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Vol. 291, Issue 3, 1301-1307, December 1999
Biotherapy Program (F.M.U., K.O., Y.M.), Departments of
Virology (F.M.U., K.B.), Immunology (F.M.U., K.O., Y.M., T.J.) and
Pharmaceutical Sciences (C.-L.C.), Hughes Institute, St. Paul,
Minnesota
The purpose of the present study was to evaluate the toxicity
and pharmacokinetics of TXU (anti-CD7)-pokeweed antiviral
protein (PAP) in human immunodeficiency virus (HIV)-infected
chimpanzees and adult patients. At a total dose of 100 µg/kg, TXU-PAP
did not cause severe (grade 
3) toxicity in any of the four HIV type 1 (HIV-1)-infected or two healthy chimpanzees. The only side effects were a transient elevation of the liver enzyme alanine aminotransferase between days 2 and 14 without a concomitant rise in total bilirubin levels and a decrease in the serum albumin levels between days 1 and 5 without any concomitant weight gain or peripheral edema. TXU-PAP showed
favorable pharmacokinetics in chimpanzees with a plasma elimination
half-life of 5.1 to 12.0 h and a systemic clearance of 5.8 to 15.1 ml/h/kg. At 2 months after initiation of the TXU-PAP infusions, the
HIV-1 burden was reduced to below-detection levels in three of the four
chimpanzees, and in the remaining chimpanzee, the HIV burden was <500
RNA copies/ml at 2 weeks but returned to the pretreatment levels by 2 months. TXU-PAP was well tolerated by HIV-1-infected adult patients who
received a single 5 µg/kg i.v. infusion of TXU-PAP. TXU-PAP showed
very favorable pharmacokinetics in these patients with a relatively
long plasma elimination half-life of 12.4 ± 1.4 h, a mean
residence time of 17.9 ± 2.0 h, and a slow systemic
clearance of 2.7 ± 0.7 ml/h/kg. Concentrations of TXU-PAP
required for effective inhibition of HIV-1 replication in preclinical
models were achieved in HIV-1-infected patients at the 5 µg/kg dose
level without any adverse reactions, and the mean value for AUC was
3059 ± 721 ng · h/ml. The 1-h postinfusion plasma samples
from TXU-PAP-treated patients showed potent anti-HIV activity in vitro
and inhibited the replication of HIV in normal peripheral blood
mononuclear cells (PBMCs) even at a 1:100 dilution. Although treatment
with TXU-PAP at the 5 µg/kg dose level does not provide sustained
therapeutic levels, it was capable of reducing the viral burden in six
of six patients evaluated. To our knowledge, this is the first report
of a clinical pharmacokinetics study of a PAP immunoconjugate in
HIV-infected patients. The favorable long plasma elimination half-life
of TXU-PAP in combination with its low toxicity provides the basis for
further investigation of TXU-PAP as a potential anti-HIV agent.
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