In vivo toxicity, pharmacokinetics, and antileukemic activity of TXU (anti-CD7)-pokeweed antiviral protein immunotoxin.
We evaluated the TXU (anti-CD7)-pokeweed antiviral protein (PAP) immunotoxin in both murine and nonhuman primate models. TXU-PAP caused dose-limiting cardiac toxicity in BALB/c mice. In a SCID mouse model of invariably fatal human T-lineage acute lymphoblastic leukemia (ALL), TXU-PAP therapy resulted in a marked improvement of leukemia-free survival without any side effects. Whereas 100% of control mice treated with PBS, unconjugated TXU antibody, or B43-PAP (an immunotoxin that does not react with T-lineage ALL cells) died of disseminated human leukemia within 80 days (median survival, 37 days), 80 +/- 13% of SCID mice treated with 15 microgram of TXU-PAP (median survival, >120 days) and 100% of mice treated with 30 microgram of TXU-PAP (median survival, > 120 days) remained alive and free of leukemia for >120 days. In cynomolgus monkeys, TXU-PAP showed favorable pharmacokinetics with an elimination half-life of 8.1-8.7 h. The monkeys treated with TXU-PAP at dose levels of 0.05 mg/kg/day x 5 days and 0.10 mg/kg/day x 5 days tolerated the therapy very well, without any significant clinical compromise or side effects, and at necropsy, no gross or microscopic lesions were found. This study provides a basis for further evaluation of TXU-PAP as an investigational biotherapeutic agent in the treatment of T-lineage ALL.
Waurzyniak
B
B
Hughes Institute, St. Paul, Minnesota 55113, USA.
Schneider
E A
EA
Tumer
N
N
Yanishevski
Y
Y
Gunther
R
R
Chelstrom
L M
LM
Wendorf
H
H
Myers
D E
DE
Irvin
J D
JD
Messinger
Y
Y
Ek
O
O
Zeren
T
T
Langlie
M C
MC
Evans
W E
WE
Uckun
F M
FM
D000818:Animals; D000917:Antibody Formation; D019011:Antigens, CD7 / Q000276:immunology; D006321:Heart / Q000187:drug effects; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity*; D007074:Immunoglobulin G / Q000096:biosynthesis; D000922:Immunotoxins / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D010940:Plant Proteins / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity*; D054789:Ribosome Inactivating Proteins, Type 1; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D019011:Antigens, CD7; D018796:Immunoconjugates; D007074:Immunoglobulin G; D000922:Immunotoxins; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C111079:TXU-pokeweed antiviral protein, Phytolacca