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(Circulation. 1996;94:1412-1422.)
© 1996 American Heart Association, Inc.

Articles

Enhanced Thrombolytic and Antithrombotic Potency of a Fibrin-Targeted Plasminogen Activator in Baboons

Marschall S. Runge, MD, PhD; Laurence A. Harker, MD; Christoph Bode, MD; Johannes Ruef, BA; Andrew B. Kelly, DVM; Ulla M. Marzec, MS; Elaine Allen, PhD; Rafael Caban, BA; Shyh-Yu Shaw, PhD; Edgar Haber, MD; Stephen R. Hanson, PhD

the Cardiology Division and Sealy Center for Molecular Cardiology (M.S.R.), The University of Texas Medical Branch (Galveston); Ariad Pharmaceuticals, Inc (E.A.), Cambridge, Mass; Divisions of Hematology-Oncology (L.A.H., U.M.M., S.R.H.) and Yerkes Regional Primate Research Center (A.B.K.), Emory University School of Medicine, Atlanta, Ga (S.R.H.); Cardiovascular Biology Laboratory (E.H.), Center for the Prevention of Cardiovascular Disease, Harvard University School of Public Health, Boston, Mass; Medizinische Klinik III (Kardiologie) (C.B., J.R.), Heidelberg, Germany; and Bristol-Myers Squibb Pharmaceutical Research Institute (S.-Y.S.), Princeton, NJ.

Correspondence to Marschall S. Runge, MD, PhD, Cardiology Division, The University of Texas Medical Branch, 301 University Blvd, 5.106 John Sealy, Galveston, TX 77555-0553.

Background Thrombolytic therapy reduces mortality in patients with acute myocardial infarction, but significant limitations exist with the use of currently available agents. In the present report, we describe the thrombolytic and antithrombotic potencies of a hybrid recombinant plasminogen activator consisting of an antifibrin antibody 59D8 (AFA) and low-molecular-weight single-chain urokinase-type plasminogen activator (scuPA).

Methods and Results A thrombolysis model in which thrombi are preformed in vivo in juvenile baboons was developed to compare the potencies of AFA-scuPA, recombinant tissue plasminogen activator (rTPA), and recombinant scuPA (rscuPA) in lysing nonocclusive ¹¹¹In-labeled platelet-rich arterial-type thrombi and ¹²⁵I-labeled fibrin-rich venous-type thrombi. Systemic infusion of 1.89 nmol/kg AFA-scuPA produced thrombolysis that was comparable to that obtained with much higher doses of TPA (14.2 nmol/kg) and rscuPA (28.5 nmol/kg). When steady-state plasma concentrations are normalized, AFA-scuPA lyses thrombi sixfold more rapidly than scuPA and TPA (P<.001) and reduces the rate of formation more than comparable doses of rscuPA (P<.0001). At equivalent thrombolytic doses, AFA-scuPA produced fewer antihemostatic effects than either rTPA or rscuPA. Template bleeding time measurements were shorter (3.5±0.12 minutes for AFA-scuPA versus 5.3±0.36 and 5.2±0.04 minutes for rTPA and rscuPA, respectively; P<.05), ₂-antiplasmin consumption was less (P<.05), and D-dimer generation was lower (P<.05).

Conclusions We conclude that antibody targeting of scuPA to fibrin increases thrombolytic and antithrombotic potencies with less impairment of hemostasis compared with rTPA and rscuPA.

Key Words: arteriosclerosis • plasminogen activators • thrombolysis • thrombosis

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