting of either A chain immunotoxins with a greatly improved stability in vivo or so-called 'blocked' ricin immunotoxins, have been demonstrated to be extremely effective in several animal models. Preliminary results of the current clinical trials suggest a possible clinical use of immunotoxins in leukemia and lymphoma patients. Genetically engineered fusion toxins have become available, which consist of a growth factor or a cytokine fused to a toxin moiety. In this paper, we will review the features of the three groups of immunotoxins which are most frequently used, i.e., ricin A chain and similar immunotoxins, blocked ricin immunotoxins, and recombinant toxins constructed with Pseudomonas exotoxin or diphtheria toxin.