In vivo toxicity and pharmacokinetic features of B43 (anti-CD19)-genistein immunoconjugate in nonhuman primates.
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.
Messinger
Y
Y
Wayne Hughes Institute, St. Paul, Minnesota 55113, USA.
Yanishevski
Y
Y
Ek
O
O
Zeren
T
T
Waurzyniak
B
B
Gunther
R
R
Chelstrom
L
L
Chandan-Langlie
M
M
Schneider
E
E
Myers
D E
DE
Evans
W
W
Uckun
F M
FM
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*
D018941:Antigens, CD19; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018796:Immunoconjugates; D019833:Genistein; D011505:Protein-Tyrosine Kinases