In this issue of Blood, Nguyen et al employ high-resolution mapping to precisely define epitopes on the C2 domain of blood coagulation factor VIII (FVIII). Their results nicely complement a recent report in Blood describing the structure of a ternary complex of 2 inhibitory antibodies with the C2 domain. Together, these studies reveal fascinating molecular details on the unexpectedly large number of exposed surfaces in the C2 domain that contribute to the binding of inhibitory antibodies. These findings are relevant in the context of neutralizing anti-FVIII antibodies that develop in patients with hemophilia A. Insight into the antigenic properties of the C2 domain is needed to design FVIII variants with decreased antigenicity. Pioneering studies by Dorothea Scandella on the epitope mapping of FVIII inhibitors already pointed toward the C2 domain as a major binding site for FVIII inhibitors. The recent studies by Nguyen and Walter, combined with earlier work by Meeks et al, have provided evidence for 3 major binding sites for inhibitory anti-FVIII antibodies within the C2 domain. The overall dimensions of the C2 domain are small when compared to antibodies. Nevertheless, at least 2 and probably 3 monoclonal antibodies can simultaneously bind to the C2 domain. The mapping studies reported by Nguyen also suggest the presence of 3 distinct clusters of surface-exposed side chains on the FVIII C2 domain.
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