Download PDF
Thromb Haemost 1999; 82(02): 505-508
DOI: 10.1055/s-0037-1615872
Research Article
Schattauer GmbH

Characterization of Factor VIII B-Cell Inhibitory Epitopes

Pete Lollar
1   Department of Medicine, Emory University, Atlanta, GA, USA
› Author Affiliations
Further Information

Publication History

Publication Date:
09 December 2017 (online)

    Permissions and Reprints

Introduction

Factor VIII contains three epitopes that are the usual targets of clinically significant antibody inhibitors. Two of these epitopes are located in the A2 and C2 domains of factor VIII. The third epitope appears to be in the A3 domain. Ongoing studies continue to provide higher resolution maps of these epitopes and to understand the mechanism by which inhibitors produce a bleeding diathesis. The manipulation of inhibitor epitopes using recombinant DNA technology may lead to improved forms of factor VIII that have lower antigenicity and/or lower immunogenicity.

 

  • References

  • 1 Lusher JM, Arkin S, Abildgaard CF, Schwartz RS. Kogenate Previously Untreated Patient Study Group. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and the development of inhibitors. N Engl J Med. 1993; 328: 453-459.
    CrossrefPubMedGoogle Scholar
  • 2 Kasper CK, Aledort LM, Counts RB, Edson JR, Frantatoni J, Gree D, Hampton JW, Hilgartner MW, Lazerson J, Levine PH, Lazerson J, McMillan C, Penner J, Shapiro S, Shulman NR. A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh. 1975; 34: 869-872.
    PubMedGoogle Scholar
  • 3 Fulcher CA, Mahoney SD, Roberts JR, Kasper CK, Zimmerman TS. Localization of human factor FVIII inhibitor epitopes to two polypeptide fragments. Proc Natl Acad Sci USA. 1985; 82: 7728-7732.
    CrossrefPubMedGoogle Scholar
  • 4 Scandella D, Mahoney SD, Mattingly M, Roeder D, Timmons L, Fulcher CA. 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
  • 5 Scandella D, Mattingly M, de Graaf S, Fulcher CA. Localization of epitopes for human factor VIII inhibitor antibodies by immunoblotting and antibody neutralization. Blood 1989; 74: 1618-1626.
    PubMedGoogle Scholar
  • 6 Scandella D, Mattingly M, Prescott R. A recombinant factor VIII A2 domain polypeptide quantitatively neutralizes human inhibitor antibodies which bind to A2. Blood 1993; 82: 1767-1775.
    PubMedGoogle Scholar
  • 7 Prescott R, Nakai H, Saenko EL, Scharrer I, Nilsson IM, Humphries J, Hurst D, Bray G, Scandella D. Recombinate and Kogenate Study Groups. The inhibitory antibody response is more complex in hemophilia A patients than in most nonhemophiliacs with fVIII autoantibodies. Blood 1997; 89: 3663-3671.
    PubMedGoogle Scholar
  • 8 Lollar P, Parker ET, Curtis JE, Helgerson SL, Hoyer LW, Scott ME, Scandella D. Inhibition of human factor VIIIa by anti-A2 subunit antibodies. J Clin Invest. 1994; 93: 2497-2504.
    CrossrefPubMedGoogle Scholar
  • 9 Lubin IM, Healey JF, Scandella D, Runge MS, Lollar P. Elimination of a major inhibitor epitope in factor VIII. J Biol Chem. 1994; 269: 8639-8641.
    PubMedGoogle Scholar
  • 10 Healey JF, Lubin IM, Nakai H, Saenko EL, Hoyer LW, Scandella D, Lollar P. 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 Healey JF, Scandella D, Lollar P. Expression of a recombinant hybrid human/porcine factor VIII molecule with reduced reactivity toward anti-C2 domain inhibitory antibodies. Blood 1996; 88: 658a.
    PubMedGoogle Scholar
  • 12 Shulman NR, Hirschman RJ. Acquired hemophilia. Trans Assoc Am Physicians. 1969; 82: 388-397.
    PubMedGoogle Scholar
  • 13 Lloyd JV, Street AM, Berry E, McPherson J, Ekert H, Lammi A, McWhirter WR, Duncan EM, Maxwell EL, Rowell J, Baker RI, Leahy MF, Jupe D. Cross-reactivity to porcine factor VIII of factor VIII inhibitors in patients with haemophilia in Australia and New Zealand. Australian New Zealand J Med. 1997; 27 (06) 658-664.
