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 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 antiviral and antiproliferative activity of different rIFN-alpha subtypes and rIFN-alpha 1/alpha 2 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-alpha 2 and rIFN-alpha 6, but not or slightly that of rIFN-alpha 1, -alpha 7, -alpha 8 and -alpha 14. Furthermore, of four different rIFN-alpha 1/alpha 2 hybrids tested, Tab inhibited only those which contained the N-terminal residues 17-64 of rIFN-alpha 2. Comparison of the primary sequences of neutralized and not neutralized subtypes suggests an epitope involving the residues 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 antiproliferative activity of rIFN-alpha 2, -alpha 6, -alpha 7, -alpha 8, and -alpha 14. They also neutralized all four rIFN-alpha 1/alpha 2 hybrids tested. These data demonstrate that Tab are highly specific for the therapeutic IFN-alpha subtype and specifically neutralize rIFN-alpha 2 by binding to its N-terminal functional domain.
Nolte
K U
KU
Dept. of Clinical Immunology, Medical School of Hannover, Germany.
Günther
G
G
von Wussow
P
P
D000906:Antibodies / Q000276:immunology*; D000939:Epitopes; D006801:Humans; D007370:Interferon Type I / Q000276:immunology* / Q000627:therapeutic use; D007943:Leukemia, Hairy Cell / Q000628:therapy; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000628:therapy; D011994:Recombinant Proteins
D000906:Antibodies; D000939:Epitopes; D007370:Interferon Type I; D011994:Recombinant Proteins