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Targeting diphtheria toxin to growth factor receptors

1995; Elsevier BV; Volume: 6; Issue: 5 Linguagem: Inglês

10.1006/scbi.1995.0034

1096-3650

John R. Murphy, Johanna C. vanderSpek,

Microbial Inactivation Methods

Biochemical, genetic and X-ray crystallographic analysis of diphtheria toxin have demonstrated that the native toxin is composed of three structural domains that function in an ordered fashion to intoxicate a eukaryotic cell. With the knowledge that, if delivered to the cytosol, a single molecule of the catalytic domain is lethal for the cell, we have used recombinant DNA methods to genetically replace the native toxin receptor binding domain with a series of growth factors. The resulting diphtheria toxin-related cytokine fusion proteins, or fusion toxins bind to their respective receptors, are internalized by receptor-mediated endocytosis, and efficiently eliminate target cell populations by the adenosine diphosphate ribosylation of elongation factor 2. Based upon the results of preclinical studies, DAB486IL-2, DAB389IL-2 and DAB389EGF have, or are in the process of being evaluated in Phase I/II clinical trials. To date, administration of the diphtheria toxin-based fusion proteins targeted toward the high affinity IL-2 receptor have been found to be safe, well tolerated, and capable of inducing remission in refractory hematologic malignancies.