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

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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.