Epitopes recognized by neutralizing therapy-induced human anti-interferon-α antibodies are localized within the N-terminal functional domain of recombinant interferon-α2

Abstract

During prolonged recombinant interferon (rIFN)-α2 therapy, a minority of patients develop high-titer neutralizing IFN-α antibodies. Sera from nine IFN-α antibody-positive patients were studied to characterize the specificity of anti-IFN-α neutralizing antibodies by their ability to inhibit the antiviral and antiproliferative activity of different rIFN-α subtypes and rIFN-α1/α2 hybrids. These therapy-induced antibodies (Tab) were compared with IFN-α-specific autoantibodies (Aab) from two patients with systemic lupus erythematosus who had never received any exogenous IFN-α. Although IFN-α subtypes are closely related in structure, Tab inhibited the antiviral activity of only recombinant (r)IFN-α2 and rIFN-α6, but not or slightly that of rIFN-α1, -α7, -α8 and -α14. Furthermore, of four different rIFN-α1/α2 hybrids tested, Tab inhibited only those which contained the N-terminal residues 17-64 of rIFN-α2. Comparison of the primary sequences of neutralized and not neutralized subtypes suggests an epitope involving the residues 22-31 of IFN-α2 is recognized. Thus, Tab block rIFN-α2 by reacting with only one of two functional domains. In contrast, Aab possessed a broad specificity and neutralized both the antiviral and antiproliferative activity of rIFN-α2, -α6, -α7, -α8 and -α14. They also neutralized all four rIFN-α1/α2 hybrids tested. These data demonstrate that Tab are highly specific for the therapeutic IFN-α subtype and specifically neutralize rIFN-α2 by binding to its N-terminal functional domain.