Targeting of antibody-conjugated plasminogen activators to the pulmonary vasculature

Vladimir R. Muzykantov, Elliot S. Barnathan, Elena Nikolaevna Atochina, Alice Kuo, Sergei M. Danilov, Aron B. Fisher

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Thrombolytic therapy has not been widely used for pulmonary embolism due to less than optimal results with conventional plasminogen activators. We propose a new approach to deliver plasminogen activators to the luminal surface of the pulmonary vasculature to potentially improve dissolution of pulmonary thromboemboli. Our previous studies have documented that a monoclonal antibody (mAb) to angiotensin-converting enzyme (anti- angiotensin-converting enzyme mAb 9B9) accumulates in the lungs of various animal species after systemic administration. We coupled 125I-labeled biotinylated plasminogen activators (single-chain urokinase plasminogen activator, tissue-type plasminogen activator and streptokinase) to biotinylated mAb 9B9, using streptavidin as a cross-linker. The fibrinolytic activity of plasminogen activators was not changed significantly by either biotinylation or by coupling to streptavidin. Antibody-conjugated plasminogen activators bind to the antigen immobilized in plastic wells and provide lysis of fibrin clots formed in these wells. Therefore, antibody-conjugated plasminogen activators bound to their target antigen retain their capacity to activate plasminogen. One hour after i.v. injection of mAb 9B9-conjugated radiolabeled biotinylated single-chain urokinase plasminogen activator, biotinylated tissue-type plasminogen activator or biotinylated-streptokinase in rats, the level of radiolabel was 7.4 ± 0.8, 5.9 ± 0.4 and 3.6 ± 0.4% of injected dose/g (ID/g) of lung tissue vs. 0.5 ± 0.01,0.3 ± 0.01 and 0.6 ± 0.3% ID/g after injection of the same activators conjugated with control mouse IgG (P <.01 in all cases). Injection of mAb 9B9-conjugated radiolabeled plasminogen activator led to its rapid pulmonary uptake with a peak value 6.2 ± 1.2% ID/g attained 3 hr after injection. One day later, 2.2 ± 0.5% of the injected radioactivity was found per gram of lung tissue, although the blood level was 0.13 ± 0.03% ID/g (lung/blood ratio 16.7 ± 0.3). Therefore, conjugation of plasminogen activators with anti- angiotensin-converting enzyme mAb 9B9 provides their specific targeting to and prolonged association with the pulmonary vasculature. These results provide a basis for study of the local pulmonary fibrinolysis by mAb 9B9- conjugated plasminogen activators.

Original languageEnglish
Pages (from-to)1026-1034
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume279
Issue number2
Publication statusPublished - Nov 1996
Externally publishedYes

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Plasminogen Activators
Lung
Antibodies
Monoclonal Antibodies
Peptidyl-Dipeptidase A
Injections
Streptokinase
Streptavidin
Urokinase-Type Plasminogen Activator
Tissue Plasminogen Activator
Biotinylation
Antigens
Plasminogen
Thrombolytic Therapy
Fibrinolysis
Fibrin
Pulmonary Embolism
Radioactivity
Plastics
Immunoglobulin G

ASJC Scopus subject areas

  • Pharmacology

Cite this

Muzykantov, V. R., Barnathan, E. S., Atochina, E. N., Kuo, A., Danilov, S. M., & Fisher, A. B. (1996). Targeting of antibody-conjugated plasminogen activators to the pulmonary vasculature. Journal of Pharmacology and Experimental Therapeutics, 279(2), 1026-1034.

Targeting of antibody-conjugated plasminogen activators to the pulmonary vasculature. / Muzykantov, Vladimir R.; Barnathan, Elliot S.; Atochina, Elena Nikolaevna; Kuo, Alice; Danilov, Sergei M.; Fisher, Aron B.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 279, No. 2, 11.1996, p. 1026-1034.

Research output: Contribution to journalArticle

Muzykantov, VR, Barnathan, ES, Atochina, EN, Kuo, A, Danilov, SM & Fisher, AB 1996, 'Targeting of antibody-conjugated plasminogen activators to the pulmonary vasculature', Journal of Pharmacology and Experimental Therapeutics, vol. 279, no. 2, pp. 1026-1034.
Muzykantov, Vladimir R. ; Barnathan, Elliot S. ; Atochina, Elena Nikolaevna ; Kuo, Alice ; Danilov, Sergei M. ; Fisher, Aron B. / Targeting of antibody-conjugated plasminogen activators to the pulmonary vasculature. In: Journal of Pharmacology and Experimental Therapeutics. 1996 ; Vol. 279, No. 2. pp. 1026-1034.
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