IN-VIVO TOXICITY AND PHARMACOKINETIC FEATURES OF B43 (ANTI-CD19)-GENISTEIN IMMUNOCONJUGATE IN NONHUMAN-PRIMATES

B43 (anti-CD19)-genistein immunoconjugate targets genistein, a natural ly occurring protein tyrosine kinase-inhibitory isoflavone to the memb rane-associated antiapoptotic CD19-LYN complexes and triggers apoptoti c cell death. In this preclinical study, the toxicity profiles of B43- genistein as well as unconjugated genistein were evaluated in cynomolg us monkeys. B43-genistein and genistein were administered either as si ngle bolus injections or daily injections for 5-10 consecutive days vi a the i.v. route to monkeys. Neither genistein nor B43-genistein was t oxic to cynomolgus monkeys, and no test article-related histopathologi cal lesions were found in any of the two genistein-treated or five B43 -genistein-treated cynomolgus monkeys. B43-genistein showed a favorabl e pharmacokinetics in monkeys, with a plasma half-life of 10-23 h, Pla sma samples from B43-genistein-treated monkeys elicited potent and CD1 9 antigen-specific antileukemic activity against human CD19(+) leukemi a cells in vitro. To our knowledge, this is the first preclinical toxi city and pharmacokinetic study of a tyrosine kinase inhibitor-containi ng immunoconjugate in nonhuman primates.