Interferon β neutralizing antibodies in multiple sclerosis: neutralizing activity and cross-reactivity with three different preparations

Abstract

The presence and titer of neutralizing antibodies (NABs) was evaluated by an antiviral biological assay in 387 samples of 111 multiple sclerosis (MS) patients treated with one of the three commercial preparations of interferon beta (IFNβ). Fifty NAB positive samples were found in 19 patients: 11 treated with IFNβ-1b (Betaferon®) and eight with IFNβ-1a (five with Avonex® and three with Rebif®). All the 38 NABs+ samples of patients treated with IFNβ-1b cross-reacted with IFNβ-1a of both commercial types. The median level of neutralizing units (NUs) of the sera was higher when tested against IFNβ-1a than against IFNβ-1b (p=0.000 vs. Avonexr® and p=0.003 vs. Rebif®).

In line with these data, the NABs+ sera of patients treated with IFNβ-1a cross-reacted with IFNβ-1b and the level of NUs were lower when tested against IFNβ-1b than against IFNβ-1a (p=0.003). The different amount of NUs against IFNβ types 1a and 1b could be due to the presence of aggregates in the IFNβ-1b preparation. The different levels of cross-reactivity of NABs could reduce the bioavailability and therapeutic efficacy of IFNβ in NABs+ patients switching from IFNβ-1b to IFNβ-1a.

Introduction

Two types of recombinant human interferon beta (IFNβ), IFNβ-1a and IFNβ-1b, are used in the treatment of remitting-relapsing multiple sclerosis (RR-MS). In Europe, three different commercial preparations of IFNβ are available: one type is constituted by IFNβ-1b (Betaferon®) and two types by IFNβ-1a (Rebif® and Avonex®), which differ for excipients, route of administration and dosage.

IFNβ-1b and IFNβ-1a have the same receptor binding region, but IFNβ-1b is a non-glycosylated molecule that has a Met-1 deletion and a Cys-17 to Ser mutation (Mark et al., 1984), while IFNβ-1a is a glycosylated polypeptide with the predicted natural amino acid sequence (Holliday and Benfield, 1997).

Treatment with IFNβ has been associated with the appearance of antibodies, called binding antibodies, that can bind IFNβ itself. Factors influencing the development of anti-IFNβ antibodies and their clinical role are not defined, but the subset of antibodies called neutralizing antibodies (NABs) could have an important clinic significance, because they neutralize the biological functions of IFN (Arnason and Dianzani, 1998).

Recently, Khan and Dhib-Jalbut (1998) found that binding antibodies to Betaferon® cross-react with Avonex® and vice versa; in that study, not all patients positive for NABs to IFNβ-1b could be tested for cross-reactivity to IFNβ-1a, and it was not evaluated if NABs neutralized different quantities of the three commercial preparations of IFNβ.

In the present study, we tested the cross-reactivity and the titer of NABs against three different preparations of IFNβ, because cross-reactivity and differences in NABs titer could influence the medical decision of switching from one preparation of IFNβ to another.