In vivo toxicity and pharmacokinetic features of B43(Anti-CD19)-Genistein immunoconjugate.
B43(anti-CD19)-Genistein immunoconjugate targets genistein, a naturally occurring protein tyrosine kinase inhibitory isoflavone to the membrane-associated anti-apoptotic 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 mice. B43-Genistein and genistein were administered either as single bolus injections or daily injections for 10 consecutive days via the intraperitoneal route to mice. Genistein was not toxic to mice at the highest dose of 40 mg/kg and no test article-related histopathological lesions were found in any of the 64 genistein-treated mice. B43-Genistein had a significantly longer elimination half-life and slower plasma and tissue clearance than unconjugated genistein. B43-Genistein was not toxic to mice at the highest single dose of 40 mg/kg or highest cumulative dose of 100 mg/kg and no test article-related histopathological lesions were found in any of the 108 mice treated with B43-genistein. To our knowledge, this is the first preclinical toxicity and pharmacokinetic study of a tyrosine kinase inhibitor-containing immunoconjugate.
Ek
O
O
Wayne Hughes Institute, St. Paul, MN, USA.
Yanishevski
Y
Y
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 / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D019540:Area Under Curve; D004195:Disease Models, Animal; D005260:Female; D019833:Genistein / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D015448:Leukemia, B-Cell / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID
D018941:Antigens, CD19; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D019833:Genistein