The Costs of Neutralisation


Paolicelli D, Iannazzo S, Santoni L, Iaffaldano A, Di Lecce V, Manni A, Lavolpe V, Tortorella C, D’Onghia M, Direnzo V, Puma E, Trojano M. The Cost of Relapsing-Remitting Multiple Sclerosis Patients Who Develop Neutralizing Antibodies during Interferon Beta Therapy.  PLoS One. 2016 Jul 8;11(7):e0159214. doi: 10.1371/journal.pone.0159214. eCollection 2016.BACKGROUND:

Relapsing Remitting Multiple Sclerosis (RRMS) patients treated with interferon beta (IFN beta) can develop neutralizing antibodies (NAbs) that reduce treatment efficacy. Several clinical studies explored the association of NAb+ status with increased disease activity.
OBJECTIVE: The aim of this study was to estimate the cost of RRMS patients who develop NAbs while treated with IFN beta by the Italian National Healthcare Service (NHS) and the Italian Society perspectives.
METHODS: The clinical data derived from a published observational study on 567 RRMS Italian patients treated with IFN beta. The management cost data derived from the published literature. Cost data were inflated to Euro 2014.
RESULTS: The annual direct cost to treat a patient was estimated in €15,428 in the NAb+ cohort and €14,317 in the NAb- cohort. The annual societal cost was estimated in €33,890 and €30,790 in NAb+ and NAb- patients, respectively. The cost increase related to the NAb+ status was €3,100 in the Italian societal perspective and €1,111 in the Italian NHS perspective.
CONCLUSION: The results of this economic evaluation suggest the presence of an association between NAb+ status and increased costs for the management of RRMS in Italy. Further pharmacoeconomic research will be needed to confirm this first result

This report indicates that there is an economic cost of neutralisating antibodies, which bind to the active site of in this case beta interferon. There is also a human cost because if you have neutralising antibodies, the drug stops working and so you are getting damage to you nerves.

Proteins have the potential to cause binding antibodies and some of them may be neutralizing.
Chimeric antibodies are part human and part animal. This element can trigger antibodies an example is rituximab (chimeric anti-CD20) that causes neutralizing antibodies in about 10-20% of people. Humanizsed antibodies only have the binding bits of animal antibodies and the rest is human so should induce less antibodies. Ocrelizumab (humaniized ant-CD20) causes less than 1% neutralizing antibodies. Totally human antibodies should induce less. Ofatumumab (human ant-CD20) did not induce these following infusion (Sorenson et al. 2014). 
However, there is a very obvious odd one out. This is alemtuzumab (humanised anti-CD52). This induces marked T and B cell depletion but anti-Alemtuzumab antibodies are induced in a staggering 80+% of people. This aspect was mentioned in (Pivotal Trials Cohen et al. 2012 and Coles et al. 2012) where it was said that it doesn’t affect the depletion or the occurance or severity of the infusions reactions that occur in over 90% (90.1% CARE-1, 96.9% CARE-II) of people, however remember people are getting steroids and anti-histamines which would control an anaphylactoid response caused by antibody reactions to alemtuzumab. 
However the bits skipped in pivotal trial reports,were that it appears that of the 80+% people making anti-alemtzumab, more than 90% have inhibitory (another word for neutralizing) antibodies. They apparently do not influence alemtuzumab action. Wonder if this contributes to those that require repeated infusions

Ziemssen T, Arnold DL, Cohen JA, Coles AJ, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Palmer J, Margolin DH, Richards S, Sung C, Panzara MA, Compston DAS Immunogenicity of alemtuzumab does not impact safety and efficacy in relapsing remitting multiple sclerosis patients in the CARE-MS I study.Multiple Sclerosis Journal 2013; 19: (S1) 212-213.

I was told that these don’t happen, so people have missed this bit of small print. The question is why does this happen? 

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  • Does anyone have a stronger reaction to the infusion, side effects are more likely to develop NABs? Genetics behind it, as those genetic polymorphisms that seem to generate aberrant responses to interferons?

    • The manufacturers say in that the antibodies have essentially no effect which is hard to believe. Infusions are given under the cover of steroids and anti histamines that would control infusion reactions and most people get them anyway.

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