Saturday, 13 October 2012

Research: Antibodies against Tysabri

Lundkvist M, Engdahl E, Holmén C, Movérare R, Olsson T, Hillert J, Fogdell-Hahn A. Characterization of anti-natalizumab antibodies in multiple sclerosis patients. Mult Scler. 2012 Oct 8. [Epub ahead of print]

A small proportion of multiple sclerosis (MS) patients treated with natalizumab develop anti-drug antibodies.

OBJECTIVE: The objective of this paper is to characterize the anti-natalizumab antibody response and to investigate differences between persistently and transiently antibody-positive patients.

METHODS:Screening for anti-natalizumab antibodies was performed using a standardized bridging ELISA. Antibody-positive samples were further analyzed for IgM and IgG1-4 antibodies using ELISA and ImmunoCAP®.

RESULTS: Anti-natalizumab antibodies developed in 57 of 1379 (4.1%) treated patients after about a treatment duration of three months. Of the positive patients, 20 (35%) patients reverted to negative, 19 (33%) patients were confirmed persistently positive and 18 (32%) patients were unconfirmed positive. Significantly higher anti-natalizumab antibody levels were detected in persistently compared to transiently positive patients. A cutoff value predicting persistence of antibodies could be determined with a sensitivity of 0.84 and a specificity of 0.80. IgM and IgG4 antibody levels were significantly higher in persistently compared to transiently positive patients, and IgG1, IgG2 and IgG4 increased significantly over time.

CONCLUSIONS: The level of total anti-natalizumab antibodies in a first positive sample can be used to predict patients at risk for persisting antibody positivity. However, neither IgM nor IgG1-4 antibodies could be used to discriminate between transiently and persistently positive patients.

This study shows that about 4% of people develop antibodies that react with tysabri within about 3 months of which about a third become subsequently negative. If there antibodies neutralise the effect of tysabri it will not work and could cause allergic reactions when tysabri is administered. there was no influence of antibody isotype i.e. IgM or IgG1-4  All drugs made out of protein cause antibodies to be generated and therefore have the risk that their function would be neutralised. It is important to know if this happens such that you can change drug. The worry with antibodies is if the antibody response is common to other therapeutic antibodies.

5 comments:

  1. Ref 'The worry with antibodies is if the antibody response is common to other therapeutic antibodies'

    Not sure I understand this. What exactly is the worry?

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  2. Yep you are probably right in hind sight maybe a daft comment from me, but if you get immune responses to bits outside the antigen binding region that natizuimab neutralizing antibody would neutralise others like alemtuzumab, rituiximab dacluzimab etc etc.

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  3. It was a question, not a statement! I was asking from the point of view of somebody who had to stop natalizumab because of antibodies and is now on rituximab.
    The treating neurologists were worried the same problem could happen again with rituximab, but nothing else was available so they finally agreed (after a long period on no treatment)

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  4. If you have antibodies to nataluzimab it should be feasible to test if there are antibodies to rituximab. If I had the two I could do it but I guess there should be some way of testing, maybe Prof G knows if there are tests to see babs (binding antibodies) and nab (neutralizing) for rituximab.

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  5. I have been on Tysabri now for 16 treatments, and even though the drug is a miracle drug I am still afraid of it killing me. We all have to die, but the idea of being in a catatonic state after 6 months before you die is what I am afraid of. I tried all the other ABC drugs, and had allergic reactions to them so I had to go onto Tysabri, and even though I was off for three years my new doctor put me right back on it again this year. When it first came out it was supposed to reprogram your immune system and after 12 months a person could stop thinking the cells were retrained. Biogen tests me monthly for the JC virus since I had a scare back in 2009, but I cannot wait until I can go onto another medication. The stress of thinking I will die or be in a cationic state after6 month’s kills me mentally.

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