Biochemical, genetic and X-ray crystallographic analysis of diphtheria
toxin have demonstrated that the native toxin is composed of three st
ructural 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 to
xin receptor binding domain with a series of growth factors. The resul
ting diphtheria toxin-related cytokine fusion proteins, or fusion toxi
ns bind to their respective receptors, are internalized by receptor-me
diated endocytosis, and efficiently eliminate target cell populations
by the adenosine diphosphate ribosylation of elongation factor 2. Base
d upon the results of preclinical studies, DAB(486)IL-2, DAB(389)IL-2
and DAB(389)EGF have, or are in the process of being evaluated in Phas
e I/II clinical trials. To date, administration of the diphtheria toxi
n-based fusion proteins targeted toward the high affinity IL-2 recepto
r have been found to be safe, well tolerated and capable of inducing r
emission in refractory hematologic malignancies. (C) 1995 Academic Pre
ss Ltd