    PubMedGoogle Scholar
  • 14 Lubin IM, Healey JF, Scandella D, Lollar P. Analysis of the human factor VIII A2 inhibitor epitope by alanine scanning mutagenesis. J Biol Chem. 1997; 272: 30191-30195.
    CrossrefPubMedGoogle Scholar
  • 15 Ortel TL, Quinn-Allen MA, Keller FG, Peterson JA, Larocca D, Kane WH. Localization of functionally important epitopes within the second C-type domain of coagulation factor V using recombinant chimeras. J Biol Chem. 1994; 269: 15898-15905.
    PubMedGoogle Scholar
  • 16 Pemberton S, Lindley P, Zaitsev V, Card G, Tuddenham EGD, Kemball-Cook G. A molecular model for the triplicated A domains of human factor VIII based on the crystal structure of human caeruloplasmin. Blood 1997; 89: 2413-2421.
    PubMedGoogle Scholar
  • 17 Ziatseva I, Zaitsev V, Card G, Moshkov K, Bax B, Ralph A, Lindley P. The X-ray structure of human serum ceruloplasmin at 3.1 Angstroms: nature of the copper centres. JBIC 1996; 1: 15-23.
    CrossrefPubMedGoogle Scholar
  • 18 Laver WG, Air GM, Webster RG, Smith-Gill SJ. Epitopes on protein antigens: misconceptions and realities. Cell 1990; 61: 553-556.
    CrossrefPubMedGoogle Scholar
  • 19 Jin L, Fendly BM, Wells JA. High resolution functional analysis of antibody-antigen interactions. J Mol Biol. 1992; 226: 851-865.
    CrossrefPubMedGoogle Scholar
  • 20 Arai M, Scandella D, Hoyer LW. Molecular basis of factor-VIII inhibition by human antibodies -antibodies that bind to the factor-VIII light chain prevent the interaction of factor-VIII with phospholipid. J Clin Invest. 1989; 83: 1978-1984.
    CrossrefPubMedGoogle Scholar
  • 21 Healey JF, Barrow RT, Tamim HM, Lubin IM, Shima M, Scandella D, Lollar P. Residues Glu2181-Val2243 contain a major determinant of the inhibitory epitope in the C2 djomain of human factor VIII. Blood 1998; 92: 3701-3709.
    PubMedGoogle Scholar
  • 22 Foster PA, Fulcher CA, Houghten RA, Zimmerman TS. Synthetic factor VIII peptides with amino acid sequences contained within the C2 domain of factor VIII inhibit factor VIII binding to phosphatidylserine. Blood 1990; 75: 1999-2004.
    PubMedGoogle Scholar
  • 23 Saenko EL, Shima M, Rajalakshmi KJ, Scandella D. A role for the C2 domain of factor binding to von Willebrand factor. J Biol Chem. 1994; 269: 11601-11605.
    PubMedGoogle Scholar
  • 24 Gilbert GE, Baleja JD. Membrane-binding peptide from the C2 domain of factor VIII forms an amphipathic structure as determined by NMR spectroscopy. Biochemistry 1995; 34: 3022-3031.
    CrossrefPubMedGoogle Scholar
  • 25 Shima M, Scandella D, Yoshioka A, Nakai H, Tanaka I, Kamisue S, Terada S, Fukui H. A factor VIII neutralizing monoclonal antibody and a human inhibitor alloantibody recognizing epitopes in the C2 domain inhibit binding to von Willebrand factor and to phosphatidylserine. Thromb Haemost. 1993; 69: 240-246.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Scandella D, Gilbert GE, Shima M, Nakai H, Eagleson C, Felch M, Prescott R, Rajalakshmi KJ, Hoyer LW, Saenko E. Some human inhibitor antibodies recognize a common epitope corresponding to C2 domain amino acids 2248-2312 which overlap a phospholipid binding site. Blood 1995; 86: 1811-1819.
    PubMedGoogle Scholar
  • 27 Saenko EL, Scandella D. The acidic region of the factor VIII light chain and the C2 domain together form the high affinity binding site for von Willebrand factor. J Biol Chem. 1997; 272: 18007-18014.
    CrossrefPubMedGoogle Scholar
  • 28 Foster PA, Fulcher CA, Houghten RA, Zimmerman TS. An immunogenic region with residues Val1670-Glu1684 of the factor VIII light chain induces antibodies which inhibit binding of factor VIII to von Willebrand factor. J Biol Chem. 1988; 263: 5230-5234.
