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Thrombolytic and pharmacokinetic properties of an immunoconjugate of
single-chain urokinase-type plasminogen activator (u-PA) and a bispecific
monoclonal antibody against fibrin and against u-PA in baboons
Y Imura, JM Stassen, T Kurokawa, S Iwasa, HR Lijnen and D Collen
Center for Thrombosis and Vascular Research, University of Leuven, Belgium.
Targeting of plasminogen activators to the fibrin component of a thrombus
with the use of monoclonal antibodies (MA) directed against human fibrin
may enhance their thrombolytic potency and fibrin- specificity. The
thrombolytic and pharmacokinetic properties of rscu- PA/MA-FU1-74, an
immunoconjugate of recombinant single-chain urokinase- type plasminogen
activator (rscu-PA) and a bispecific MA directed against u-PA and against
the beta-chain of human fibrin (MA-FU1-74), were investigated in baboons
with a [125I]fibrin-labeled autologous blood clot in the femoral vein.
Continuous intravenous infusion of rscu- PA/MA-FU1-74 (1:1.2 molar ratio)
over 2 hours showed a fivefold increased thrombolytic potency (lysis per
unit dose) over that of unconjugated rscu-PA, as evidenced both by a higher
maximal rate of lysis (380% +/- 68% v 78% +/- 25% lysis per mg u-PA
equivalent of compound administered per kg body weight, P less than .001),
and by a lower dose at which the maximal rate of lysis occurs (0.19 +/-
0.03 v 0.82 +/- 0.10 mg compound per kg body weight, P less than .001). The
specific thrombolytic activity (percent lysis per unit steady-state plasma
u-PA antigen level) was lower for rscu-PA/MA-FU1-74 than for rscu-PA, as
shown by both a lower maximal rate of lysis (60% +/- 13% v 220% +/- 22%
lysis per microgram/mL u-PA antigen level in plasma, P less than .001) and
a higher plasma antigen level at which maximal lysis is achieved (1.2 +/-
0.17 v 0.20 +/- 0.01 microgram/mL, P less than .001). The thrombolytic
potency of rscu-PA/MA-UK1-3, an immunoconjugate of rscu-PA with the
parental anti-u-PA antibody was similar to that of unconjugated rscu-PA.
Clot lysis was achieved without systemic fibrinogen or alpha 2-antiplasmin
consumption, and with a minor transient prolongation of the bleeding time.
After the end of the infusions, u-PA-related antigen disappeared from
plasma in a biphasic manner, with an initial half-life of 3.3 +/- 0.4
minutes for rscu-PA, 13 +/- 1 minutes for rscu-PA/MA-FU1-74, and 13 +/- 1
minutes for rscu-PA/MA-UK1-3, with corresponding plasma clearances of 340
+/- 28, 10 +/- 1, and 37 +/- 4 mL/min, respectively (mean +/- SEM). rscu-
PA/MA-FU1-74 has a fivefold higher thrombolytic potency than unconjugated
rscu-PA, as a result both of fibrin targeting by the specific idiotype of
the antibody and of a slower plasma clearance.
Volume 79,
Issue 9,
pp. 2322-2329,
05/01/1992
Copyright © 1992 by The American Society of Hematology
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