Characterization of Factor VIII B-Cell Inhibitory Epitopes

Pete Lollar

doi:10.1055/s-0037-1615872

Thrombosis and Haemostasis, Table of Contents

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

¹Department of Medicine, Emory University, Atlanta, GA, USA

› Author Affiliations

Abstract

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.

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References

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
12 Shulman NR, Hirschman RJ. Acquired hemophilia. Trans Assoc Am Physicians. 1969; 82: 388-397.
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.
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.
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.
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.
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.
18 Laver WG, Air GM, Webster RG, Smith-Gill SJ. Epitopes on protein antigens: misconceptions and realities. Cell 1990; 61: 553-556.
19 Jin L, Fendly BM, Wells JA. High resolution functional analysis of antibody-antigen interactions. J Mol Biol. 1992; 226: 851-865.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
34 Andersson LO, Brown JE. Interaction of Factor VIII-von Willebrand Factor with phospholipid vesicles. Biochem J. 1981; 200: 161-167.
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.
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.
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.
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.
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.
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.
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.
42 Brettler DM. Inhibitors in congenital haemophilia. Baillieres Clin Haematol. 1996; 9: 319-329.
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.
44 Koshihara K, Qian J, Lollar P, Hoyer LW. Immunoblot crossreactivity of factor VIII inhibitors with porcine factor VIII. Blood 1995; 86: 2183-2190.