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Neutralising antibodies to the beta interferons
  1. A J Coles
  1. Department of Neurology, Box 165, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK
  1. Correspondence to:
 Dr A Coles;

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Determining and preventing neutralising antibodies

The amazing ability of the immune system to make fine distinctions between self and non-self is critical to its function—but a problem for treatments that mimic natural proteins, such as recombinant human factor VIII, whose use is significantly compromised by neutralising antibodies. So too is interferon beta treatment of multiple sclerosis. Antibodies against the beta interferons have usually1,2 but not always,3 been associated with increased clinical and magnetic resonance imaging markers of disease activity. Therefore, the clinician needs to know how common such antibodies are, how reliably they are detected, what to do if they are discovered, and how to prevent them. Answers to some of these questions come from an Italian study in this issue (pp 148–53)4 of 125 patients on the three available interferon beta products.

Unsurprisingly, Bertoletto et al found that Avonex, an interferon beta 1a, generated fewer antibody responses than interferon beta 1b (Betaferon), which is more “foreign” to the immune system. Interferon beta 1a is produced by mammalian cells and is identical to the natural cytokine in sequence and glycosylation, whereas interferon beta 1b has two sequence differences (des-Met-1 and Cys17Ser) and, being produced in Escherichia coli, is not glycosylated. Rebif, the other interferon beta 1a, induced fewer antibodies than Betaferon but more than Avonex. Although these differences were not significant in Bertoletto et al’s series, they reflect a ranking that is emerging clearly from the literature, especially from the largest study on 754 patients in Denmark.5 Rebif probably provokes more antibodies than Avonex, despite being chemically identical, because the immune system finds Rebif’s delivery route and dosing (22–44 mg in three weekly subcutaneous doses) more “unnatural” than that of Avonex (30 mg in one weekly intramuscular dose).

The prevalence of antibodies against interferon beta is confused in the literature, ranging from 28–80% of patients treated with Betaferon. In part this may reflect when patients were tested. Bertoletto et al found that neutralising antibodies may be transient and may appear at any time from 3 to 18 months after starting treatment. But also there are technical issues. Binding assays such as enzyme linked immunosorbent assays (ELISAs) are relatively easy to standardise but do not distinguish antibodies that impair interferon beta function (“neutralising” antibodies) from those that do not. Bioassays can discriminate these but they are difficult to compare across centres. Bertoletto et al used the most popular: patient’s serum was tested for its ability to prevent interferon beta inhibiting encephalomyocarditis virus from killing a human lung carcinoma cell line. They reported the prevalence of persistent neutralising antibodies, after 18 months of treatment, as 32% in patients who received Betaferon, 19% for Rebif, and 4% for Avonex. The thresholds for positivity in such studies are arbitrary and have not been validated against clinical data.

Once a patient has persistent neutralising antibodies, switching to another interferon beta is illogical, as the antibodies cross react. Nor would a “drug holiday” help, as the immune system has a long memory. Strategies to prevent neutralising antibodies may include using a tolerising drug to initiate treatment, concomitant immunosuppression, mucosal routes of administration, and either much higher or lower doses.

Determining and preventing neutralising antibodies


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  • Conflict of interest: AC has received a fee for speaking at a conference organised by Serono.

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