ELIMINATION OF A MAJOR INHIBITOR EPITOPE IN FACTOR-VIII

The A2 and C2 domains of human blood coagulation factor VIII (fVIII) c ontain the epitopes targeted by most inhibitory allo- and autoantibodi es. Human inhibitors usually display limited or no reaction with porci ne fVIII. We constructed an active, recombinant hybrid human/porcine f VIII molecule by replacing the putative human fVIII A2 domain epitope with the homologous porcine sequence. The hybrid retained full activit y in the presence of antibodies with specificity restricted to the hum an A2 epitope. In contrast, the hybrid was neutralized by an anti-C2 a ntibody. These findings provide a basis for fine epitope mapping and f or therapy of the inhibitor patient.