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Semin Thromb Hemost 2000; Volume 26(Number 02): 143-150
DOI: 10.1055/s-2000-9816
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 760-0888

Phage Display Technology: A Tool to Explore the Diversity of Inhibitors to Blood Coagulation Factor VIII

Jan Voorberg, Edward N. Van Den Brink
  • Department of Plasma Proteins, CLB, Amsterdam, The Netherlands, and Laboratory for Experimental and Clinical Immunology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
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Publication History

Publication Date:
31 December 2000 (online)

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ABSTRACT

Hemophilia A is a X-linked bleeding disorder that is caused by the functional absence of blood coagulation factor VIII. The bleeding tendency in hemophilia A patients can be corrected by the administration of plasma-derived or recombinant factor VIII concentrates. A serious complication in hemophilia care is the development of factor VIII neutralizing antibodies (inhibitors) that arise as a consequence of factor VIII replacement therapy. The majority of factor VIII inhibitors are directed toward epitopes located within the A2, A3, and C2 domains of factor VIII. In this article, we summarize current knowledge on the epitope specificity of factor VIII inhibitors. In addition, we will discuss recent information on the molecular characteristics of human anti-factor VIII antibodies generated by phage display technology.

KEYWORD

Factor VIII - hemophilia - factor VIII inhibitors - phage display - scFv

REFERENCES

  • 1 Bidwell E, Denson K W, Dike G W. Antibody nature of the inhibitor to antihemophilic globulin (factor 8).  Nature . 1966;  210 746-747
    PubMedGoogle Scholar
  • 2 Hoyer L W. Hemophilia A.  N Engl J Med . 1994;  330 38-47
    CrossrefPubMedGoogle Scholar
  • 3 Jacquemin M G, Desqueper B G, Benhida A. Mechanism and kinetics of factor VIII inactivation: Study with an IgG4 monoclonal antibody derived from a hemophilia A patient with an inhibitor.  Blood . 1998;  92 416-506
    PubMedGoogle Scholar
  • 4 Davies J, Van den Brink N E, Baglin T P. Primary structure of the variable domains of factor VIII antibodies obtained from inhibitor patient B cell RNA by V gene phage display technology.  Thromb Haemost . 1997;  suppl:575A (Abstract)
    PubMedGoogle Scholar
  • 5 Van den Brink N E, Turenhout E AM, Davies J. VH domains of human inhibitors directed towards the factor VIII light chain contain an unusually large CDR3.  Haemophilia. 1998;  4 (Abstract) 230A
    PubMedGoogle Scholar
  • 6 Van den Brink N E, Turenhout E AM, Davies J. Human antibodies with specificity for the C2 domain of factor VIII are derived from VH1 germline genes.  Blood . 2000;  95 558-563
    PubMedGoogle Scholar
  • 7 Fulcher C A, DeGraaf Mahoney S, Roberts J R. Localization of human factor VIII inhibitor epitopes to two polypeptide fragments.  Proc Natl Acad Sci USA . 1985;  82 7728-7732
    CrossrefPubMedGoogle Scholar
  • 8 Scandella D, DeGraaf Mahoney S, Mattingly M. Epitope mapping of human factor VIII inhibitor antibodies by deletion analysis of factor VIII fragments expressed in Escherichia coli Proc Natl Acad Sci USA .  1988;  85 6152-6156
    CrossrefPubMedGoogle Scholar
  • 9 Scandella D, Gilbert G E, Shima M. Some factor VIII inhibitor antibodies recognize a common epitope corresponding to C2 domain amino acids 2248 through 2312, which overlap a phospholipid-binding site.  Blood . 1995;  86 1811-1819
    PubMedGoogle Scholar
  • 10 Healey J F, Lubin I M, Nakai H. Residues 484-508 contain a major determinant of the inhibitory epitope in the A2 domain of human factor VIII.  J Biol Chem . 1995;  270 14505-14509
    CrossrefPubMedGoogle Scholar
  • 11 Lubin I M, Healey J F, Barrow R T. Analysis of the human factor VIII A2 inhibitor epitope by alanine scanning mutagenesis.  J Biol Chem . 1997;  272 30191-30195
    CrossrefPubMedGoogle Scholar
  • 12 Healey J F, Barrow R T, Tamim H M. Residues Glu2181-Val2243 contain a major determinant of the inhibitory epitope in the C2 domain of human factor VIII.  Blood . 1998;  92 3701-3709
    PubMedGoogle Scholar
  • 13 Villoutreux B O, Bucher P, Hoffmann K. Molecular models for the two discoidin domains of human blood coagulation factor V.  J Molecular Models . 1998;  4 268-275
    PubMedGoogle Scholar
  • 14 Pellerquer J-L, Gale A J, Griffin J H. Homology models of the C domains of blood coagulation factors V and VIII: A proposed membrane binding mode for FV and FVIII C2 domains.  Blood Cells Mol Dis . 1998;  15 448-461
    PubMedGoogle Scholar
