Endothelial targeting of a recombinant construct fusing a PECAM-1 single-chain variable antibody fragment (scFv) with prourokinase facilitates prophylactic thrombolysis in the pulmonary vasculature. Academic Article uri icon

Overview

MeSH

  • Animals
  • Cell Line
  • Drosophila
  • Humans
  • Mice
  • Recombinant Proteins

MeSH Major

  • Antigens, CD31
  • Endothelial Cells
  • Immunoglobulin Fragments
  • Lung
  • Thrombosis
  • Urokinase-Type Plasminogen Activator

abstract

  • Means to prevent thrombus extension and local recurrence remain suboptimal, in part because of the limited effectiveness of existing thrombolytics. In theory, plasminogen activators could be used for this purpose if they could be anchored to the vascular lumen by targeting stably expressed, noninternalized determinants such as platelet-endothelial-cell adhesion molecule 1 (PECAM-1). We designed a recombinant molecule fusing low-molecular-weight single-chain prourokinase plasminogen activator (lmw-scuPA) with a single-chain variable fragment (scFv) of a PECAM-1 antibody to generate the prodrug scFv/lmw-scuPA. Cleavage by plasmin generated fibrinolytically active 2-chain lmw-uPA. This fusion protein (1) bound specifically to PECAM-1-expressing cells; (2) was rapidly cleared from blood after intravenous injection; (3) accumulated in the lungs of wild-type C57BL6/J, but not PECAM-1 null mice; and (4) lysed pulmonary emboli formed subsequently more effectively than lmw-scuPA, thereby providing support for the concept of thromboprophylaxis using recombinant scFv-fibrinolytic fusion proteins that target endothelium.

publication date

  • December 15, 2005

has subject area

  • Animals
  • Antigens, CD31
  • Cell Line
  • Drosophila
  • Endothelial Cells
  • Humans
  • Immunoglobulin Fragments
  • Lung
  • Mice
  • Recombinant Proteins
  • Thrombosis
  • Urokinase-Type Plasminogen Activator

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC1895234

Digital Object Identifier (DOI)

  • 10.1182/blood-2005-05-2002

PubMed ID

  • 16144802

Additional Document Info

start page

  • 4191

end page

  • 4198

volume

  • 106

number

  • 13