Immunogenicity of Interferon Beta in Multiple Sclerosis

Interferon beta remains a cornerstone disease-modifying therapy in relapsing forms of multiple sclerosis. However, its utility is compromised by immunogenicity, whereby patients develop anti-drug antibodies that bind to and neutralise the cytokine, undermining its biological activity and clinical efficacy. The frequency of neutralising antibody formation varies with formulation and administration route, reaching almost half of treated individuals for certain subcutaneous preparations. Immunogenicity arises from a complex interplay of factors including host genetics, particularly HLA alleles, the molecular characteristics of interferon beta preparations, and the dynamics of antigen presentation and cytokine signalling. Clinically, the emergence of neutralising antibodies correlates with diminished induction of downstream markers such as phosphorylated STAT1 and MxA mRNA, leading to suboptimal control of disease activity. Advances in assay technologies span enzyme-linked immunosorbent formats, bioassays, phosphoflow cytometry and novel transcriptomic and metabolomic approaches, all aimed at early detection and personalised management. Understanding and mitigating interferon beta immunogenicity is essential to optimise long-term disease control, guide treatment switching and inform the development of next-generation biopharmaceuticals with reduced immunological risk.

Research from Nature Portfolio

Recent studies have interrogated cross-reactivity among neutralising antibodies elicited by different interferon beta formulations and characterised their impact on intracellular signalling. Investigations demonstrate that higher antibody titres not only neutralise the administered molecule but also inhibit phosphorylation of STAT1 across diverse interferon beta variants. This linear relationship between neutralising titre and JAK-STAT pathway inhibition suggests that measurement of phosphorylated STAT1 could serve as a universal, functional surrogate marker for immunogenicity, streamlining clinical assessment and guiding therapeutic decisions when switching between interferon beta products.

Immunogenicity of Interferon Beta in Multiple Sclerosis publication trend

The graph below shows the total number of articles in immunogenicity of interferon beta in multiple sclerosis across all publications each year (not limited to Nature Index journals).

Technical terms

Neutralising antibodies: Autoantibodies that bind to interferon beta and block its interaction with cellular receptors, abrogating downstream signalling.

Anti-drug antibodies (ADA): Immunoglobulins generated by the host immune system against therapeutic interferon beta, encompassing both binding and neutralising types.

JAK-STAT signalling pathway: A cytokine-activated intracellular cascade in which Janus kinases phosphorylate STAT transcription factors, driving gene expression.

Phosphorylated STAT1 (pSTAT1): The activated form of STAT1 following cytokine receptor engagement, used as a functional readout of interferon beta activity.

HLA haplotype: A specific combination of human leukocyte antigen alleles that influences antigen presentation and susceptibility to immunogenic responses.

Metabolomics: The comprehensive analysis of small-molecule metabolites in biological samples to identify biomarkers of disease or treatment response.

References

1. Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort Analysis. PLOS ONE (2016).
2. Human Leukocyte Antigen Genes and Interferon Beta Preparations Influence Risk of Developing Neutralizing Anti-Drug Antibodies in Multiple Sclerosis. PLOS ONE (2014).
3. Deficient Phosphorylation of Stat1 in Leukocytes Identifies Neutralizing Antibodies in Multiple Sclerosis Patients Treated with Interferon-Beta. PLOS ONE (2014).
4. MxA mRNA Quantification and Disability Progression in Interferon Beta-Treated Multiple Sclerosis Patients. PLOS ONE (2014).
5. Development and Validation of an Enzyme-Linked Immunosorbent Assay for the Detection of Binding Anti-Drug Antibodies against Interferon Beta. Frontiers in Neurology (2017).
6. Using Serum Metabolomics to Predict Development of Anti-drug Antibodies in Multiple Sclerosis Patients Treated With IFNβ. Frontiers in Immunology (2020).
7. Cross-reactivity of antibodies against interferon beta in multiple sclerosis patients and interference of the JAK-STAT signaling pathway. Scientific Reports (2017).
8. Treatment- and population-specific genetic risk factors for anti-drug antibodies against interferon-beta: a GWAS. BMC Medicine (2020).
9. Long-Term Consequences of High Titer Neutralizing Antibodies to Interferon-β in Multiple Sclerosis. Frontiers in Immunology (2020).