Diane P. Williams

Diphtheria Toxin-Related Peptide Hormone Fusion Proteins: New Toxins with Therapeutic Potential

The genetic replacement of either the native diphtheria toxin or Pseudomonas exotoxin A receptor binding domain with eukaryotic cell receptor-specific polypeptide hormones or growth factor sequences has resulted in the development of a new class of biological response modifier — the fusion toxin (1, 2, 3, 4, 5, 6). The first of these fusion toxins, DAB486-IL-2, is currently in human Phase I clinical trials and the early results clearly domonstrate that this molecule is safe, well-tolerated, and biologically active in the elimination of high affinity IL-2 receptor positive leukemia and lymphoma cells without adverse side-effect (LeMaistre, personal communication). DAB486-IL-2 is a bipartite fusion protein composed of diphtheria toxin fragment A and fragment B sequences to Ala486 linked to Pro2 through Thr133 of human interleukin-2 (IL-2) (2). This chimeric protein is the product of a genetic fusion between a truncated gene encoding fragment A and the membrane associating domains of fragment B of diphtheria toxin and a synthetic gene encoding human IL-2 (7). DAB486-IL-2 has been shown to selectively bind to high affinity IL-2 receptors, be internalized by receptor-mediated endocytosis, and facilitate the delivery of diphtheria toxin fragment A to the cytosol of target cells (8,9). Recent studies have defined the minimal size of fragment B that is required to deliver fragment A across the endocytic vesicle membrane in target cells, and defined the site of proteolytic processing involved in the release of fragment A from the intact fusion toxin molecule (10,11).