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IFN-a2A, when administered three times weekly for several weeks/months, was found effective in treating several forms of hepatitis. Remission is observed in 30-45% of patients
THE CYTOKINES—THE INTERFERON FAMILY 213
suffering from chronic hepatitis B, while a complete recovery is noted in up to 20% of cases. The drug induces sustained remission in up to 30% of patients suffering from chronic hepatitis C, but can ease clinical symptoms of this disease in up to 75% of such patients. Ongoing studies also indicate its efficacy in treating chronic hepatitis D, although relapse is frequently observed upon cessation of therapy. The drug is normally administered by the intramuscular (i.m.) or subcutaneous (s.c.—directly beneath the skin) injection. Peak plasma concentrations of the IFN are observed more quickly upon i.m. injection (4 h versus 7.5 h). The elimination half-life of the drug ranges from 2.5 to 3.5 h.
IFN-a preparations have also proved efficacious in the treatment of additional viral-induced medical conditions. rhIFN-a2B, as well as IFN-an3 are already approved for the treatment of sexually transmitted genital warts, caused by a human papilloma virus. While this condition is often unresponsive to various additional therapies, direct injection of the IFN into the wart causes its destruction in up to 70% of patients. Another member of the papilloma virus family is associated with the development of benign growths in the larynx (laryngeal papillomatosis). This condition can be successfully treated with IFN-a preparations, as can certain papilloma-related epithelial cell cancers, such as cervical intraepithelial neoplasm (epithelial cells are those that cover all external surfaces of the body, and line hollow structures — with the exception of blood and lymph vessels). IFN-a’s ability to combat a range of additional virally-induced diseases, including AIDS, is currently being appraised in clinical trials.
Medical uses of IFN-b
RhIFN-b has found medical application in the treatment of relapsing-remitting multiple sclerosis (MS), a chronic disease of the nervous system. This disease normally presents in young adults (more commonly women) aged 20-40. It is characterized by damage to the myelin sheath, which surrounds neurons of the central nervous system, and in this way compromises neural function. Clinical presentations include shaky movement, muscle weakness, paralysis, defects in speech, vision and other higher mental functions. The most predominant form of the condition is characterized by recurrent relapses followed by remission. MS appears to be an autoimmune disease, in which elements of immunity (mainly lymphocytes and macrophages) cooperate in the destruction of the myelin. What triggers onset of the condition is unknown, although genetic and environmental factors (including viral infection) have been implicated.
IFN-b preparations approved for medical use to date include Betaferon, Betaseron, Avonex and Rebif (Table 4.8). The former two products are produced in recombinant E. coli cells, whereas the latter two are produced in CHO cell lines. Manufacture using E. coli generates a non-glycosylated product, although lack of native glycosylation does not negatively affect its therapeutic efficacy. Typically, IFN-b-based drugs reduce the frequency of relapses by about 30% in many patients. In some instances, a sustained reduction in the accumulation of MS brain lesions (as measured by magnetic resonance imaging) is also observed. However, there is little evidence that IFN-b significantly alters overall progression of the disease. A summary overview of the production of one such product (Betaferon) is presented in Figure 4.7.
The molecular mechanism by which IFN-b induces its therapeutic effect is complex and not fully understood. It is believed that the pathology of multiple sclerosis is linked to the activation and proliferation of T lymphocytes specific for epitopes found on specific myelin antigens. Upon migration to the brain, these lymphocytes trigger an inflammatory response mediated by the production of pro-inflammatory cytokines, most notably IFN-g, IL-1, IL-2 and TNF-a. The inflammatory response, in addition to other elements of immunity (e.g. antibodies and
E. coli fermentation -> Cellular recovery
IB recovery (centrifugation) <--- Homogenization
Butanol extraction -> Refolding
Size exclusion chromatography 4---- Size exclusion chromatography
Formulation and filling Freeze-drying