Elimination of a major inhibitor epitope in factor VIII.
The A2 and C2 domains of human blood coagulation factor VIII (fVIII) contain the epitopes targeted by most inhibitory allo- and autoantibodies. Human inhibitors usually display limited or no reaction with porcine fVIII. We constructed an active, recombinant hybrid human/porcine fVIII molecule by replacing the putative human fVIII A2 domain epitope with the homologous porcine sequence. The hybrid retained full activity in the presence of antibodies with specificity restricted to the human A2 epitope. In contrast, the hybrid was neutralized by an anti-C2 antibody. These findings provide a basis for fine epitope mapping and for therapy of the inhibitor patient.
Lubin
I M
IM
Department of Medicine, Emory University, Atlanta, Georgia 30322.
Healey
J F
JF
Scandella
D
D
Runge
M S
MS
Lollar
P
P
D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001483:Base Sequence; D001777:Blood Coagulation; D017931:DNA Primers / Q000737:chemistry; D000939:Epitopes; D005169:Factor VIII / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007518:Isoantibodies / Q000276:immunology; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins / Q000276:immunology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013552:Swine
D001323:Autoantibodies; D017931:DNA Primers; D000939:Epitopes; D007518:Isoantibodies; D011993:Recombinant Fusion Proteins; D005169:Factor VIII