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Thromb Haemost 1992; 67(01): 166-171
DOI: 10.1055/s-0038-1648400
Original Articles
Schattauer GmbH Stuttgart

Fine Mapping of Monoclonal Antibody Epitopes on Human von Willebrand Factor Using a Recombinant Peptide Library

David Ginsburg
1   The Howard Hughes Medical Institute and Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA
2   The Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
,
Paula L Bockenstedt
2   The Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
,
Elizabeth A Allen
1   The Howard Hughes Medical Institute and Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA
,
David A Fox
2   The Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
,
Paul A Foster
4   The Department of Molecular and Experimental Medicine and Committee on Vascular Biology, Scripps Clinic and Research Foundation, La Jolla, CA, USA
,
Zaverio M Ruggeri
4   The Department of Molecular and Experimental Medicine and Committee on Vascular Biology, Scripps Clinic and Research Foundation, La Jolla, CA, USA
,
Theodore S Zimmerman
4   The Department of Molecular and Experimental Medicine and Committee on Vascular Biology, Scripps Clinic and Research Foundation, La Jolla, CA, USA
,
Robert R Montgomery
3   The Blood Center of Southeastern Wisconsin and Medical College of Wisconsin, Milwaukee, WI, USA
,
Wadie F Bahou
2   The Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
,
Timothy A Johnson
1   The Howard Hughes Medical Institute and Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA
,
Angela Y Yang
1   The Howard Hughes Medical Institute and Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA
› Author Affiliations
Further Information

Publication History

Received 11 April 1991

Accepted after revision 24 July 1991

Publication Date:
02 July 2018 (online)

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Summary

A recombinant human von Willebrand factor (vWF) cDNA fragment library was constructed in λgtll for the localization of anti-vWF monoclonal antibody epitopes. Twelve of 21 monoclonal antibodies screened identified epitopes expressed in λgtll as β-galactosidase fusion proteins. By sequence analysis, these antigenic determinants were localized to segments ranging from 17 to 105 amino acids in length. Four epitopes apparently shared by more than one antibody were identified, suggesting the presence of immuno-dominant epitopes within vWF. Monoclonal antibody C3, which blocks factor VIII (FVIII) binding to vWF, bound to the same epitope previously identified by a second monoclonal antibody which also blocks this function, suggesting that this region may be at or near the vWF/FVIII binding domain. Three antibodies recognize the same region within the vWF A2 repeat. Mutations near this region appear to be responsible for Type IIA von Willebrand’s disease. The co-localization of these antibodies suggests that this domain might be exposed on the surface of vWF, consistent with its apparent increased sensitivity to plasma proteases.

 

