Beta interferon neutralizing antibodies determined by your genes

Link J, Lundkvist Ryner M, Fink K, Hermanrud C, Lima I, Brynedal B, Kockum I, Hillert J, Fogdell-Hahn A. Human leucocyte antigen genes and interferon Beta preparations influence risk of developing neutralizing anti-drug antibodies in multiple sclerosis. PLoS One. 2014 Mar 7;9(3):e90479. doi: 10.1371/journal.pone.0090479. eCollection 2014.

A significant proportion of patients with multiple sclerosis who receive interferon beta (IFNβ) therapy develop neutralizing antibodies (NAbs) that reduce drug efficacy. To investigate if HLA class I and II alleles are associated with development of NAbs against IFNβ we analyzed whether NAb status and development of NAb titres high enough to be biologically relevant (>150 tenfold reduction units/ml) correlated with the HLA allele group carriage in a cohort of 903 Swedish patients with multiple sclerosis treated with either intramuscular IFNβ-1a, subcutaneous IFNβ-1a or subcutaneous IFNβ-1b. 

Carriage of HLA-DRB1*15 was associated with increased risk of developing NAbs and high NAb titres. After stratification based on type of IFNβ preparation, HLA-DRB1*15 carriage was observed to increase the risk of developing NAbs as well as high NAb titres against both subcutaneous and intramuscular IFNβ-1a. Furthermore, in patients receiving subcutaneous IFNβ-1a carriage of HLA-DQA1*05 decreased the risk for high NAb titres. In IFNβ-1b treated patients, HLA-DRB1*04 increased the risk of developing high NAb titres, and in a subgroup analysis of DRB1*04 alleles the risk for NAbs was increased in DRB1*04:01 carriers. In conclusion, there is a preparation-specific genetically determined risk to develop NAbs against IFNβ high enough to be clinically relevant in treatment decisions for patients with multiple sclerosis if confirmed in future studies. However, choice of IFNβ preparation still remains the single most significant determinant for the risk of developing NAbs.

If you develop neutralizing antibodies to the beta interferons stop working. The risk for high NAb titres overall was 1.6-fold in people carrying the MS risk haplotype DRB1*15, and for people receiving IFNβ-1a the risk was increased up to 8-fold.

This shows that for the two different types of recombinant IFNβ molecules, DRB1*15 for IFNβ-1a and DRB1*04 for IFNβ-1b, indicating an IFNβ molecule dependent genetically determined risk to develop NAbs against IFNβ. There are several possible explanations that could account for differences in immunogenic potential. Sequence alterations, different formulation contents with a potential to evoke the immunological response, and different propensities to form aggregates  are all factors that might have a higher impact on NAb development. The different HLA associations found here might be explained by different binding affinities to the two types of IFNβ molecules to different HLA alleles.  However this study suggests that dependent on your genes expressed it may determine how good your drugs work. This is called “pharmacogenomics”.

Although HLA alleles influence the risk of NAbs within the treatment groups it is clear that NAb development in people with MS treated with IFNβ-1a is also influenced by several additional factors. Thus, IFNβ-1a injected intramuscularly is still the least immunogenic way of receiving IFNβ even for HLADRB1*15 carriers and none of the analyzed HLA allele groups lowered the risk of subcutaneously injected IFNβ to the level of intramuscularly injected IFNβ-1a. The skin harbours a high frequency of dendritic cells efficient in presenting antigens, easily provoked by repeated injections of IFNβ and potentially explaining higher immunogenicity of the subcutaneously administrated IFNβ products compared to the intramuscularly administered product.
Approximately 20% of IFNβ-treated patients develop NAb titres high enough to block treatment bio-efficacy. Since up to 60% of people with MS carry DRB1*15 and some 30% carry DRB1*04, and since the risk of high titre NAbs is increased several times (ORs 3–4) in carriers of respective risk alleles, it may well be relevant to base treatment decisions on HLA genotype. For example empirical data suggest that DRB1*15 carriers would have a 35% risk of losing efficacy of s.c. IFNβ-1a but less than 10% on IFNβ-1b (provided they did not carry DRB1*04 on their other chromosome). The reverse risks would be seen for a DRB1*15-negative carrier, who carries DRB1*04, on IFNβ-1b.
Maybe more work in needed to firm-up these risks, but it shows how your genes could help you decide in making treatment choices. This is working towards “personalised medicine”.  
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