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Title: Vascular immunotargeting to endothelial determinant ICAM-1 enables optimal partnering of recombinant scFv-Thrombomodulin fusion with endogenous cofactor
Authors: Greineder C.F.
Chacko A.-M. 
Zaytsev S.
Zern B.J.
Carnemolla R.
Hood E.D.
Han J.
Ding B.-S.
Esmon C.T.
Muzykantov V.R.
Keywords: Acute Lung Injury
Antigens, CD
Antigens, CD31
Cell Line
Endothelial Cells
Endothelium, Vascular
Intercellular Adhesion Molecule-1
Intercellular Junctions
Mice, Inbred C57BL
Molecular Targeted Therapy
Protein C
Receptors, Cell Surface
Single-Chain Antibodies
Issue Date: 2013
Citation: Greineder C.F., Chacko A.-M., Zaytsev S., Zern B.J., Carnemolla R., Hood E.D., Han J., Ding B.-S., Esmon C.T., Muzykantov V.R. (2013). Vascular immunotargeting to endothelial determinant ICAM-1 enables optimal partnering of recombinant scFv-Thrombomodulin fusion with endogenous cofactor. PLoS ONE 8 (11) : e80110. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
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. © 2013 Greineder et al.
Source Title: PLoS ONE
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0080110
Rights: Attribution 4.0 International
Appears in Collections:Staff Publications

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