Vascular immunotargeting to endothelial determinant ICAM-1 enables optimal partnering of recombinant scFv-thrombomodulin fusion with endogenous cofactor. Academic Article uri icon

Overview

MeSH

  • Animals
  • Antigens, CD31
  • Cell Line
  • Endothelial Cells
  • Endothelium, Vascular
  • Humans
  • Intercellular Junctions
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy
  • Protein C

MeSH Major

  • Acute Lung Injury
  • Antigens, CD
  • Immunoconjugates
  • Intercellular Adhesion Molecule-1
  • Receptors, Cell Surface
  • Single-Chain Antibodies
  • Thrombomodulin

abstract

  • The use of targeted therapeutics to replenish pathologically deficient proteins on the luminal endothelial membrane has the potential to revolutionize emergency and cardiovascular medicine. Untargeted recombinant proteins, like activated protein C (APC) and thrombomodulin (TM), have demonstrated beneficial effects in acute vascular disorders, but have failed to have a major impact on clinical care. We recently reported that TM fused with an scFv antibody fragment to platelet endothelial cell adhesion molecule-1 (PECAM-1) exerts therapeutic effects superior to untargeted TM. PECAM-1 is localized to cell-cell junctions, however, whereas the endothelial protein C receptor (EPCR), the key co-factor of TM/APC, is exposed in the apical membrane. Here we tested whether anchoring TM to the intercellular adhesion molecule (ICAM-1) favors scFv/TM collaboration with EPCR. Indeed: i) endothelial targeting scFv/TM to ICAM-1 provides ~15-fold greater activation of protein C than its PECAM-targeted counterpart; ii) blocking EPCR reduces protein C activation by scFv/TM anchored to endothelial ICAM-1, but not PECAM-1; and iii) anti-ICAM scFv/TM fusion provides more profound anti-inflammatory effects than anti-PECAM scFv/TM in a mouse model of acute lung injury. These findings, obtained using new translational constructs, emphasize the importance of targeting protein therapeutics to the proper surface determinant, in order to optimize their microenvironment and beneficial effects.

publication date

  • 2013

has subject area

  • Acute Lung Injury
  • Animals
  • Antigens, CD
  • Antigens, CD31
  • Cell Line
  • Endothelial Cells
  • Endothelium, Vascular
  • Humans
  • Immunoconjugates
  • Intercellular Adhesion Molecule-1
  • Intercellular Junctions
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy
  • Protein C
  • Receptors, Cell Surface
  • Single-Chain Antibodies
  • Thrombomodulin

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3828233

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0080110

PubMed ID

  • 24244621

Additional Document Info

start page

  • e80110

volume

  • 8

number

  • 11