  • References

  • 1 Mancuso DJ, Tuley EA, Westfield LA, Worrall NK, Shelton-Inloes BB, Sorace JM, Alevy YG, Sadler JE. Structure of the gene for human von Willebrand factor. J Biol Chem 1989; 264: 19514-19527
    PubMedGoogle Scholar
  • 2 Ginsburg D, Handin RI, Bonthron DT, Donlon TA, Bruns GAP, Latt SA, Orkin SH. Human von Willebrand factor (vWF): isolation of cDNA clones and chromosomal localization. Science 1985; 228: 1401-1406
    CrossrefPubMedGoogle Scholar
  • 3 Ruggeri ZM, Zimmerman TS. Von Willebrand factor and von Willebrand disease. Blood 1987; 70: 895-904
    PubMedGoogle Scholar
  • 4 Weiss HJ, Hawiger J, Ruggeri ZM, Turitto VT, Thiagarajan P, Hoffmann T. Fibrinogen-independent platelet adhesion and thrombus formation on subendothelium mediated by glycoprotein Ilb-IIIa complex at high shear rate. J Clin Invest 1989; 83: 288-297
    CrossrefPubMedGoogle Scholar
  • 5 Verweij CL, Diergaarde PJ, Hart M, Pannekoek H. Full-length von Willebrand factor (vWF) cDNA encodes a highly repetitive protein considerably larger than the mature vWF subunit. EMBO 1986; 5: 1839-1847
    CrossrefPubMedGoogle Scholar
  • 6 Bonthron DT, Handin RI, Kaufman RJ, Wasley LC, Orr EC, Mitsock LM, Ewenstein B, Loscalzo J, Ginsburg D, Orkin SH. Structure of pre-pro-von Willebrand factor and its expression in heterologous cells. Nature 1986; 324: 270-273
    CrossrefPubMedGoogle Scholar
  • 7 Sadler EJ, Shelton-Inloes BB, Sorace JM, Harlan JM, Titani K, Davie EW. Cloning and characterization of two cDNAs coding for human von Willebrand factor. Proc Natl Acad Sci USA 1985; 82: 6394-6398
    CrossrefPubMedGoogle Scholar
  • 8 Lynch DC, Zimmerman TS, Collins CJ, Brown M, Morin MJ, Ling EH, Livingston DM. Molecular cloning of cDNA for human von Willebrand factor: Authentication by a new method. Cell 1985; 41: 49-56
    CrossrefPubMedGoogle Scholar
  • 9 Verweij CL, de Vries CJM, Distel B, van Zonneveld A-J, van Kessel AG, van Mourik JA, Pannekoek H. Construction of cDNA coding for human von Willebrand factor using antibody probes for colonyscreening and mapping of the chromosomal gene. Nucl Acids Res 1985; 13: 4699-4717
    CrossrefPubMedGoogle Scholar
  • 10 Girma J-P, Meyer D, Verweij CL, Pannekoek H, Sixma JJ. Structure-function relationship of human von Willebrand factor. Blood 1987; 70: 605-611
    PubMedGoogle Scholar
  • 11 Girma J-P, Kalafatis M, Pietu G, Lavergne J-M, Chopek MW, Edgington TS, Meyer D. Mapping of distinct von Willebrand factor domains interacting with platelet GPIb and GPIIb/IIIa and with collagen using monoclonal antibodies. Blood 1986; 67: 1356-1366
    PubMedGoogle Scholar
  • 12 Houdijk WP, Schiphorst ME, Sixma JJ. Identification of functional domains on von Willebrand factor by binding of tryptic fragments to collagen and to platelets in the presence of ristocetin. Blood 1986; 67: 1498-1503
    PubMedGoogle Scholar
  • 13 Goodall AH, Meyer D. Registry of monoclonal antibodies to factor VIII and von Willebrand factor. Thromb Haemostas 1985; 54: 878-891
    PubMedGoogle Scholar
  • 14 Pareti FI, Niiya K, McPherson JM, Ruggeri ZM. Isolation and characterization of two domains of human von Willebrand factor that interact with fibrillar collagen types I and III. J Biol Chem 1987; 262: 13835-13841
    CrossrefPubMedGoogle Scholar
  • 15 Mohri H, Fujimura Y, Shima M, Yoshioka A, Houghten RA, Ruggeri ZM, Zimmerman TS. Structure of the von Willebrand factor domain interacting with glycoprotein lb. J Biol Chem 1988; 263: 17901-17904
    PubMedGoogle Scholar
  • 16 Berliner S, Niiya K, Roberts JR, Houghten RA, Ruggeri ZM. Generation and characterization of peptide-specific antibodies that inhibit von Willebrand factor binding to glycoprotein Ilb-IIIa without interfering with other adhesive molecules. J Biol Chem 1988; 263: 7500-7506
