Pharmacokinetic features, immunogenicity, and toxicity of B43(anti-CD19)-pokeweed antiviral protein immunotoxin in cynomolgus monkeys.
We studied the pharmacokinetic features, immunogenicity, and toxicity of B43-pokeweed antiviral protein (PAP) immunotoxin in 13 cynomolgus monkeys. The disposition of B43-PAP in two monkeys, when administered as a single i.v. bolus dose, was characterized by a slow clearance (1-2 ml/h/kg) with a very discrete peripheral distribution. B43-PAP was retained and distributed largely in the blood as the sole compartment with no significant equilibration with the extravascular compartment. The circulating B43-PAP immunotoxin detected in monkey plasma samples by ELISA and protein immunoblotting was both immunoreactive with, and active against, human leukemic cells in vitro. In systemic immunogenicity and toxicity studies, which involved 11 cynomolgus monkeys, each monkey received a total of seven i.v. doses of B43-PAP at a specific dose level of the dose escalation schedule. B43-PAP-treated monkeys mounted a dose-dependent humoral immune response against both the mouse IgG and PAP moieties of the immunotoxin. When administered i.v. either on an every-day or every-other-day schedule, B43-PAP was very well tolerated, with no significant clinical or laboratory signs of toxicity at total dose levels ranging from 0.007 to 0.7 mg/kg. A transient episode of a mild capillary leak with a grade 2 hypoalbuminemia and 2+ proteinuria was observed at total dose levels equal to or higher than 0.35 mg/kg. At total dose levels of 3.5 and 7.0 mg/kg, B43-PAP caused dose-limiting renal toxicity due to severe renal tubular necrosis. The present study completes the preclinical evaluation of B43-PAP and provides the basis for its clinical evaluation in children with therapy-refractory B-lineage acute lymphoblastic leukemia.
Uckun
F M
FM
Biotherapy Institute, University of Minnesota Academic Health Center, Roseville, Minnesota, USA.
Yanishevski
Y
Y
Tumer
N
N
Waurzyniak
B
B
Messinger
Y
Y
Chelstrom
L M
LM
Lisowski
E A
EA
Ek
O
O
Zeren
T
T
Wendorf
H
H
Langlie
M C
MC
Irvin
J D
JD
Myers
D E
DE
Fuller
G B
GB
Evans
W
W
Gunther
R
R
D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology*; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D006801:Humans; D000922:Immunotoxins / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007700:Kinetics; D008252:Macaca fascicularis; D051379:Mice; D008954:Models, Biological; D009699:N-Glycosyl Hydrolases; D010940:Plant Proteins / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D011507:Proteinuria; D054789:Ribosome Inactivating Proteins, Type 1
D018941:Antigens, CD19; D000998:Antiviral Agents; D000922:Immunotoxins; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D009699:N-Glycosyl Hydrolases; C024275:pokeweed antiviral protein