Prophylactic thrombolysis by thrombin-activated latent prourokinase targeted to PECAM-1 in the pulmonary vasculature. Academic Article uri icon

Overview

MeSH

  • Animals
  • Fibrinogen
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein Binding
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • Tissue Distribution

MeSH Major

  • Antigens, CD31
  • Endothelium, Vascular
  • Pulmonary Circulation
  • Thrombin
  • Thrombolytic Therapy
  • Urokinase-Type Plasminogen Activator

abstract

  • A recombinant prodrug, single-chain urokinase-type plasminogen activator (scuPA) fused to an anti-PECAM-1 antibody single-chain variable fragment (anti-PECAM scFv/scuPA) targets endothelium and augments thrombolysis in the pulmonary vasculature.(1) To avoid premature activation and inactivation and to limit systemic toxicity, we replaced the native plasmin activation site in scFv/low-molecular-weight (lmw)-scuPA with a thrombin activation site, generating anti-PECAM scFv/uPA-T that (1) is latent and activated by thrombin instead of plasmin; (2) binds to PECAM-1; (3) does not consume plasma fibrinogen; (4) accumulates in mouse lungs after intravenous injection; and (5) resists PA inhibitor PAI-1 until activated by thrombin. In mouse models of pulmonary thrombosis caused by thromboplastin and ischemia-reperfusion (I/R), scFv/uPA-T provided more potent thromboprophylaxis and greater lung protection than plasmin-sensitive scFv/uPA. Endothelium-targeted thromboprophylaxis triggered by a prothrombotic enzyme illustrates a novel approach to time- and site-specific regulation of proteolytic reactions that can be modulated for therapeutic benefit.

publication date

  • February 15, 2008

has subject area

  • Animals
  • Antigens, CD31
  • Endothelium, Vascular
  • Fibrinogen
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein Binding
  • Pulmonary Circulation
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • Thrombin
  • Thrombolytic Therapy
  • Tissue Distribution
  • Urokinase-Type Plasminogen Activator

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2234048

Digital Object Identifier (DOI)

  • 10.1182/blood-2007-07-103002

PubMed ID

  • 18045968

Additional Document Info

start page

  • 1999

end page

  • 2006

volume

  • 111

number

  • 4