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Thrombin Binding Predicts the Effects of Sequence Changes in a Human Monoclonal Antiphospholipid Antibody on Its In Vivo Biologic Actions ¹

Ian Giles^2,*,, Charis Pericleous^*,, Xiaowei Liu, Jasmine Ehsanullah^*,, Lindsey Clarke, Paul Brogan, Marvin Newton-West^¶, Robert Swerlick^¶, Anastasia Lambrianides^*,, Pojen Chen^||, David Latchman, David Isenberg^*, Silvia Pierangeli^# and Anisur Rahman^*,

^* Centre for Rheumatology, Department of Medicine, Medical Molecular Biology Unit and Infectious Disease and Immunology Unit, Institute of Child Health, University College, London, United Kingdom; Department of Microbiology, Immunology and Biochemistry, Morehouse School of Medicine, Atlanta, GA 30310; ^¶ Department of Dermatology, Emory University School of Medicine, Atlanta, GA 30322; ^|| Department of Medicine, Division of Rheumatology, University of California, Los Angeles, CA 90095; ^# Department of Internal Medicine, Division of Rheumatology, University of Texas Medical Branch, Galveston, TX 77555

The mechanisms by which antiphospholipid Abs (aPL) cause thrombosis are not fully understood. It is clear that binding to a number of phospholipid-associated Ags is important but it is difficult to identify which Ag-binding properties are most closely linked to the ability to cause biologic effects such as promotion of thrombosis and activation of endothelial cells. We have previously used an in vitro expression system to produce a panel of human monoclonal IgG molecules between which we engineered small differences in sequence leading to significant well-defined changes in binding properties. In this study, we assess the properties of five of these IgG molecules in assays of biologic function in vitro and in vivo. The i.p. injection of these IgG into mice subjected to a femoral vein pinch stimulus showed that only those IgG that showed strong binding to thrombin promoted in vivo venous thrombosis and leukocyte adherence. However, this finding did not hold true for the effects of these IgG on activation of cultured endothelial cells in vitro, where there was a less clear relationship between binding properties and biologic effects.

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 This work was supported by funds from the Arthritis Research Campaign, Rosetrees Trust and Nuffield Foundation, Oliver Bird PhD Studentship.

² Address correspondence and reprint requests to Dr. Ian Giles, Centre for Rheumatology Research, Room 331, 3rd Floor Windeyer Institute, 46 Cleveland Street, London W1T 4JF, U.K. E-mail address: i.giles{at}ich.ucl.ac.uk

³ Abbreviations used in this paper: APS, aPL syndrome; aPL, antiphospholipid Ab; β₂GPI, β₂-glycoprotein I; CL, cardiolipin; EC, endothelial cell; EMP, endothelial microparticle; GPLU, IgG phospholipid unit; PC, phosphatidylcholine; PS, phosphatidylserine.