Toxicology and pharmacokinetics of DT388IL3, a fusion toxin consisting of a truncated diphtheria toxin (DT388) linked to human interleukin 3 (IL3), in cynomolgus monkeys

Leukemia & Lymphoma
Kimberley A CohenArthur E Frankel

Abstract

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 ...Continue Reading

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Citations

Dec 23, 2004·Cancer Immunology, Immunotherapy : CII·Kimberley A CohenArthur E Frankel
May 14, 2010·PloS One·Yi ZhangDavid Morton Waisman
Jul 7, 2007·Expert Opinion on Therapeutic Targets·Brynn T Kvinlaug, Brian J P Huntly
Feb 12, 2014·Biomarker Research·Ugo TestaArthur Frankel
Nov 5, 2019·Frontiers in Microbiology·Fatemeh ShafieeAli Jahanian-Najafabadi
Sep 1, 2019·International Journal of Molecular Sciences·Peter ValentDominik Wolf
Dec 1, 2016·International Journal of Hematologic Oncology·Germana CastelliUgo Testa
Oct 24, 2019·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Boris GorovitsArno Kromminga
Jan 18, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Lina HanMarina Konopleva

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