  • 15 McMullen B A, Fujikawa K, Davie E W. Locations of disulfide bonds and free cysteines in the heavy and light chain of recombinant human factor VIII (antihemophilic factor A).  Protein Sci . 1995;  4 740-746
    PubMedGoogle Scholar
  • 16 Pratt K P, Shen B W, Fujikawa K. Structure of the C2 of human factor VIII at 1.5 Å resolution.  Nature . 1999;  402 439-442
    CrossrefPubMedGoogle Scholar
  • 17 Scandella D, Mattingly M, Prescott R. A recombinant factor VIII A2 domain polypeptide quantitatively neutralizes human inhibitor antibodies that bind to A2.  Blood . 1993;  82 1767-1775
    PubMedGoogle Scholar
  • 18 Fijnvandraat K, Celie P HN, Turenhout E AM. A human alloantibody interferes with binding of factor IXa to the factor VIII light chain.  Blood . 1998;  91 2347-2352
    PubMedGoogle Scholar
  • 19 Zhong D, Saenko E L, Shima M. Some human inhibitor antibodies interfere with factor VIII binding to factor IX.  Blood . 1998;  92 136-142
    PubMedGoogle Scholar
  • 20 Lenting P J, Van de Loo P J-W, Donath M-JSH, et al. The sequence Glu1811-Lys1818 of human blood coagulation factor VIII comprises a binding site for activated factor IX.  J Biol Chem . 1996;  271 1935-1940
    CrossrefPubMedGoogle Scholar
  • 21 Prescott R, Nakai H, Saenko E L. The inhibitor antibody response is more complex in hemophilia A patients than in most nonhemophiliacs with factor VIII autoantibodies. Recombinate and Kogenate study groups.  Blood . 1997;  89 3663-3671
    PubMedGoogle Scholar
  • 22 Foster P A, Fulcher C A, Houghten R A. Localization of the binding regions of a murine monoclonal anti-factor VIII antibody and a human anti-factor VIII alloantibody, both of which inhibit factor VIII procoagulant activity, to amino acid residues threonine351-serine365 of the factor VIII heavy chain.  J Clin Invest . 1988;  82 123-128
    CrossrefPubMedGoogle Scholar
  • 23 Tonegawa S. Somatic generation of antibody diversity.  Nature . 1983;  302 575-581
    CrossrefPubMedGoogle Scholar
  • 24 Rajewsky K. Clonal selection and learning in the antibody system.  Nature . 1996;  381 751-758
    CrossrefPubMedGoogle Scholar
  • 25 Stavnezer J. Immunoglobulin class switching.  Curr Opin Immunol . 1996;  8 199-205
    CrossrefPubMedGoogle Scholar
  • 26 Hoyer L W, Gawryl M S, De la Fuente B. Immunochemical characterization of factor VIII inhibitors. In: Hoyer LW, ed. Factor VIII Inhibitors, Progress in Clinical and Biological Research, Vol 150 New York: Liss 1988: 73-85
    Google Scholar
  • 27 Fulcher C A, De Graaf Mahoney S, Zimmerman T S. FVIII inhibitor IgG subclass and FVIII polypeptide specificity determined by immunoblotting.  Blood . 1987;  69 1475-1480
    PubMedGoogle Scholar
  • 28 Aalberse R C, van der Gaag R, van Leeuwen J. Serological aspects of IgG4 antibodies. I. Prolonged immunization results in an IgG4 restricted response.  J Immunol . 1983;  130 722-726
    PubMedGoogle Scholar
  • 29 Cook G P, Tomlinson I M. The human immunoglobulin VH repertoire.  Immunol Today . 1995;  16 237-242
    CrossrefPubMedGoogle Scholar
  • 30 Williams S C, Winter G. Cloning and sequencing of human immunoglobulin Vλ gene segments.  Eur J Immunol . 1993;  23 1456-1461
    PubMedGoogle Scholar
  • 31 Cox J PL, Tomlinson I M, Winter G. A directory of human germ-line Vκ segments reveals a strong bias in their usage.  Eur J Immunol . 1994;  24 827-836
    PubMedGoogle Scholar
  • 32 Matsuda F, Ishii K, Bourvagnet P. The complete nucleotide sequence of the human immunoglobulin heavy chain variable region locus.  J Exp Med . 1998;  188 2151-2162
    CrossrefPubMedGoogle Scholar
  • 33 Marks J D, Hoogenboom H R, Bonnert T P. By-passing immunization.  Human antibodies from V-gene libraries displayed on phage. J Mol Biol . 1991;  222 581-597
    PubMedGoogle Scholar
  • 34 Griffin H M, Ouwehand W H. A human monoclonal antibody specific for the leucine-33 (p1A1, HPA-la) form of platelet glycoprotein IIIa from a V gene phage display library.  Blood . 1995;  86 4430-4436
    PubMedGoogle Scholar
  • 35 De Wildt M T R, Hoet R MA, Van Venrooij J W. Analysis of heavy and light chain pairings indicates that receptor editing shapes the human antibody repertoire.  J Mol Biol . 1999;  285 895-901
    CrossrefPubMedGoogle Scholar
  • 36 Ohlin M, Borrebaeck C A. Characteristics of human antibody repertoires following active immune responses in vivo.  Mol Immunol . 1996;  33 583-592
    CrossrefPubMedGoogle Scholar
  • 37 Kabat E A, Wu T T, Parry H M, Gottesman K E, Foeller C. Sequences of Immunological Interest.  ed 5. Bethesda, MD: U.S. Department of Health and Human Services 1991
    Google Scholar
      >