ABSTRACT
The advent of biopharmaceuticals (BPs) has led to significant improvements in the treatment of many chronic inflammatory diseases, and the number of BPs on the market and of diseases treated reflects their success. However, repetitive parenteral administration and intrinsic immunogenic properties of the drug can elicit an immune response, leading to production of anti-drug antibodies (ADA). This is a major limitation of the use of BPs and has to be taken into consideration in clinical practice and during drug development. With increasing knowledge about the immunogenicity of BPs and regular ADA testing in patients, we ensure optimized long-term treatment for the individual and thus optimal use of health care resources. This field has already been extensively investigated in the treatment of multiple sclerosis with IFN-ß, but there is a clear need for consensus from academia, health care providers and the BP industry in managing ADA across all BPs and diseases.
Subject(s)
Antibodies , Immunologic Factors , Multiple Sclerosis , Antibodies/immunology , Humans , Immunologic Factors/immunology , Immunologic Factors/therapeutic use , Interferon-beta/immunology , Interferon-beta/therapeutic use , Multiple Sclerosis/blood , Multiple Sclerosis/drug therapy , Multiple Sclerosis/immunology , Portraits as TopicABSTRACT
A significant proportion of patients with multiple sclerosis who receive interferon beta (IFNß) 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 IFNß 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 IFNß-1a, subcutaneous IFNß-1a or subcutaneous IFNß-1b. Carriage of HLA-DRB1*15 was associated with increased risk of developing NAbs and high NAb titers. After stratification based on type of IFNß 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 IFNß-1a. Furthermore, in patients receiving subcutaneous IFNß-1a carriage of HLA-DQA1*05 decreased the risk for high NAb titers. In IFNß-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 IFNß high enough to be clinically relevant in treatment decisions for patients with multiple sclerosis if confirmed in future studies. However, choice of IFNß preparation still remains the single most significant determinant for the risk of developing NAbs.