Immunogenicity of interferon‐β in multiple sclerosis patients: Influence of preparation, dosage, dose frequency, and route of administration

Abstract

A total of 754 consecutive patients with relapsing-remitting multiple sclerosis were investigated for interferon-beta (IFNbeta) antibodies by protein-G affinity chromatography and antiviral neutralization bioassay during 24 months on 6 MIU (22 microg) of subcutaneous IFNbeta-1a once weekly (n = 143) or three times weekly (n = 160), 6 MIU (30 microg) of intramuscular IFNbeta-1a once weekly (n = 140), or 8 MIU every other day of IFNbeta-1b (n = 311). The proportion of binding antibodies was higher in those receiving IFNbeta-1b compared with 6 MIU of IFNbeta-1a three times weekly (97 vs 89% at 12 months), and fewer became positive if 6 MIU of IFNbeta-1a was administered once weekly (58 vs 89%). Fewer patients on intramuscular than subcutaneous IFNbeta-1a became positive (33 vs 58%). The binding and neutralizing capacities were higher in the IFNbeta-1b group than in the IFNbeta-1a groups; these differences, however, were not significant after 12 months. The number of positive patients varied considerably and depended on the amount of IFN added to the bioassay; adding 10 LU/ml or more masked antibody detection. Antibodies induced by either preparation neutralized both IFNbeta species but not IFNalpha. In conclusion, IFNbeta-induced antibodies are frequently found in multiple sclerosis patients, and IFNbeta-1b is more immunogenic than IFNbeta-1a. The immunogenicity of IFNbeta-1a increases with the frequency of administration and if it is given subcutaneously.

Immunogenicity of interferon beta: differences among products

“…The neutralizing capacities of sera from patients who had positive results on testing for antibodies were almost identical at 12 and 18 months in patients treated with IFNβ-1b and those treated with 22 µg of IFNβ-1a-Rebif once or three times weekly, whereas sera from patients treated with IFNβ-1a-Avonex showed significantly lower neutralizing capacity. Antibodies against the three products crossreacted with all three products, and the incidence of NAbs against IFNβ-1a-Rebif increased with increased frequency of administration [32].…”

“…Therefore, a review of the comparative trials, which used a single assay method, is necessary to critically evaluate differences in immunogenicity among IFNβs. Several studies have compared the incidence of NAbs among IFNβ products [3,6,15,23,32,37]. However, herein we review only studies that did the following: contained a reasonable number of patients, followed patients for ≥ 12 months, and controlled for the potential interference of residual IFNβ in peripheral blood after injection (blood collection occurred ≥ 36 hours after IFNβ injection).…”

“…Ross et al [32] conducted a study that compared immunogenicity among the three IFNβ products in patients with RRMS. Since the introduction of IFNβ in Denmark, blood samples taken 48 hours after IFNβ injection have been collected at regular intervals as part of a national protocol.…”

NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis (NORMIMS study): a randomised, placebo-controlled trial

“…We measured neutralising antibody concentrations at baseline and weeks 24, 48, 72, and 96 with an antiviral neutralisation bioassay (Biomonitor, Copenhagen, Denmark). 16 We defined a sample as positive for neutralising antibodies if it had a neutralising capacity of at least 20%, because this value was previously shown as the lowest concentration of neutralising antibodies to have clinical importance. 17 We used the "anytime positive, always positive" (ie, based on one positive sample) principle to classify patients as positive for neutralising antibodies.…”

Neutralizing antibodies to interferon beta in patients with multiple sclerosis: scientific background and clinical implications

“…Hence, IFNβ-1b therapy is more immunogenic than IFNβ-1a therapy, and IFNβ-1a-Rebif treatment is more immunogenic than IFNβ-1a-Avonex treatment. Factors that likely contribute to differences in immunogenicity among these formulations include differences in chemical structure, route of administration, dose, and frequency of administration [3, 11,12,19].…”