ArticleThe Journal of biological chemistry2013
Characterization and solution structure of the factor VIII C2 domain in a ternary complex with classical and non-classical inhibitor antibodies.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 19 citations in OpenAlex.
- Decoding full-length factor VIII through the structural and functional lens of its B domain.Blood vessels, thrombosis & hemostasis · 2026Article
- Blunting specific T-dependent antibody responses with engineered "decoy" B cells.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Small-Angle X-Ray Scattering for Macromolecular Complexes.Advances in experimental medicine and biology · 2024Article
- A New in Silico Antibody Similarity Measure Both Identifies Large Sets of Epitope Binders with Distinct CDRs and Accurately Predicts Off-Target Reactivity.International journal of molecular sciences · 2022Article
- Structure of Blood Coagulation Factor VIII in Complex With an Anti-C2 Domain Non-Classical, Pathogenic Antibody Inhibitor.Frontiers in immunology · 2021Article
- Anti-Drug Antibodies: Emerging Approaches to Predict, Reduce or Reverse Biotherapeutic Immunogenicity.Antibodies (Basel, Switzerland) · 2018Review
- Engineering less immunogenic and antigenic FVIII proteins.Cellular immunology · 2016Review
- Structure of the Human Factor VIII C2 Domain in Complex with the 3E6 Inhibitory Antibody.Scientific reports · 2015Article
- Article
- Six amino acid residues in a 1200 Å2 interface mediate binding of factor VIII to an IgG4κ inhibitory antibody.PloS one · 2015Article
- Expanding the ortholog approach for hemophilia treatment complicated by factor VIII inhibitors.Journal of thrombosis and haemostasis : JTH · 2015Article
- Article
- Article
- Epitope mapping of inhibitory antibodies targeting the C2 domain of coagulation factor VIII by hydrogen-deuterium exchange mass spectrometry.Journal of thrombosis and haemostasis : JTH · 2013Article
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
Abstract
The most significant complication for patients with severe cases of congenital or acquired hemophilia A is the development of inhibitor antibodies against coagulation factor VIII (fVIII). The C2 domain of fVIII is a significant antigenic target of anti-fVIII antibodies. Here, we have utilized small angle x-ray scattering (SAXS) and biochemical techniques to characterize interactions between two different classes of anti-C2 domain inhibitor antibodies and the isolated C2 domain. Multiple assays indicated that antibodies 3E6 and G99 bind independently to the fVIII C2 domain and can form a stable ternary complex. SAXS-derived numerical estimates of dimensional parameters for all studied complexes agree with the proportions of the constituent proteins. Ab initio modeling of the SAXS data results in a long kinked structure of the ternary complex, showing an angle centered at the C2 domain of ∼130°. Guided by biochemical data, rigid body modeling of subunits into the molecular envelope of the ternary complex suggests that antibody 3E6 recognizes a C2 domain epitope consisting of the Arg(2209)-Ser(2216) and Leu(2178)-Asp(2187) loops. In contrast, antibody G99 recognizes the C2 domain primarily through the Pro(2221)-Trp(2229) loop. These two epitopes are on opposing sides of the fVIII C2 domain, are consistent with the solvent accessibility in the context of the entire fVIII molecule, and provide further structural detail regarding the pathogenic immune response to fVIII.
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