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Title: Thrombolytic profiles of clot-targeted plasminogen activators. Parameters determining potency and initial and maximal rates
Authors: Holvoet, Paul ×
Dewerchin, Mieke
Stassen, Jean-Marie
Lijnen, Roger
Tollenaere, T
Gaffney, P J
Collen, Desire #
Issue Date: Mar-1993
Series Title: Circulation vol:87 issue:3 pages:1007-16
Abstract: BACKGROUND. Targeting of plasminogen activators to the thrombus by means of fibrin-specific monoclonal antibodies may enhance their thrombolytic potency. The kinetics of clot binding of two human fibrin-specific monoclonal antibodies (MA-12B3 and MA-15C5) and of clot lysis with their chemical 1:1 stoichiometric complexes with recombinant single-chain urokinase-type plasminogen activator (rscu-PA) (rscu-PA/MA-12B3 and rscu-PA/MA-15C5) were determined in hamsters and rabbits. Thrombolytic potencies, maximal rates of clot lysis, and the duration of the lag phases before clot lysis of the antibody/rscu-PA conjugates were compared with those of rscu-PA and tissue-type plasminogen activator (rt-PA). METHODS AND RESULTS. Bolus injection of 7.5 micrograms of 125I-labeled antibody in rabbits with an extracorporeal arteriovenous loop containing a 0.3-mL human plasma clot produced clot-to-blood ratios of 6.6 +/- 1.0 (mean +/- SEM) for MA-12B3 and 1.1 +/- 0.15 for MA-15C5 (p < 0.001 versus MA-12B3) within 6 hours. Progressive digestion of the clot did not alter the binding of MA-12B3 but resulted in as much as a 10-fold increase of the binding of MA-15C5. The conjugates infused intravenously over 90 minutes in hamsters with a human plasma clot in the pulmonary artery produced dose-related in vivo clot lysis. Thrombolytic potencies (maximal slope of the percent lysis versus dose in milligrams of u-PA equivalent per kilogram body weight) were 2,500 +/- 440 for rscu-PA/MA-12B3, 3,600 +/- 640 for rscu-PA/MA-15C5 (p = NS vs. rscu-PA/MA-12B3), 60 +/- 8 for rscu-PA (p < 0.001 versus both conjugates), and 380 +/- 66 for rt-PA (p < 0.001 versus both conjugates). The plasma clearances of the conjugates were fourfold to sixfold slower than those of rscu-PA and rt-PA. Maximal rates of clot lysis, determined by continuous external radioisotope scanning over the thorax, were 0.90 +/- 0.13%, 0.91 +/- 0.17%, 0.84 +/- 0.12%, and 1.1 +/- 0.16% lysis per minute for rscu-PA/MA-12B3, rscu-PA/MA-15C5, rscu-PA, and rt-PA, respectively; these maximal rates were obtained with 0.016, 0.016, 1.0, and 0.25 mg/kg, respectively, and were associated with minimal lag phases of 18 +/- 3.2, 28 +/- 4.9, 34 +/- 3.7, and 25 +/- 3.9 minutes, respectively. CONCLUSIONS. The thrombolytic potency of the rscu-PA/antifibrin conjugates is determined by their clearance, as well as by rate and extent of initial binding to clots and by changes in binding during clot lysis. Clot targeting of rscu-PA with fibrin-specific antibodies increases its thrombolytic potency but does not alter the maximal rate or the minimal lag phase of clot lysis. These parameters appear to be independent of the nature of the plasminogen activator and of targeting.
ISSN: 0009-7322
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Atherosclerosis and Metabolism (-)
Molecular and Vascular Biology
Laboratory of Angiogenesis and Vascular Metabolism (VIB-KU Leuven Centre for Cancer Biology) (+)
× corresponding author
# (joint) last author

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