title: In vivo toxicity and pharmacokinetic features of B43 (anti-CD19)-genistein immunoconjugate in nonhuman primates.
abstract: B43 (anti-CD19)-genistein immunoconjugate targets genistein, a naturally occurring protein tyrosine kinase-inhibitory isoflavone to the membrane-associated antiapoptotic CD19-LYN complexes and triggers apoptotic cell death. In this preclinical study, the toxicity profiles of B43-genistein as well as unconjugated genistein were evaluated in cynomolgus monkeys. B43-genistein and genistein were administered either as single bolus injections or daily injections for 5-10 consecutive days via the i.v. route to monkeys. Neither genistein nor B43-genistein was toxic to cynomolgus monkeys, and no test article-related histopathological lesions were found in any of the two genistein-treated or five B43-genistein-treated cynomolgus monkeys. B43-genistein showed a favorable pharmacokinetics in monkeys, with a plasma half-life of 10-23 h. Plasma samples from B43-genistein-treated monkeys elicited potent and CD19 antigenspecific antileukemic activity against human CD19+ leukemia cells in vitro. To our knowledge, this is the first preclinical toxicity and pharmacokinetic study of a tyrosine kinase inhibitor-containing immunoconjugate in nonhuman primates.
authors.affiliation: Wayne Hughes Institute, St. Paul, Minnesota 55113, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Messinger
authors.forename: Y
authors.initials: Y
authors.lastname: Yanishevski
authors.forename: O
authors.initials: O
authors.lastname: Ek
authors.forename: T
authors.initials: T
authors.lastname: Zeren
authors.forename: B
authors.initials: B
authors.lastname: Waurzyniak
authors.forename: R
authors.initials: R
authors.lastname: Gunther
authors.forename: L
authors.initials: L
authors.lastname: Chelstrom
authors.forename: M
authors.initials: M
authors.lastname: Chandan-Langlie
authors.forename: E
authors.initials: E
authors.lastname: Schneider
authors.forename: D E
authors.initials: DE
authors.lastname: Myers
authors.forename: W
authors.initials: W
authors.lastname: Evans
authors.forename: F M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology*; D000970:Antineoplastic Agents / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D019833:Genistein / Q000633:toxicity*; D018796:Immunoconjugates / Q000493:pharmacokinetics / Q000633:toxicity*; D008252:Macaca fascicularis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D018941:Antigens, CD19; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018796:Immunoconjugates; D019833:Genistein; D011505:Protein-Tyrosine Kinases