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

Abstract

Patients with multiple sclerosis (MS) treated with interferon β (IFNβ) preparations develop varying levels of antibodies that neutralize the biological effects of IFNβ, 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 IFNβ 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 IFNβ products: Avonex(®) (intramuscular IFNβ-1a), Rebif(®) (subcutaneous (SC) IFNβ-1a) at 22 and 44 μg, and Betaseron(®) (SC IFNβ-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 IFNβ-1a) 44 μg and least (7.5%) with Avonex (intramuscular IFNβ-1a), whereas Betaseron (IFNβ-1b) and Rebif 22 μg 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 IFNβ-1a 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 IFNβ product-dose combinations became more evident in patients with MS when both NAb frequency and the full range of NAb titer magnitude were measured.

Therapeutic outcomes, assessments, risk factors and mitigation efforts of immunogenicity of therapeutic protein products

“…Development of immunogenicity against these TPP is likely due to a patient specific breakage of peripheral tolerance, central tolerance or due to antigenic differences between endogenous and replacement factor TPPs. For example, peripheral tolerance may be broken when treating MS patients with high doses of interferon beta over a long period of time [74,75]. Novel structural formats and molecular designs, and primary sequences that contain B cell and T cell epitopes, could be recognized as non-human and induce immune responses [76][77][78][79][80].…”

Evaluation of the impact of neutralizing antibodies on IFNβ response

“…All the studies have demonstrated that IFNβ-1a i.m. is the least immunogenic IFNβ, with 2-7.5% patients who will become Nab-positive [19][20][21]. IFNβ-1b and IFNβ-1a s.c. cause positivity of 15-35% patients [19][20][21][22][23]).…”

“…is the least immunogenic IFNβ, with 2-7.5% patients who will become Nab-positive [19][20][21]. IFNβ-1b and IFNβ-1a s.c. cause positivity of 15-35% patients [19][20][21][22][23]). The importance of the formulation in influencing the risk of NAbs development is suggested by the reduction of Nabs-positive patients reported with IFNβ-1a s.c. new formulation versus the traditional formulation (14.8% and 24%, respectively) [24,25].…”

The case for measuring anti-drug antibodies in people with multiple sclerosis

“…Firstly, immunogenicity clearly differs between products [4]. IFN-b-1b (Betaferon Ò ), which is a bacterially produced non-glycosylated product with minor differences from the natural IFN-b, induces nADA in 38-47% [4], but not at very high titers [5]. This could be described as generating high seroprevalence but modest immunogenicity.…”

“…This could be described as generating high seroprevalence but modest immunogenicity. IFN-b-1a (Avonex Ò , Rebif Ò ) is a mammalianproduced product with glycosylation and the same amino acid sequence as the natural IFN-b, which induces nADA in fewer patients but provokes higher titers, that is, lower seroprevalence but higher immunogenicity [5]. Second, there is also a clear difference depending on how the drug is administered.…”