Toxicology and pharmacokinetics of DT388IL3, a fusion toxin consisting of a truncated diphtheria toxin (DT388) linked to human interleukin 3 (IL3), in cynomolgus monkeys.
The fusion toxin DT388IL3 composed of the catalytic and translocation domains of diphtheria toxin (DT388) linked to interleukin-3 (IL3) was administered to 6 cynomolgus monkeys which possessed cross-reactive IL3 receptors. Groups of 2 animals (1 male and 1 female) received up to 6 every other day slow intravenous infusions of 40, 60, or 100 microg/kg DT388IL3. Monkeys given 40 or 60 microg/kg showed mild or moderate transient malaise and anorexia, respectively, without evidence of organ damage by blood tests or histopathology. Animals treated at 100 microg/kg showed severe malaise and anorexia. The female monkey had moderate to severe vasculitis in multiple tissues. Necropsies were performed on the 40 microg/kg monkeys on day 14 and the 100 microg/kg monkeys on days 6 and 7. DT388IL3 plasma half-life was approximately 30 min with a peak concentration of 0.45 microg/ml or 10,000 pM (IC50 for AML blasts treated in vitro was 6 pM). Immune responses were minimal in 4 animals tested at 12 days and 2 animals tested at 30 days post treatment with anti-DT388IL3 levels < 1 microg/ml. Bone marrow aspirates were obtained on all animals at day 19 or at necropsy and revealed myeloid suppression in the females and myeloid hyperplasia in the males irrespective of dose groups. The maximal tolerated dose of 60 microg/kg for 6 doses is markedly higher than other recombinant diphtheria toxins and provides a dose level sufficient for anti-leukemic activity in vitro and in rodent models. Thus, we propose this agent is a promising drug for AML patients.
Cohen
Kimberley A
KA
Department of Comparative Medicine and Cancer Biology, Wake Forest Health Sciences, Winston-Salem, NC 27157, USA.
Liu
Tie Fu
TF
Cline
J Mark
JM
Wagner
Janice D
JD
Hall
Philip D
PD
Frankel
Arthur E
AE
D000818:Animals; D000855:Anorexia / Q000139:chemically induced; D001854:Bone Marrow Cells / Q000187:drug effects; D004167:Diphtheria Toxin / Q000493:pharmacokinetics* / Q000633:toxicity*; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007377:Interleukin-3 / Q000493:pharmacokinetics* / Q000633:toxicity*; D008252:Macaca fascicularis; D008297:Male; D020714:Maximum Tolerated Dose; D016185:Receptors, Interleukin-3 / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics* / Q000633:toxicity*; D014657:Vasculitis / Q000139:chemically induced
D004167:Diphtheria Toxin; D007377:Interleukin-3; D016185:Receptors, Interleukin-3; D011993:Recombinant Fusion Proteins; C407154:diphtheria toxin-interleukin-3 fusion protein, recombinant