Plasma protein β-2-glycoprotein 1 mediates interaction between the anti-tumor monoclonal antibody 3G4 and anionic phospholipids on endothelial cells

Troy A. Luster, Jin He, Xianming Huang, Sourindra N. Maiti, Alan J. Schroit, Philip G. De Groot, Philip E. Thorpe

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

A promising target on tumor vasculature is phosphatidylserine (PS), an anionic phospholipid that resides exclusively on the inner leaflet of the plasma membrane of resting mammalian cells. We have shown previously that PS becomes exposed on the surface of endothelial cells (EC) in solid tumors. To target PS on tumor vasculature, the murine monoclonal antibody 3G4 was developed. 3G4 localizes to tumor vasculature, inhibits tumor growth, and enhances anti-tumor chemotherapies without toxicity in mice. A chimeric version of 3G4 is in clinical trials. In this study, we investigated the basis for the interaction between 3G4 and EC with surface-exposed PS. We demonstrate that antibody binding to PS is dependent on plasma protein β-2-glycoprotein 1 (β2GP1). β2GP1 is a 50-kDa glycoprotein that binds weakly to anionic phospholipids under physiological conditions. We show that 3G4 enhances binding of β2GP1 to EC induced to expose PS. We also show that divalent 3G4-β2GP1 complexes are required for enhanced binding, since 3G4 Fab′ fragments do not bind EC with exposed PS. Finally, we demonstrate that an artificial dimeric β2GP1 construct binds to EC with exposed PS in the absence of 3G4, confirming that antibody binding is mediated by dimerization of β2GP1. Together, these data indicate that 3G4 targets tumor EC by increasing the avidity of β2GP1 for anionic phospholipids through formation of multivalent 3G4-β2GP1 complexes.

Original languageEnglish (US)
Pages (from-to)29863-29871
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number40
DOIs
StatePublished - Oct 6 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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