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Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 558-563
Human antibodies with specificity for the C2 domain of factor VIII
are derived from VH1 germline genes
Edward N. van den Brink,
Ellen A. M. Turenhout,
Julian Davies,
Niels Bovenschen,
Karin Fijnvandraat,
Willem H. Ouwehand,
Marjolein Peters, and
Jan Voorberg
From the Department of Blood Coagulation, CLB,
Amsterdam; the Laboratory for Experimental and Clinical Immunology,
Academic Medical Centre, University of Amsterdam, Amsterdam; Emma
Children's Hospital Academic Medical Centre, Amsterdam, The
Netherlands; the Department of Hematology, University of Cambridge; the
National Blood Service, Cambridge; and the National Institute for
Biological Standards and Control, Potters Bar, United Kingdom.
A serious complication in hemophilia care is the development of
factor VIII (FVIII) neutralizing antibodies (inhibitors). The authors
used V gene phage display technology to define human anti-FVIII
antibodies at the molecular level. The IgG4-specific, variable,
heavy-chain gene repertoire of a patient with acquired hemophilia was
combined with a nonimmune, variable, light-chain gene repertoire for
display as single-chain variable domain antibody fragments (scFv) on
filamentous phage. ScFv were selected by 4 rounds of panning on
immobilized FVIII light chain. Sequence analysis revealed that isolated
scFv were characterized by VH domains encoded by germline
genes DP-10, DP-14, and DP-88, all belonging to the VH1
gene family. All clones displayed extensive hypermutation and were
characterized by unusually long CDR3 sequences of 20 to 23 amino acids.
Immunoprecipitation revealed that all scFv examined bound to the C2
domain of FVIII. Furthermore, isolated scFv competed with an inhibitory
murine monoclonal antibody for binding to the C2 domain. Even though
scFv bound FVIII with high affinity, they did not inhibit FVIII
activity. Interestingly, the addition of scFv diminished the inhibitory
potential of patient-derived antibodies with C2 domain specificity.
These results suggest that the epitope of a significant portion of
anti-C2 domain antibodies overlaps with that of the scFv isolated in
this study.
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