Protein Aggregates Seem to Play a Key Role Among the Parameters Influencing the Antigenicity of Interferon Alpha (IFN-α) in Normal and Transgenic Mice

Abstract

Purpose. During long-term treatment of various malignant or viral diseases with IFN-α up to 20% of patients develop anti-IFN-α antibodies for as yet unknown reasons.

Methods. To address this issue, a mouse model using Balb/C mice was established and the relevance of several potentially anti-IFN-α antibodies inducing factors was studied.

Results. The model revealed that both a higher frequency of injections and a higher dosage of IFN-α were more immunogenic and that the route of administration affected the antibody response to IFN-α. The intrinsic immunostimulatory activity of IFN-α itself also enhanced the immune response. IFN-α protein aggregates (IFN-α-IFN-α and human serum albumin (HSA)-IFN-α aggregates), which were recently identified in all marketed IFN-α products, were significantly more immunogenic than IFN-α monomers. These aggregates broke the tolerance against human IFN-α monomers in human IFN-α transgenic mice.

Conclusions. Based on these animal studies it is proposed that the immune response to IFN-α in humans is most probably elicited by a combination of several factors among which IFN-α protein aggregates seem to play a key role.