Human Leukocyte Antigen Genes and Interferon Beta Preparations Influence Risk of Developing Neutralizing Anti-Drug Antibodies in Multiple Sclerosis

Abstract

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 titers 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 titers. 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 titers 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 titers. In IFNβ-1b treated patients, HLA-DRB1*04 increased the risk of developing high NAb titers, 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.

Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort Analysis

“…Since 2012, samples were analyzed with the commercially available iLite anti-Human IFNβ-1a bioassay (Biomonitor/Eurodiagnostica). In a recent publication a strong correlation of NAb titers was found on a series of 118 serum samples titrated with the MPA and the MGA assay in the Swedish central laboratory [12]. There were also significant correlations between NAb titer levels measured with MGA and iLite [18].…”

Antidrug Antibodies: B Cell Immunity Against Therapy

“…Both genetic factors and environmental factors associated with risk of nADA have been identified. There are three studies showing an HLA association with ADA against IFN‐ β , but not all alleles identified could be confirmed in the different cohorts. Factors such as differences in study design, definition of nADA positivity and different allele frequencies in the studied populations could explain the discrepancies between these studies.…”

The Swedish MS registry – clinical support tool and scientific resource

“…Another example when the cross-analysis of different data sets available on patients in the SMSreg has allowed new discoveries is the identification of different HLA genotypes that increase the risk of antibodies to different interferon beta species (22) and that this risk is also influenced by smoking (23).…”