Tuesday, 3 July 2018

Antibodies to PEG interferon may affect its action

Int Immunopharmacol. 2018 Jun 27;62:1-6. doi: 10.1016/j.intimp.2018.06.030. [Epub ahead of print]

Interaction of PEGylated interferon-beta with antibodies to recombinant interferon-beta.

Gilli F, De La Torre AL, Royce DB, Pachner AR.


Because PEGylated molecules exhibit different physicochemical properties from those of the parent molecules, PEGylated interferonβ-1a (pegIFNβ-1a) may be able to be used with retained bioactivity in Multiple Sclerosis (MS) patients who have previously developed neutralizing antibodies (NABs) to recombinant interferonβ (rIFNβ). Hence, the objective of the present study was to test whether pegIFNβ-1a is less antigenic for NABs in vitro than rIFNβ. Two in vitro assays were used to quantitate NABs in 115 sera obtained from MS patients included in the INSIGHT study: the cytopathic effect (CPE) assay, and the MxA protein induction assay. NABs cross-reactivity was assessed by comparing dilutions of serum with fixed doses of rIFNβ-1a Avonex® and pegIFNβ-1a Plegridy®. NABs were shown to cross-react in both assays. The y-intercept (c), the slope of the line of agreement (b), the Pearson coefficients as well as the Bland-Altman analysis, indicated that there is good level of agreement between NAB titers against the two IFNβ-1a formulations, with both the CPE (c = 0.1044 ± 0.1305; b = 0.8438 ± 0.06654; r2 = 0.587; bias index ± SD = -0.01702 ± 0.6334), and the MxA protein induction (c = 0.08246 ± 0.1229; b = 0.8878 ± 0.06613; r2 = 0.615; bias index ± SD = -0.09965 ± 0.6467) assays. Until further in vivo evidence is established, clinicians should consider the current in vitro data demonstrating NAB cross-reactivity between pegIFNβ-1a and rIFNβ when discussing new treatment options with MS patients.

A historian will tell you that history does nothing but repeat itself: the next week, the next month, and even the next year. Probably not difficult write about, and ever predictable in its punch line: the same arguments, the same explanations, and even the same solutions. It would appear we're all sat in an endless time loop, only limited by as far as we can see; our life. Science also, it would seem is not immune to this doldrum, only the method of portrayal of the analysis bearing any interest.

This publication is a case in example. We know that a therapeutic agent has a potential to have its action negated by neutralizing effects (in this case neutralizing antibodies Nabs or anti-drug antibodies) produced by our own body. Anything foreign introduced into the body can generate this response. In fact, in MS therapeutics the earliest demonstration of this was the production of Nabs against interferon beta (IFN) formulations (particularly IFNβ-1b Betaseron/Extavia and rIFNβ-1a Rebif, and to a lesser extent rIFNβ-1a Avonex). These antibodies can either reduce or completely negate the therapeutic action of the drug by interfering with binding of the drug to the target receptor.

Pegylated IFNβ-1a or Plegridy, is a modified version of IFNβ-1a via the addition of pegylation to one end of the protein. The peglyation has been demonstrated to increase it solubility and half-life, allowing for its fortnightly use, unlike the earlier interferon formulations that are injected more frequently. But does the pegylation protect the compound from the production of Nabs? The immunogenicity of pegIFNβ-1a has been demonstrated to be <1%, and thus should only have minimal reduction in its activity.

But, things are never that simple, and surprise, surprise it would appear that the effect of generation of Nabs is the same between older beta interferons and the newer pegylated version. Moreover, switching from the older formulations to the newer one may still result in therapeutic failure, owing to the cross-reactivity of these antibodies.

Gilli and colleagues in this publication looked at 115 blood samples and identified antibodies to either rIFNβ-1a (n = 67) or rIFNβ-1b (n = 48). They then determined Nabs cross-reactivity by comparing fixed dilutions of patients blood samples (which contains the antibodies) against fixed doses of rIFNβ-1a Avonex and pegIFNβ-1a Plegridy. They found that there was no difference between the immunogenicity of the two interferon beta formulations. In fact, the Nabs to  rIFNβ and pegIFNβ-1a have a high-degree of cross-reactivity (anti-rIFNβ-1a NAB titers were shown to cross-react with pegIFNβ-1a using two different assays). Even at low nab levels, wherein there is faster recovery of the bioactivity of the drug, this effect was maintained through to pegIFNβ-1a (so the washout period is likely to be large).

The cross-reactivity could be predicted by the similarities between rIFNβ and pegIFNβ-1a at a molecular level in terms of the protein amino acid (building blocks of the protein) sequence and their structure.

However, this is all in-vitro work, it would be useful to know what goes on at an in-vivo level and see whether there is a reduction in the effectiveness of pegIFNβ-1a after switching from rIFNβ, in terms of relapses and/or MRI activity.


  1. I ran into this issue and was subsequently switched over to Copaxone. My neuro told me that neutralizing antibodies to Copaxone do not affect its clinical efficacy. Is this correct?

    1. Copaxone generates what’s called acetate-reactive antibodies. They are felt not to be neutralizing in their activity and therefore don’t affect the Copaxone activity. So, in the past when a person developed neutralizing antibodies to an interferon, the strategy was to swap to Copaxone.

    2. Wondering about Alemtuzumab and how much of a problem, if any, these antibodies are in relation to the efficacy of this most potent drug?

    3. Neutralising antibodies to Alemtuzumb (quite a common phenomenon after the second infusion) will reduce its effectiveness significantly.

    4. Thank you MD2. Makes me wonder why Cladribine is not more widely used instead of Alemtuzumab. Have there been any problems with antibodies and Ocrelizumab?

    5. You're welcome,from what I've seen, so far, there is a low incidence of antibodies to ocrelizumab.

  2. Where is this month's unrelated comments?


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