Frequency and Magnitude of Interferon β Neutralizing Antibodies in the Evaluation of Interferon β Immunogenicity in Patients with Multiple Sclerosis

Patients with multiple sclerosis (MS) treated with interferon beta (IFN beta) preparations develop varying levels of antibodies that neutralize the biological effects of IFN beta, reduce its in vivo bioavailability, and diminish its therapeutic efficacy. The aim was to determine as distinct measures of immunogenicity the occurrence (frequency) and the magnitude (level) of IFN beta neutralizing antibody (NAb) formation in a large Canadian population as a cross-sectional study of patients with MS treated in a clinical practice setting with different, equally available IFN beta products: Avonex (R) (intramuscular IFN beta-1 alpha), Rebif (R) (subcutaneous (SC) IFN beta-1 alpha) at 22 and 44 mu g, and Betaseron (R) (SC IFN beta-1b). Over a 3-year period 3,124 serum samples from 2,711 patients with MS were submitted by neurologists in MS clinics distributed across Canada and tested for NAbs in a single independent laboratory, utilizing a quantitative, standardized NAb bioassay. NAb frequency was greatest (35%) with Rebif (SC IFN beta-1 alpha) 44 mg and least (7.5%) with Avonex (intramuscular IFN beta-1 alpha), whereas Betaseron (IFN beta-1b) and Rebif 22 mu g were in between (22%). NAb serum levels at magnitudes considered high, >= 100 tenfold reduction units (TRU)/mL, were found in 65%-83% of patients with detectable NAbs. Nearly half (42%-47%) of NAb-positive patients given IFN beta-1 alpha preparations had very high titers (>= 1,000 TRU/mL), whereas only 22% of NAb-positive patients on Betaseron had titers >1,000 TRU/mL. Differences in patterns of NAb formation among the four IFN beta product-dose combinations became more evident in patients with MS when both NAb frequency and the full range of NAb titer magnitude were measured.