Structure of a factor VIII C2 domain–immunoglobulin G4k Fab complex: identification of an inhibitory antibody epitope on the surface of factor VIII

Abstract

The development of an immune response to infused factor VIII is a complication affecting many patients with hemophilia A. Inhibitor antibodies bind to antigenic determinants on the factor VIII molecule and block its procoagulant activity. A patient-derived inhibitory immunoglobulin G4k antibody (BO2C11) produced by an immortalized memory B-lymphocyte cell line interferes with the binding of factor VIII to phospholipid surfaces and to von Willebrand factor. The structure of a Fab fragment derived from this antibody complexed with the factor VIII C2 domain was determined at 2.0 Å resolution. The Fab interacts with solventexposed basic and hydrophobic side chains that form a membrane-association surface of factor VIII. This atomic resolution structure suggests a variety of amino acid substitutions in the C2 domain of factor VIII that might prevent the binding of anti-C2 inhibitor antibodies without significantly compromising the procoagulant functions of factor VIII. (Blood. 2001;98:13-19)

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Cite this paper

@inproceedings{Spiegel2001StructureOA, title={Structure of a factor VIII C2 domain–immunoglobulin G4k Fab complex: identification of an inhibitory antibody epitope on the surface of factor VIII}, author={Paul Clint Spiegel and Marc G. Jacquemin and Jean-Marie R. Saint-Remy and Barry L. Stoddard and Kathleen P Pratt}, year={2001} }