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

Citation
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
Citations number
30
Categorie Soggetti
Pharmacology & Toxicology
Journal title
TOXICOLOGY AND APPLIED PHARMACOLOGY
ISSN journal
0041008X → ACNP
Volume
158
Issue
2
Year of publication
1999
Pages
152 - 160
Database
ISI
SICI code
0041-008X(19990715)158:2<152:TAPODA>2.0.ZU;2-B
Abstract
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.