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Blood, 1 April 2004, Vol. 103, No. 7, pp. 2617-2623. Prepublished online as a Blood First Edition Paper on December 11, 2003; DOI 10.1182/blood-2003-07-2207. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-07-2207v1 103/7/2617    most recent 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 Gilles, J. G. G. Articles by Saint-Remy, J.-M. R. Search for Related Content PubMed PubMed Citation Articles by Gilles, J. G. G. Articles by Saint-Remy, J.-M. R. Related Collections Hemostasis, Thrombosis, and Vascular Biology Immunobiology Immunotherapy Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY In vivo neutralization of a C2 domain–specific human anti–Factor VIII inhibitor by an anti-idiotypic antibody Jean Guy G. Gilles, Sabrina C. Grailly, Marc De Maeyer, Marc G. Jacquemin, Luc P. VanderElst, and Jean-Marie R. Saint-Remy From the Center for Molecular and Vascular Biology, University of Leuven, Belgium; and Laboratorium Biomoleculaire Modelling, University of Leuven, Belgium. Factor VIII (FVIII) administration elicits specific inhibitory antibodies (Abs) in about 25% of patients with hemophilia A. The majority of such Abs reacts with FVIII C2 domain. mAbBO2C11 is a high-affinity human monoclonal antibody (mAb) directed toward the C2 domain, which is representative of a major class of human FVIII inhibitors. Anti-idiotypic Abs were raised to mAbBO2C11 to establish their neutralizing potential toward inhibitors. One mouse anti-idiotypic mAb, mAb14C12, specifically prevented mAbBO2C11 binding to FVIII C2 domain and fully neutralized mAbBO2C11 functional inhibitory properties. Modeling of the 3-D conformation of mAb14C12 VH and alignment with the 3-D structure of the C2 domain showed putative 31 surface-exposed amino acid residues either identical or homologous to the C2 domain. These included one C2 phospholipid-binding site, Leu2251-Leu2252, but not Met2199-Phe2200. Forty putative contact residues with mAbBO2C11 were identified. mAb14C12 dose-dependently neutralized mAbBO2C11 inhibitory activity in mice with hemophilia A reconstituted with human recombinant FVIII (rFVIII), allowing full expression of FVIII activity. It also neutralized in an immunoprecipitation assay approximately 50% of polyclonal anti-C2 Abs obtained from 3 of 6 unrelated patients. mAb14C12 is the first example of an anti-idiotypic Ab that fully restores FVIII activity in vivo in the presence of an anti-C2 inhibitor. The present results establish the in vitro and in vivo proof of concept for idiotype-mediated neutralization of a major class of FVIII inhibitors. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Idiotype-mediated neutralization of factor VIII inhibitor antibodies Kathleen P. Pratt Blood 2004 103: 2436-2437. [Full Text] [PDF] This article has been cited by other articles: 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] S. Planque, M. A. Escobar, K. C. Smith, H. Taguchi, Y. Nishiyama, E. Donnachie, K. P. Pratt, and S. Paul Covalent Inactivation of Factor VIII Antibodies from Hemophilia A Patients by an Electrophilic FVIII Analog J. Biol. Chem., May 2, 2008; 283(18): 11876 - 11886. [Abstract] [Full Text] [PDF]

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