The reason is that some patients develop neutralising antibodies to the interferon protein - effectively mounting an immune response against the drug that prevents it working as intended.
Now, researchers at Genencor International have discovered the area in beta interferon that stimulates the antibody response. This could lead to the development of a new-generation interferon that does not have this side effect, allowing patients to stay on therapy and continue to derive the benefit of a reduced risk of relapse.
Along with collaborators from the University Campus Bio-Medico in Rome, Italy, the scientists have identified an immunogenic region in the human protein sequence that activates human CD4+ helper T cells, the first step in the cascade that can lead to the production of neutralising antibodies. The data are published in Genes and Immunity (21 January).
Genencor has already carried out specific amino acid changes to the beta interferon sequence that result in a significantly lower activation of human CD4+ helper T cells. This information can guide modifications to the molecule that may reduce or eliminate the immunogenicity of the drug and thereby improve its effectiveness, according to the company.
The researchers also determined the genetic signatures (HLA haplotypes) of those individuals in the population who are likely to have an immune response to beta interferon.
Interestingly, these studies revealed that individuals with this genetic predisposition also have a higher tendency to developing MS. An intriguing possibility raised by this unexpected finding is that the HLA association between a response to beta interferon and susceptibility for the development of MS might be linked, opening up new pathways for research.
"The data reveal a potential pathway to a better second-generation drug for this disease," said Mark Goldsmith, Genencor's senior vice president of healthcare. He also said that the study is a validation of Genencor's HLA haplotype-searching technology - called I-mune - which may be to enable more effective therapies to reach patients by reducing immunogenicity problems that are often encountered in late stages of clinical trials of protein drugs.