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Blood, 1 August 2004, Vol. 104, No. 3, pp. 704-710. Prepublished online as a Blood First Edition Paper on April 8, 2004; DOI 10.1182/blood-2003-11-3891. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-11-3891v1 104/3/704    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 Parker, E. T. Articles by Lollar, P. Search for Related Content PubMed PubMed Citation Articles by Parker, E. T. Articles by Lollar, P. Related Collections Hemostasis, Thrombosis, and Vascular Biology Immunobiology Free Research Articles Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Reduction of the inhibitory antibody response to human factor VIII in hemophilia A mice by mutagenesis of the A2 domain B-cell epitope Ernest T. Parker, John F. Healey, Rachel T. Barrow, Heather N. Craddock, and Pete Lollar From the Winship Cancer Institute, Emory University, Atlanta, GA. Approximately 25% of patients with hemophilia A develop inhibitory antibodies after treatment with factor VIII. Most of the inhibitory activity is directed against epitopes in the A2 and C2 domains. Anti-A2 inhibitory antibodies recognize a 25-residue segment bounded by R484-I508. Several antigenic residues in this segment have been identified, including R484, R489, and P492. The immunogenicity of purified recombinant B domain–deleted (BDD) human factor VIII molecules containing mutations at R484A/R489A or R484A/R489A/P492A was studied in hemophilia A mice. Inhibitory antibody titers in mice receiving the R484A/R489A/P492A mutant, but not the R484A/R489A mutant, were significantly lower than in mice receiving control human BDD factor VIII. The specific coagulant activity and the in vivo clearance and hemostatic efficacy in hemophilia A mice of the R484A/R489A/P492A mutant were indistinguishable from human BDD factor VIII. Thus, the inhibitory antibody response to human factor VIII can be reduced by mutagenesis of a B-cell epitope without apparent loss of function, suggesting that this approach may be useful for developing a safer form of factor VIII in patients with hemophilia A. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Mutagenesis lowers factor VIII immunogenicity David W. Scott and Natalya M. Ananyeva Blood 2004 104: 598-599. [Full Text] [PDF] This article has been cited by other articles: S. L. Meeks, J. F. Healey, E. T. Parker, R. T. Barrow, and P. Lollar Antihuman factor VIII C2 domain antibodies in hemophilia A mice recognize a functionally complex continuous spectrum of epitopes dominated by inhibitors of factor VIII activation Blood, December 15, 2007; 110(13): 4234 - 4242. [Abstract] [Full Text] [PDF] L. M. Ide, B. Gangadharan, K.-Y. Chiang, C. B. Doering, and H. T. Spencer Hematopoietic stem-cell gene therapy of hemophilia A incorporating a porcine factor VIII transgene and nonmyeloablative conditioning regimens Blood, October 15, 2007; 110(8): 2855 - 2863. [Abstract] [Full Text] [PDF] B. Gangadharan, E. T. Parker, L. M. Ide, H. T. Spencer, and C. B. Doering High-level expression of porcine factor VIII from genetically modified bone marrow-derived stem cells Blood, May 15, 2006; 107(10): 3859 - 3864. [Abstract] [Full Text] [PDF] T. C. Lei and D. W. Scott Induction of tolerance to factor VIII inhibitors by gene therapy with immunodominant A2 and C2 domains presented by B cells as Ig fusion proteins Blood, June 15, 2005; 105(12): 4865 - 4870. [Abstract] [Full Text] [PDF]

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