HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 40, 29863-29871, October 6, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/40/29863    most recent M605252200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Luster, T. A. Articles by Thorpe, P. E. Search for Related Content PubMed PubMed Citation Articles by Luster, T. A. Articles by Thorpe, P. E. Social Bookmarking                      What's this?

Plasma Protein -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^¶, and Philip E. Thorpe¹

From the Simmons Comprehensive Cancer Center, Hamon Center for Therapeutic Oncology Research, the Department of Pharmacology and the Department of Radiation Oncology, the University of Texas Southwestern Medical Center, Dallas, Texas 75390, the Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and the ^¶Department of Hematology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands

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 -2-glycoprotein 1 (2GP1). 2GP1 is a 50-kDa glycoprotein that binds weakly to anionic phospholipids under physiological conditions. We show that 3G4 enhances binding of 2GP1 to EC induced to expose PS. We also show that divalent 3G4-2GP1 complexes are required for enhanced binding, since 3G4 Fab' fragments do not bind EC with exposed PS. Finally, we demonstrate that an artificial dimeric 2GP1 construct binds to EC with exposed PS in the absence of 3G4, confirming that antibody binding is mediated by dimerization of 2GP1. Together, these data indicate that 3G4 targets tumor EC by increasing the avidity of 2GP1 for anionic phospholipids through formation of multivalent 3G4-2GP1 complexes.

Received for publication, June 1, 2006 , and in revised form, July 20, 2006.

^* This work was supported by a Sponsored Research Agreement with Peregrine Pharmaceuticals Inc., the Gillson Longenbaugh Foundation, and a postdoctoral fellowship from the American Cancer Society (to T. A. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9041. Tel.: 214-648-1499; Fax: 214-648-1613; E-mail: philip.thorpe{at}utsouthwestern.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. Jennewein, M. A. Lewis, D. Zhao, E. Tsyganov, N. Slavine, J. He, L. Watkins, V. D. Kodibagkar, S. O'Kelly, P. Kulkarni, et al. Vascular Imaging of Solid Tumors in Rats with a Radioactive Arsenic-Labeled Antibody that Binds Exposed Phosphatidylserine Clin. Cancer Res., March 1, 2008; 14(5): 1377 - 1385. [Abstract] [Full Text] [PDF]

				S. N. Maiti, K. Balasubramanian, J. A. Ramoth, and A. J. Schroit {beta}-2-Glycoprotein 1-dependent Macrophage Uptake of Apoptotic Cells: BINDING TO LIPOPROTEIN RECEPTOR-RELATED PROTEIN RECEPTOR FAMILY MEMBERS J. Biol. Chem., February 15, 2008; 283(7): 3761 - 3766. [Abstract] [Full Text] [PDF]

				J. He, T. A. Luster, and P. E. Thorpe Radiation-Enhanced Vascular Targeting of Human Lung Cancers in Mice with a Monoclonal Antibody That Binds Anionic Phospholipids Clin. Cancer Res., September 1, 2007; 13(17): 5211 - 5218. [Abstract] [Full Text] [PDF]