Epitopes recognized by neutralizing therapy-induced human anti-interferon-alpha antibodies are localized within the N-terminal functional domain of recombinant interferon-alpha2

During prolonged recombinant interferon (rIFN)-alpha2 therapy, a minority of patients develop high-titer neutralizing IFN-alpha antibodies. Sera from nine IFN-alpha antibody-positive patients were studied to characterize the specificity of anti-IFN-alpha neutralizing antibodies by their ability to inhibit the anitviral and antiproliferative activity of differnet rIFN-alpha subtypes and rIFN-alpha1/alpha2 hybrids. These therapy-induced antibodies (TaB) were compared with IFN-alpha-specific autoantibodies (Aab) from two patients with systemic lupus erythematosus who had never received any exogenous IFN-alpha. Although IFN-alpha subtypes are closely related in structure, Tab inhibited the antiviral activity of only recombinant (r)IFN-alpha2 and rIFN-alpha6, but not or slightly that of rIFN-alpha1, -alpha7,-alpha9 and alpha14. Furthermore, of four different rIFN-alpha1/alpha2 hybrids tested, Tab inhibited only those which contained the N-terminal residues 17-64 of rIFN-alpha2