Thrombolytic and Pharmacokinetic Properties of a Recombinant Chimeric Plasminogen Activator Consisting of a Fibrin Fragment D-Dimer Specific Humanized Monoclonal Antibody and a Truncated Single-Chain Urokinase

M Dewerchin; A-M Vandamme; P Holvoet; F De Cock; G Lemmens; H R Lijnen; J-M Stassen; D Collen

doi:10.1055/s-0038-1656344

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1992; 68(02): 170-179
DOI: 10.1055/s-0038-1656344

Original Article

Schattauer GmbH Stuttgart

Thrombolytic and Pharmacokinetic Properties of a Recombinant Chimeric Plasminogen Activator Consisting of a Fibrin Fragment D-Dimer Specific Humanized Monoclonal Antibody and a Truncated Single-Chain Urokinase

M Dewerchin

The Center for Thrombosis and Vascular Research, University of Leuven, Belgium

,

A-M Vandamme

The Center for Thrombosis and Vascular Research, University of Leuven, Belgium

,

P Holvoet

The Center for Thrombosis and Vascular Research, University of Leuven, Belgium

,

F De Cock

The Center for Thrombosis and Vascular Research, University of Leuven, Belgium

,

G Lemmens

The Center for Thrombosis and Vascular Research, University of Leuven, Belgium

,

H R Lijnen

The Center for Thrombosis and Vascular Research, University of Leuven, Belgium

,

J-M Stassen

The Center for Thrombosis and Vascular Research, University of Leuven, Belgium

,

D Collen

The Center for Thrombosis and Vascular Research, University of Leuven, Belgium

› Author Affiliations

Abstract

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Summary

A recombinant chimeric plasminogen activator consisting of a humanized monoclonal antibody specific for cross-linked human fibrin (MA-15C5Hu) and a 32 kDa single-chain urokinase-type plasminogen activator (scu-PA-32k) comprising amino acids Leu¹⁴⁴-Leu⁴¹¹, MA-15C5Hu/scu-PA-32k, was previously found to have a 12-fold higher fibrinolytic potency than recombinant scu-PA-32k towards a human plasma clot in a human plasma milieu in vitro (Vandamme et al., Eur J Biochem 1992; 205: 139–46). Therefore, the thrombolytic and pharmacokinetic properties of MA-15C5Hu/scu-PA-32k were compared with those of recombinant single-chain urokinase-type plasminogen activator (scu-PA) in 3 different venous thrombosis models in vivo. In hamsters with a pulmonary embolus consisting of a human plasma clot, the thrombolytic potency (% lysis per dose in mg/kg administered) of MA-15C5Hu/scu-PA-32k was 23-fold higher than that of scu-PA (p <0.0005). In rabbits with a jugular vein clot prepared from human plasma, the thrombolytic potency of MA-15C5Hu/scu-PA-32k was 11-fold higher than that of scu-PA (p = 0.012). In baboons with an autologous whole blood clot in the femoral vein, the chimera had a 5-fold higher thrombolytic potency than scu-PA. In all three animal species, the clearance of the chimera was 10- to 27-fold reduced as compared to scu-PA. The specific thrombolytic activity (% lysis per µg/ml steady-state plasma u-PA antigen) was increased up to 7-fold with MA-15C5Hu/scu-PA-32k as compared with scu-PA, which is indicative of targeting of the chimera to the clot. No fibrinogen breakdown or α₂-antiplasmin depletion was observed during thrombolysis with the chimera.

Thus, MA-15C5Hu/scu-PA-32k constitutes a recombinant chimeric plasminogen activator with a significantly enhanced thrombolytic potency in 3 different animal models of venous thrombosis.

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References

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