Case Study: Immunogenicity of Interferon-Beta

While autoantibodies (autoAbs) to IFN-beta are rarely found in humans, antibodies (Abs) to IFN-beta are frequently seen in patients receiving prolonged therapies with recombinant human IFN-beta. As autoAbs, they neutralize wild-type IFN-beta, they cross-react with both currently used IFNbeta biopharmaceuticals, but not IFN-alpha, and they interfere with biological and immunometric assays for IFN-beta in vitro and in vivo. Although anti- IFN-beta Abs usually neutralize IFN-beta in vivo, making further therapies useless, there is experimental support for the idea that some anti-IFN-beta Abs, at least early during ‘immunization‘, may function as enhancers and paradoxically prolong and amplify the activities of IFN-beta in vivo. There are significant difficulties in obtaining reliable methods for monitoring patients on prolonged IFN-beta therapies. These include IFN-beta analyses in blood required for optimal and individualized therapies, and Ab detection induced during therapy. In an effort to assess the clinical relevance of in vitro Ab measurements, many investigators distinguish between ‘binding’ Abs (BAbs) and in vitro ‘neutralizing’ Abs (NAbs) even though such a distinction may not be justified in real terms. For example, the so-called non-neutralizing BAbs may affect drug bioavailability and drug clearance, while NAbs may not necessarily neutralize circulating IFN-beta in vivo. Moreover, anti-IFN-beta Abs may cause serious complications and theoretically initiate autoimmune reactions whether or not they neutralize in vivo. Regular screening for NAbs and discontinuation of therapy in multiple sclerosis patients with sustained high-level NAbs are now generally recommended.