    PubMedGoogle Scholar
  • 17 Piétu G, Meulien P, Cherel G, Diaz J, Baruch D, Courtney M, Meyer D. Production in Escherichia coli of a biologically active subfragment of von Willebrand factor corresponding to the platelet glycoprotein lb, collagen and heparin binding domains. Biochem Biophys Res Commun 1989; 164: 1339-1347
    CrossrefPubMedGoogle Scholar
  • 18 Fujimura Y, Titani K, Holland LZ, Russell SR, Roberts JR, Elder JH, Ruggeri ZM, Zimmerman TS. Von Willebrand factor: a reduced and alkylated 52/48-kDa fragment beginning at amino acid residue 449 contains the domain interacting with platelet glycoprotein lb. J Biol Chem 1986; 261: 381-385
    PubMedGoogle Scholar
  • 19 Fujimura Y, Titani K, Holland LZ, Roberts JR, Kostel P, Ruggeri ZM, Zimmerman TS. A heparin-binding domain of human von Willebrand factor. J Biol Chem 1987; 262: 1734-1739
    PubMedGoogle Scholar
  • 20 Roth GJ, Titani K, Hoyer LW, Hickey MJ. Localization of binding sites within human von Willebrand factor for monomeric Type III collagen. Biochemistry 1986; 25: 8357-8361
    CrossrefPubMedGoogle Scholar
  • 21 Mohri H, Yoshioka A, Zimmerman TS, Ruggeri ZM. Isolation of the von Willebrand factor domain interacting with platelet glycoprotein lb, heparin, and collagen and characterization of its three distinct functional sites. J Biol Chem 1989; 264: 17361-17367
    PubMedGoogle Scholar
  • 22 Foster PA, Fulcher CA, Marti T, Titani K, Zimmerman TS. A major factor VIII binding domain resides within the amino-terminal 272 amino acid residues of von Willebrand factor. J Biol Chem 1987; 262: 8443-8446
    PubMedGoogle Scholar
  • 23 Takahashi Y, Kalafatis M, Girma J-P, Sewerin K, Andersson LO, Meyer D. Localization of a factor VIII binding domain on a 34 kilodalton fragment of the N-terminal portion of von Willebrand factor. Blood 1987; 70: 1679-1682
    PubMedGoogle Scholar
  • 24 Nunberg JH, Rodgers G, Gilbert JH, Snead RM. Method to map antigenic determinants recognized by monoclonal antibodies: Localization of a determinant of virus neutralization on the feline leukemia virus envelope protein gp70. Proc Natl Acad Sci USA 1984; 81: 3675-3679
    CrossrefPubMedGoogle Scholar
  • 25 Mehra V, Sweetser D, Young RA. Efficient mapping of protein antigenic determinants. Proc Natl Acad Sci USA 1986; 83: 7013-7017
    CrossrefPubMedGoogle Scholar
  • 26 Ware J, Toomey JR, Stafford DW. Epitope localization of anti-factor VIII monoclonal antibodies determined by recombinant peptides. Thromb Haemostas 1989; 61: 225-229
    PubMedGoogle Scholar
  • 27 Frazier D, Smith KJ, Cheung W-F, Ware J, Lin S-W, Thompson AR, Reisner H, Bajaj SP, Stafford DW. Mapping of monoclonal antibodies to human factor IX. Blood 1989; 74: 971-977
    PubMedGoogle Scholar
  • 28 McGraw R, Frazier D, de Serres M, Reisner H, Stafford D. Antigenic determinant in human coagulation factor IX: immunological screening and DNA sequence analysis of recombinant phage map a monoclonal antibody to residues III through 132 of the zymogen. Blood 1986; 67: 1344-1348
    PubMedGoogle Scholar
  • 29 Sambrook JF. Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor; NY: 1989
  • 30 Young RA, Davis RW. Immunoscreening Lambda gtll recombinant DNA expression libraries. Genet Eng 1985; 7: 29-41
    PubMedGoogle Scholar
  • 31 Ginsburg D, Zeheb R, Yang AY, Rafferty UM, Andreasen PA, Nielsen L, Dano K, Lebo RV, Gelehrter TD. cDNA cloning of human plasminogen activator-inhibitor from endothelial cells. J Clin Invest 1986; 78: 1673-1680
    CrossrefPubMedGoogle Scholar
  • 32 Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227: 680-685
    CrossrefPubMedGoogle Scholar
