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This Article Full Text Full Text (PDF) Alert me when this article is cited 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by van den Brink, E. N. Articles by Voorberg, J. Search for Related Content PubMed PubMed Citation Articles by van den Brink, E. N. Articles by Voorberg, J. Related Collections Hemostasis, Thrombosis, and Vascular Biology Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 February 2001, Vol. 97, No. 4, pp. 966-972 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Multiple VH genes are used to assemble human antibodies directed toward the A3-C1 domains of factor VIII Edward N. van den Brink, Ellen A. M. Turenhout, Niels Bovenschen, Bram G. A. D. H. Heijnen, Koen Mertens, Marjolein Peters, and Jan Voorberg From the Department of Plasma Proteins, CLB, Amsterdam; Laboratory for Experimental and Clinical Immunology, Academic Medical Center, University of Amsterdam, Amsterdam; Emma Children's Hospital AMC, Amsterdam; and Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands. A well-known complication of factor VIII replacement therapy in patients with hemophilia A is the development of inhibitory antibodies. Several studies have demonstrated the presence of a binding site for factor VIII inhibitors in the A3 domain. Six different human monoclonal single-chain variable domain antibody fragments (scFv) directed toward the A3-C1 domains of factor VIII have been isolated, using phage display technology. Sequence analysis revealed that the VH domains of 2 scFv were encoded by germline gene segments from the VH1 gene family and 4 by germline gene segments belonging to the VH3 gene family. Epitope mapping of the scFv was performed, using a series of hybrid factor VIII/factor V light chain fragments. This analysis revealed that 5 of 6 scFv were directed against a region encompassing amino acid sequence Q1778-D1840 in the A3 domain, a previously identified binding site for factor VIII inhibitors. Only 2 of 5 scFv directed against amino acid sequence Q1778-D1840 inhibited the procoagulant activity of factor VIII. Our results define the properties of human antibodies directed against region Q1778-D1840 in the A3 domain. Binding of one, noninhibitory scFv was independent of the region Q1778-D1840, suggesting the presence of an additional binding site for anti-factor VIII antibodies in the A3-C1 domains of factor VIII. © 2001 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Meems, A. B. Meijer, D. B. Cullinan, K. Mertens, and G. E. Gilbert Factor VIII C1 domain residues Lys 2092 and Phe 2093 contribute to membrane binding and cofactor activity Blood, October 29, 2009; 114(18): 3938 - 3946. [Abstract] [Full Text] [PDF] S. Lacroix-Desmazes, A.-M. Navarrete, S. Andre, J. Bayry, S. V. Kaveri, and S. Dasgupta Dynamics of factor VIII interactions determine its immunologic fate in hemophilia A Blood, July 15, 2008; 112(2): 240 - 249. [Abstract] [Full Text] [PDF] N. Bovenschen, R. C. Boertjes, G. van Stempvoort, J. Voorberg, P. J. Lenting, A. B. Meijer, and K. Mertens Low Density Lipoprotein Receptor-related Protein and Factor IXa Share Structural Requirements for Binding to the A3 Domain of Coagulation Factor VIII J. Biol. Chem., March 7, 2003; 278(11): 9370 - 9377. [Abstract] [Full Text] [PDF]

	Copyright © 2001 by American Society of Hematology         Online ISSN: 1528-0020