Human antibodies with specificity for the C2 domain of factor VIII are derived from VH1 germline genes.
作者： Edward N. van den Brink , Ellen A. M. Turenhout , Julian Davies , Niels Bovenschen , Karin Fijnvandraat
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摘要: 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 at molecular level. IgG4-specific, variable, heavy-chain repertoire a patient with acquired was combined nonimmune, light-chain for as single-chain variable domain antibody fragments (scFv) on filamentous phage. ScFv were selected by 4 rounds panning immobilized FVIII light chain. Sequence analysis revealed that isolated scFv characterized V(H) domains encoded germline genes DP-10, DP-14, and DP-88, all belonging V(H)1 family. All clones displayed extensive hypermutation unusually long CDR3 sequences 20 23 amino acids. Immunoprecipitation examined bound C2 FVIII. Furthermore, competed an inhibitory murine monoclonal binding domain. Even though high affinity, they did not inhibit activity. Interestingly, addition diminished potential patient-derived specificity. These results suggest epitope significant portion anti-C2 overlaps this study. (Blood. 2000;95:558-563)
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