Friday, 23 December 2016

What is a neutralizing response?

Bachelet D, Hässler S, Mbogning C, Link J, Ryner M, Ramanujam R, Auer M, Hyldgaard Jensen PE, Koch-Henriksen N, Warnke C, Ingenhoven K, Buck D, Grummel V, Lawton A, Donnellan N, Hincelin-Mery A, Sikkema D, Pallardy M, Kieseier B, Hemmer B, Hartung HP, Soelberg Sorensen P, Deisenhammer F, Dönnes P, Davidson J, Fogdell-Hahn A, Broët P; ABIRISK Consortium.. Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort Analysis. PLoS One. 2016;11(11):e0162752. doi: 10.1371/journal.pone.0162752.

Immunogenicity of biopharmaceutical products in multiple sclerosis is a frequent side effect which has a multifactorial aetiology. Here we study associations between   A subset of 5638 interferon-beta (IFNβ)-treated and 3440 natalizumab-treated patients having data on at least the first two years of treatment were eligible for interval-censored time-to-event analysis. 

IFNβ-1a subcutaneous and IFNβ-1b subcutaneous treated patients were at higher risk of ADA occurrence compared to IFNβ-1a intramuscular-treated patients (pooled HR = 6.4, 95% CI 4.9-8.4 and pooled HR = 8.7, 95% CI 6.6-11.4 respectively). 


IFN 1 beta is made in bacteria rather than mammalian cells for 1a and we know that subcutaneous 1a was also causing neutralizing antibodies and this was reduced by the new formulation that had fewer aggregates. Likewise it is well know that intra muscular causes less neutralizing antibody events but this advantage may be offset by being less active than the others. Importnatly as I have said many many times the subcutaneous route is a sensitizing route and in this case the subcutaneous agents caused 6-8 times more cases of neutralising responses.

There currently are trials using myelin peptides subcutaneously.

Patients older than 50 years at start of IFNβ therapy developed ADA more frequently than adult patients younger than 30 (pooled HR = 1.8, 95% CI 1.4-2.3). 

Men developed ADA more frequently than women (pooled HR = 1.3, 95% CI 1.1-1.6). 

Interestingly we observed that in Sweden and Germany, patients who started IFNβ in April were at higher risk of developing ADA (HR = 1.6, 95% CI 1.1-2.4 and HR = 2.4, 95% CI 1.5-3.9 respectively). 

Is this the month of treatment effect and it is all to do with vitamin D or does this show if you do enough comparisons one or two will show a difference.

This result is not confirmed in the other cohorts and warrants further investigations..... Does it Really?:-)

Concerning natalizumab, patients older than 45 years had a higher ADA rate (pooled HR = 1.4, 95% CI 1.0-1.8) and women developed ADA more frequently than men (pooled HR = 1.4, 95% CI 1.0-2.0). 

So says the same as the beta interferon results so more reason to start therapy in your youth.

We confirmed previously reported differences in immunogenicity of the different types of IFNβ. 

Yeah

Differences in ADA occurrence by sex and age are reported here for the first time. These findings should be further investigated taking into account other exposures and biomarkers.

So neutralizing antibodies are a problem for drugs and if they occur the drugs can stop working.

The occurrence of neutralising antibodies varies from agent to agent for the interferons it may be about 30% for natalizumab its about  6%....what happens with alemtuzumab where it occurs in 80% of people?.....Yes about 80% of people

1 comment:

  1. Something that concerned me about NABs to beta interferon - if these develop, and an individual consequently also produces NABs to their own, naturally produced beta interferon - what long term consequences may result from that? Is the individual's natural anti-inflammatory response then permanently impaired? Might their MS be worse as a result, showing more relapse activity?

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