EPITOPES RECOGNIZED BY NEUTRALIZING THERAPY-INDUCED HUMAN ANTI-INTERFERON-ALPHA ANTIBODIES ARE LOCALIZED WITHIN THE N-TERMINAL FUNCTIONAL DOMAIN OF RECOMBINANT INTERFERON-ALPHA-2

During prolonged recombinant interferon (rIFN)-alpha 2 therapy, a mino rity of patients develop high-titer neutralizing IFN-alpha antibodies. Sera from nine IFN-alpha antibody-positive patients were studied to c haracterize the specificity of anti-IFN-alpha neutralizing antibodies by their ability to inhibit the antiviral and antiproliferative activi ty of different rIFN-alpha subtypes and rIFN-alpha 1/alpha 2 hybrids. These therapy-induced antibodies (Tab) were compared with IFN-alpha-sp ecific autoantibodies (Aab) from two patients with systemic lupus eryt hematosus who had never received any exogenous IFN-alpha. Although IFN -alpha subtypes are closely related in structure, Tab inhibited the an tiviral activity of only recombinant (r)IFN-alpha 2 and rIFN-alpha 6, but not or slightly that of rIFN-alpha 1, -alpha 7, -alpha 8 and -alph a 14. Furthermore, of four different rIFN-alpha 1/alpha 2 hybrids test ed, Tab inhibited only those which contained the N-terminal residues 1 7-64 of rIFN-alpha 2. Comparison of the primary sequences of neutraliz ed and not neutralized subtypes suggests an epitope involving the resi dues 22-31 of IFN-alpha 2 is recognized. Thus, Tab block rIFN-alpha 2 by reacting with only one of two functional domains. In contrast, Aab possessed a broad specificity and neutralized both the antiviral and a ntiproliferative activity of rIFN-alpha 2, -alpha 6, -alpha 7, -alpha 8 and -alpha 14. They also neutralized all four rIFN-alpha 1/alpha 2 h ybrids tested. These data demonstrate that Tab are highly specific for the therapeutic IFN-alpha subtype and specifically neutralize rIFN-al pha 2 by binding to its N-terminal functional domain.