title: Thrombin binding predicts the effects of sequence changes in a human monoclonal antiphospholipid antibody on its in vivo biologic actions.
abstract: 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.
authors.affiliation: Department of Medicine, Centre for Rheumatology, Institute of Child Health, University College, London, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Giles
authors.forename: Charis
authors.initials: C
authors.lastname: Pericleous
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Liu
authors.forename: Jasmine
authors.initials: J
authors.lastname: Ehsanullah
authors.forename: Lindsey
authors.initials: L
authors.lastname: Clarke
authors.forename: Paul
authors.initials: P
authors.lastname: Brogan
authors.forename: Marvin
authors.initials: M
authors.lastname: Newton-West
authors.forename: Robert
authors.initials: R
authors.lastname: Swerlick
authors.forename: Anastasia
authors.initials: A
authors.lastname: Lambrianides
authors.forename: Pojen
authors.initials: P
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Latchman
authors.forename: David
authors.initials: D
authors.lastname: Isenberg
authors.forename: Silvia
authors.initials: S
authors.lastname: Pierangeli
authors.forename: Anisur
authors.initials: A
authors.lastname: Rahman