Anti-interferon antibodies in multiple sclerosis. Molecular basis and their impact on clinical efficacy

Abstract

Low levels of naturally-occurring, high-affinity antibodies directed against cytokines can be found in the circulation of individuals who have never been exposed to exogenously-supplied cytokines. These antibodies are thought to play a regulatory role in the intensity and duration of immune response. Interferon (IFN) beta has been shown to attenuate both relapsing-remitting multiple sclerosis (MS) and secondary progressive MS in several well-powered, randomized, controlled clinical trials. IFN therapy can induce the production of anti-IFN neutralizing antibodies (NAb), usually in the second 6 months of treatment, in 3 to 45% of treated patients. This variation in the proportion of NAb-positive patients is probably due to the immunogenicity of different formulations of IFN beta, as well as the assay used, which are not currently standardized. The occurrence of NAb appears to be directly correlated with the dose of therapeutic IFN administered, up to a certain dose threshold. If the dose is increased beyond this threshold, the levels of NAb decrease. The biological significance of anti-IFN NAb is not yet known, nor has it been proven conclusively that they affect the clinical response to IFN beta therapy. The presence of NAb is therefore not an indication that treatment should be changed. Indeed, any treatment decision should be based only on the clinical response to therapy.

Assessment of the immunogenicity of different interferon beta-1a formulations using ex vivo T-cell assays

“…Recombinant homologues of human proteins have the potential to induce an immunogenic response when used therapeutically [1][2][3]. The structure of the protein, particularly any lack of glycosylation, can provoke the production of binding antibodies (BAbs) and neutralising antibodies (NAbs), as can aggregates or foreign epitopes that are present in the injection solution [1,4].…”

“…In common with other recombinant proteins administered therapeutically, a minority of patients develop BAbs or NAbs while using recombinant interferon (IFN) beta for the longterm treatment of multiple sclerosis (MS) [3]. However, there is * Corresponding author.…”

Roles of Sema4A in multiple sclerosis and interferon‐β therapy efficacy

“…Myxovirus resistance protein A (MxA) is a reliable biomarker of IFN‐β bioactivity . Neutralizing antibodies (NAb) to IFN‐β are associated with a reduced clinical efficacy of therapy . Developed NAb might inhibit IFN‐β bioactivity, which is detected by the reduced expression of MxA.…”

“…[52][53][54] Neutralizing antibodies (NAb) to IFN-b are associated with a reduced clinical efficacy of therapy. 55,56 Developed NAb might inhibit IFN-b bioactivity, which is detected by the reduced expression of MxA. NAb, however, can account for only a part of non-responders.…”

In VitroAssessment of the Biologic Activity of Interferon Beta Formulations used for the Treatment of Relapsing Multiple Sclerosis

“…[14–17] Although the full clinical impact of these anti-IFN antibodies is not completely known, the presence of high titers of NAbs to IFNβ can reduce the therapeutic effects of treatment. [18–20] A new sc formulation of IFNβ-1a (Rebif New Formulation [NF]; Merck, Bari, Italy) that is produced without fetal bovine serum and without human serum albumin as an excipient, with the goals of improving injection tolerability and reducing immunogenicity, was developed.…”