    PubMedGoogle Scholar
  • 29 Leyte A, Verbeet MP, Brodniewicz-Proba T, van Mourik JA, Mertens K. The interaction between human blood-coagulation factor VIII and von Willebrand factor. Biochem J. 1989; 257: 679-683.
    CrossrefPubMedGoogle Scholar
  • 30 Shima M, Yoshioka A, Nakai H, Tanaka I, Sawamoto Y, Kamisue S, Terada S, Fukui H. Epitope localization of monoclonal antibodies against factor VIII light chain which inhibit complex formation by factor VIII with von Willebrand factor. Int J Hematol. 1991; 54: 515-522.
    PubMedGoogle Scholar
  • 31 Leyte A, van Schijndel HB, Neihrs C, Huttner WB, Verbeet MP, Mertens K, van Mourik JA. Sulfation of Tyr1680 of human blood coagulation factor VIII is essential for the interaction of factor VIII with von Willebrand factor. J Biol Chem. 1991; 266: 740-746.
    PubMedGoogle Scholar
  • 32 Lollar P, Hill-Eubanks DC, Parker CG. Association of the factor VIII light chain with von Willebrand factor. J Biol Chem. 1988; 263: 10451-10455.
    PubMedGoogle Scholar
  • 33 Lajmanovich A, Hudry-Clergeon G, Freyssinet JM, Marguerie G. Human Factor VIII procoagulant activity and phospholipid interactions. Biochim Biophys Acta. 1981; 678: 132-136.
    CrossrefPubMedGoogle Scholar
  • 34 Andersson LO, Brown JE. Interaction of Factor VIII-von Willebrand Factor with phospholipid vesicles. Biochem J. 1981; 200: 161-167.
    CrossrefPubMedGoogle Scholar
  • 35 Fay PJ, Coumans J-V, Walker FJ. von Willebrand factor mediates protection of factor VIII from activated protein C-catalyzed inactivation. J Biol Chem. 1991; 266: 2172-2177.
    PubMedGoogle Scholar
  • 36 McMullen BA, Fujikawa K, Davie EW, Hedner U, Ezban M. Locations of disulfide bonds and free cystines in the heavy and light chains of recombinant human factor VIII (antihemophilic factor A). Protein Sci. 1995; 4: 740-746.
    PubMedGoogle Scholar
  • 37 Jacquemin MG, Desqueper BG, Benhida A, Vander Elst L, Hoylaerts MF, Bakkus M, Thielemans K, Arnout J, Peerlinck K, Gilles JG, Vermylen J, Saint-Remy JM. Mechanism and kinetics of factor VIII inactivation: study with an IgG4 monoclonal antibody derived from a hemophilia A patient with inhibitor. Blood 1998; 92 (02) 496-506.
    PubMedGoogle Scholar
  • 38 Zhong D, Saenko EL, Shima M, Felch M, Scandella D. Some human inhibitor antibodies interfere with factor VIII binding to factor IX. Blood 1998; 92 (01) 136-142.
    PubMedGoogle Scholar
  • 39 Lenting PJ, van de Loo JW, Donath MJ, van Mourik JA, Mertens K. The sequence Glu1811-Lys1818 of human blood coagulation factor VIII comprises a binding site for activated factor IX. J Biol Chem. 1996; 271 (04) 1935-1940.
    CrossrefPubMedGoogle Scholar
  • 40 Fijnvandraat K, Celie PHN, Turenhout EAM, ten Cate JW, van Mourik JA, Mertens K, Peters M, Voorberg J. A human alloantibody interferes with binding of factor IXa to the factor VIII light chain. Blood 1998; 91: 2347-2352.
    PubMedGoogle Scholar
  • 41 Morrison AE, Ludlam CA, Kessler C. Use of porcine factor VIII in the treatment of patients with acquired hemophilia. Blood 1993; 81: 1513-1520.
    PubMedGoogle Scholar
  • 42 Brettler DM. Inhibitors in congenital haemophilia. Baillieres Clin Haematol. 1996; 9: 319-329.
    CrossrefPubMedGoogle Scholar
  • 43 Hay C, Lozier JN, Aledort LM, Hoyer LW, Lusher JM, Reisner HM, White II GC. editors Porcine factor VIII therapy in patients with factor VIII inhibitors. In: Inhibitors to Coagulation Factors. Plenum Press; New York: 1995: 143-151.
    Google Scholar
  • 44 Koshihara K, Qian J, Lollar P, Hoyer LW. Immunoblot crossreactivity of factor VIII inhibitors with porcine factor VIII. Blood 1995; 86: 2183-2190.
    PubMedGoogle Scholar