Targeting diphtheria toxin to growth factor receptors.
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 eukoryotic 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.
Murphy
J R
JR
Evans Department of Clinical Research, Boston University Medical Center Hospital, MA 02118, USA.
vanderSpek
J C
JC
D004167:Diphtheria Toxin / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism / Q000627:therapeutic use; D017978:Receptors, Growth Factor / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000627:therapeutic use*
D004167:Diphtheria Toxin; D007376:Interleukin-2; D017978:Receptors, Growth Factor; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox