Thursday, 6 March 2014

Clinic speak: neutralizing antibodies to interferon beta

Are  you on interferon beta? Have you been tested for NABs? #MSBlog #MSResearch #ClinicSpeak

Question: I am 26 years old and have had MS for 3 years. I have been on Betaseron for most of that time. I had only one relapse since starting Betaseron that was 10 months ago when my right hand became numb and clumsy for about 2 weeks. After this I asked my neurologist if I could have myself tested for NABs. He said it wasn’t necessary as they made little difference to the clinical outcome and my insurance company wouldn’t cover the cost of the test.

Answer: I assume that based on the trade name used that you are a US resident. This is typical scenario in the US.

What are neutralizing antibodies or NABs?

NAbs are when your own body rejects a biological or protein-based therapy such as interferon-beta. Your body treats the treatment like a vaccine and makes antibodies to them. This occurs with most protein therapies to a greater or lesser extent.

Why are they important?

Firstly, they bind to the protein drug and prevent it from binding to its target working. Not only do NABs block the action of the drug they also result in the drug being rapidly cleared from the body; NABs are nature’s way of vacuuming-up unwanted ‘foreign’ proteins. When the drug is administered into the blood stream as an infusion NABs often cause infusion reactions; this is a problem with NABs to natalizumab (Tysabri).

NABs to beta-interferon

All of the commercial interferon preparations induce NABs, however, they do so at different rates (Betaferon/Betaseron/Extavia = 25-35%, Rebif = 12-25%, Avonex = 2-5%). There are several biosimiliar drugs available in emerging markets; unfortunately we don’t know what the NAB rates are for these preparations.

NABs to beta-interferon tend to develop slowly and may detectable after only 6 months with the majority (>90%) of those who will eventually develop NABs having them detectable by 24 months of treatment. I therefore recommend that NABs are screened for at 12 months and if negative again at 24 months.

So few MSers develop NABs after 24 months that it is only worthwhile screening for them if you have not been tested before, or if a positive NAB result is going to influence your decision to stop or restart beta-interferon.

NABs prevent beta-interferon binding to cells thereby preventing it from having a therapeutic effect. MSers with high levels of NABs might as well be on a placebo; they have greater MRI activity and relapse rates when compared to MSers on beta-interferon who do not develop NABs. If followed long enough MSers with NABs also have a faster rate of disability progression. 

The Interferon wars

Are you old enough to remember the cola wars? In the 1980s Coca Cola and PepsiCo were engaged in marketing warfare in attempt to convince us that their brand of flavoured water was better than their competitors. In similar style the Pharma companies selling beta-interferon engaged in marketing warfare in attempt to convince us that their brand of beta-interferon was more efficacious or better tolerated, than their competitors. NABs was one of the main battle grounds in the interferon wars as it was a key differentiator between intramuscular beta-interferon (Avonex) and the subcutaneous formulations (Betaseron/Betaferon/Rebif). NABs develop in less than 5% of MSers on Avonex compared to ~12-25% on Rebif and ~25-35% on Betaseron/Betaferon. A lot of time and effort went into trying to convince the MS community that NABs are irrelevant. Some of the messages stuck, which is why the adoption of NAB testing is not universal despite clear professional guidelines on the issue.

The interpretation of the data on NABs to beta-interferon is complex and requires a deep understanding of the biology of NABs and beta-interferon’s mechanism of action. Beta-interferon has an impact on MS disease activity, as measured on MRI, within weeks. However, when stopping beta-interferon it takes over 6 months for MS disease activity re-emerge. Therefore if it takes 12 months for NABs to appear, which then stop beta-interferon working, the effects of NABs will be delayed and only seen after 18 months. Therefore in short studies, e.g. 12 months, NABs don’t have an impact, but clearly have an impact in longer studies.

Another bit of information that has confused some neurologists is that NABs to Betaseron/Betaferon/Extavia may disappear with time; i.e. after many years. This is not seen with NABs to Avonex or Rebif. I personally think the reason for this relates to how the immune system can be taught to become tolerant again to beta-interferon. Betaseron/Betaferon is less potent than Avonex and Rebif and therefore you have to give a larger dose, i.e. 250 micrograms every other day (Betaseron/Betaferon/Extavia) compared to 30 micrograms once a week (Avonex) or 44 micrograms 3x per week (Rebif). This larger dose eventually teaches the immune system to stop making NABs; immunologists call this high-zone tolerance. The problem with high-zone tolerance is that it takes years to work and while you wait for the NABs to disappear the beta-interferon you are on is not working. Another issue that the marketing campaigns focused on was the variability of the assays; I agree that this was a problem that has now been sorted out with new generation assays.

Despite these issues that all seem relatively simple to me, a lot of MSologists still believe that NABs are irrelevant. This is a problem as NABs are one of the reasons why MSers are non-responders to beta-interferon. Actively monitoring for NABs and switching MSers who are NAB positive will increase the effectiveness of beta-interferon.

Economics of NABs

At a population level continuing a therapy when you don’t respond to it is an enormous waste of money. We estimated that NABs to beta-interferon was costing the EU over 480 million Euros a year. The cost of a NAB test is relatively cheap when you factor in the annual cost of the treatment.

Why do MSers develop NABs?

Beta-interferon is a natural protein that is produced by cells of the immune system to fight infections and cancers. NABs are not found in normal people. Therefore why do they develop? The main reason is we are giving the protein in an unnatural way and the immune system treats this protein as foreign. MSers with a specific genetic background are more likely to develop NABs.


  1. Dear Professor
    I am currently on Avonex and had tested positive for NABs prior to starting this drug (had previously been on Rebif and then Copaxone). I was told that it was only a “marginal positive” and that I would be tested again in 1 year. Do you think it is safe to wait this long and is it likely the low level of NABs will increase?

  2. Which reference supports the cost to the EU being 480 million?

  3. I have accessed three versions of the Prescribing Information sheets for Rebif, all current and all of which quote percentages regarding the development of antibodies and note that the impact of NAbs on efficacy is unconfirmed. (More worrisome – one of them dated February 2013 notes that “the safety and efficacy of Rebif beyond two years have not been established” – is this a misprint or ???)

    I can only ask why no suggested schedule or recommendations are put forward in these documents regarding testing for NAbs. I asked my MS nurse about whether I should be tested (been on Rebif for a bit over a year) but there was no information available to help her answer my question – only percentages on detection of NAbs.

    And I couldn’t agree more about large amounts of money being spent over extended periods of time on medications which may be doing nothing much positive due to development of NAbs. Even more important, if you go with the Prof G team perspective of treating with medications that do provide benefits, what a lot of time wasted for someone if it’s going to take a year or more to find out that what they are taking is probably no longer working.

    Anyway, I haven’t been tested, and have no idea whether I have NAbs to Rebif or not, but currently it is a non-issue for me – I’m taking a “break” from Rebif as the multiple side effects I’ve been struggling with have become too much to put up with any longer.

    One last thing – do NAbs to one interferon also impact on the efficacy of the other interferons?


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