  • 33 Bahou WF, Ginsburg D, Sikkink R, Litwiller R, Fass DN. A monoclonal antibody to von Willebrand factor (vWF) inhibits factor VIII binding. Localization of its antigenic determinant to a nonadecapeptide at the amino terminus of the mature vWF polypeptide. J Clin Invest 1989; 84: 56-61
    CrossrefPubMedGoogle Scholar
  • 34 Fulcher CA, Zimmerman TS. Characterization of the human factor VIII procoagulant protein with a heterologous precipitating antibody. Proc Natl Acad Sci USA 1982; 79: 1648-1652
    CrossrefPubMedGoogle Scholar
  • 35 Liu FT, Bohn JW, Ferry EL, Yamamoto H, Molinaro CA, Sherman LA, Klinman NR, Katz DH. Monoclonal dinitrophenylspecific murine IgE antibody: preparation, isolation, and characterization. J Immunol 1980; 124: 2728-2737
    PubMedGoogle Scholar
  • 36 Kawai Y, Montgomery RR. Endothelial cell processing of von Willebrand proteins. Ann NY Acad Sci 1987; 509: 60-70
    CrossrefPubMedGoogle Scholar
  • 37 Bockenstedt P, Greenberg JM, Handin RI. Structural basis of von Willebrand factor binding to platelet glycoprotein lb and collagen: effects of disulfide reduction and limited proteolysis of polymeric von Willebrand factor. J Clin Invest 1986; 77: 743-749
    CrossrefPubMedGoogle Scholar
  • 38 Nguyen PK, Fox DA, Ginsburg D, Jourdian W, Bockenstedt P. Immunochemical homology between the phosphomannosyl receptor fibrinogen and von Willebrand’s factor (vWF). Blood 1987; 70: 392a (Abstract)
    PubMedGoogle Scholar
  • 39 Jameson BA, Wolf H. The antigenic index: a novel algorithm for predicting antigenic determinants. Comput Appl Biosci 1988; 4: 181-186
    PubMedGoogle Scholar
  • 40 Berkowitz SD, Dent J, Roberts J, Fujimura Y, Plow EF, Titani K, Ruggeri ZM, Zimmerman TS. Epitope mapping of the von Willebrand factor subunit distinguishes fragments present in normal and type IIA von Willebrand disease from those generated by plasmin. J Clin Invest 1987; 79: 524-531
    CrossrefPubMedGoogle Scholar
  • 41 Wise RJ, Orkin SH, Pittman DD, Kaufman RJ. The interaction of von Willebrand factor and factor VIII studied via mutagenesis of the recombinant molecules. Blood 1989; 74: 191a (Abstract)
    PubMedGoogle Scholar
  • 42 Morgan DO, Edman JC, Standring DN, Fried VA, Smith MC, Roth RA, Rutter WJ. Insulin-like growth factor II receptor as a multifunctional binding protein. Nature 1987; 329: 301-308
    CrossrefPubMedGoogle Scholar
  • 43 Wise RJ, Pittman DD, Handin RI, Kaufman RJ, Orkin SH. The propeptide of von Willebrand factor independently mediates the assembly of von Willebrand multimers. Cell 1988; 52: 229-236
    CrossrefPubMedGoogle Scholar
  • 44 Verweij CL, Hart M, Pannekoek H. Proteolytic cleavage of the precursor of von Willebrand factor is not essential for multimer formation. J Biol Chem 1988; 263: 7921-7924
    PubMedGoogle Scholar
  • 45 Mayadas TN, Wagner DD. In vitro multimerization of von Willebrand factor is triggered by low pH. J Biol Chem 1989; 264: 13497-13503
    PubMedGoogle Scholar
  • 46 Bockenstedt P, Nguyen PK, Johnson T, Yang A, Fox D, Ginsburg D. Identification of a new functional von Willebrand factor domain facilitating binding to platelets. Blood 1988; 72: 392a (Abstract)
    PubMedGoogle Scholar
  • 47 Ginsburg D, Konkle BA, Gill JC, Montgomery RR, Bockenstedt PL, Johnson TA, Yang AY. Molecular basis of human von Willebrand disease: Analysis of platelet von Willebrand factor mRNA. Proc Natl Acad Sci USA 1989; 86: 3723-3727
    CrossrefPubMedGoogle Scholar
  • 48 Dent JA, Berkowitz SD, Ware J, Kasper CK, Ruggeri ZM. Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand factor. Proc Natl Acad Sci USA 1990; 87: 6306-6310
    CrossrefPubMedGoogle Scholar
  • 49 Bonthron D, Orr EC, Mitsock LM, Ginsburg D, Handin RI, Orkin SH. Nucleotide sequence of pre-pro-von Willebrand factor cDNA. Nucleic Acids Res 1986; 14: 7125-7127
    CrossrefPubMedGoogle Scholar