Toxicology and pharmacokinetics of DTGM, a fusion toxin consisting of a truncated diphtheria toxin (DT388) linked to human granulocyte-macrophage colony-stimulating factor, in cynomolgus monkeys
Ce. Hotchkiss et al., Toxicology and pharmacokinetics of DTGM, a fusion toxin consisting of a truncated diphtheria toxin (DT388) linked to human granulocyte-macrophage colony-stimulating factor, in cynomolgus monkeys, TOX APPL PH, 158(2), 1999, pp. 152-160
We developed a fusion toxin consisting of the catalytic and translocation d
omains of diphtheria toxin linked to human granulocyte-macrophage colony-st
imulating factor (GM-CSF) (DTGM) for the treatment of patients with acute m
yeloid leukemia (AML), Our goal in this study was to determine the toxicity
and pharmacokinetics of DTGM in cynomolgus monkeys (Macacca fascicularis),
which possess cross-reactive GM-CSF receptors. Four groups of young adult
monkeys (6 males and 12 females) were treated with five daily bolus iv infu
sions of 1, 5, 7.5, and 10 mu g/kg DTGM. Monkeys (2 males and 2 females) tr
eated at 1 mu g/kg/day showed no significant side effects. Monkeys (2 males
and 2 females) treated at 5 mu g/kg/day showed Grade 1-2 thrombopenia (NCI
common toxicity criteria) on day 9. In contrast, monkeys (6 females) treat
ed at 7.5 mu g/kg/day developed Grade 3 neutropenia, Grade 1-2 thrombopenia
, Grade 1-3 anemia, and Grade 1-3 hypoalbuminemia. The neutropenia develope
d by day 4 in the 7.5 mu g/kg/day monkeys and by day 3 or 5 in the 10 mu g/
kg/day monkeys and resolved in both groups by day 9, but the thrombopenia,
anemia, and hypoalbuminemia persisted until day 16. Monkeys (2 male and 2 f
emale) treated with 10 mu g/kg/day showed Grade 4 neutropenia that resolved
by day 8 and Grade 2-3 anemia, hypoalbuminemia, and thrombopenia. Three of
the animals developed sepsis, DTGM plasma half-life was 30 min with a peak
concentration of 0.1 mu g/mL or 2 nM (1000-fold higher than the IC50 in vi
tro for AML blasts). Immune responses were minimal in all animals tested at
14 and 28 days with anti-DTGM levels <1 mu g/mL. All four animals at 10 mu
g/kg died or were euthanized, and necropsies were performed. Animals necro
psied on days 4 and 6 showed marked apoptasis and hypoplasia in the marrow,
which was completely resolved for animals necropsied on day 9. No injury t
o other organs, including kidney, heart, liver, central nervous system, or
lung, was seen. The drug was selectively toxic to malignant or differentiat
ed myeloid cells with little toxicity to myeloid progenitors or other organ
s. Minimal effects in nontarget tissues make DTGM a promising candidate che
motherapeutic agent. (C) 1999 Academic Press.