[Biopharmaceutics] Interferons for medical uses

In late 1950s, at that time, initial therapeutic application was rendered impractical due to extremely low levels of production in the body levels at which they are normally produced in the body. Furthermore, interferons exhibit species preference and, in some cases, strict species specificity. This rendered necessary the clinical use only of human-derived interferons in human medicine.

Up until the 1970s, interferon was sourced directly from human leukocytes obtained from transfused blood supplies. In the late 1970s, the production of interferon in significant quantities first became possible by means of mammalian cell culture. Moreover, Hybridoma technology facilitated development of sensitive interferon immunoassays. In the 1980s, recombinant DNA technology also facilitated the production of interferons in quantities large enough to satisfy potential medical needs. Up to now, most interferons have now been produced in a variety of expression systems, including E. Coli, fungi, yeast and some mammalian cell lines, such as CHO cell lines.

It has been shown that IFN-alpha could induce regression of tumors in significant numbers of patients suffering from breast cancer, lymphomas and other types of cancers. The first recombinant interferon to become available for clinical studies was IFN-a2a. The antiviral, anti-tumor, and immunomodulatory properties of these interferons assured their approval for a variety of medical uses. Clinical trials have shown the recombinant interferons to be effective in the treatment of various cancer types, with rhIFN… both approved for treatment of hairy cell leukaemia. (Rh which stands for recombinant human products produced in E. Coli) Both of them have also proven effective in the treatment of various viral conditions, most notably viral hepatitis.

Hepatitis refers to an inflammation of the liver. Also, rhIFN-a2b is already approved for the treatment of sexually transmitted genital warts, caused by a human papilloma virus. More recently, a number of modified recombinant interferon products have also gained marketing approval.

These include PEGylated interferons and the synthetic interferon product Infergen. PEGylated interferons are generated by reacting purified IFN-as with a chemically activated form of PEG. This product displays a significantly prolonged plasma half-life. The prolonged half-life appears to be due mainly to slower elimination of the molecule. Infergen is an engineered interferon recently approved for the treatment of hepatitis C. In common, producer microorganism of these interferons is E. Coli, which harbours a cytoplasmic expression vector containing the interferon gene.

The manufacturing process can be separated into 2 main processes. Upstream processing and downstream processing are physically separated, by being undertaken in separate building. The upstream part refers to the first step in which microbes/cells are grown.

The downstream part of a bioprocess refers to the part where the cell mass from the upstream are processed to meet purity and quality requirements.  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 years. It is characterized by damage to the myelin sheath, which surrounds neurons of the central nervous system, and in this way compromises neural function. The molecular mechanism by which IFN-B induces its therapeutic effect is complex and not fully understood. It is believed that the pathology of MS is linked to the activation of T-lymphocytes which trigger an inflammatory response mediated by the production of proinflammatory cytokines. This results in the destruction of myelin surrounding neuronal axons. IFN-B likely counteracts these affects, in part at least, by inhibiting production of IFN- … and hence mediating down-regulation of the pro-inflammatory response. IFN-B Preparations approved for medical use to date include Betaferon and Betaseron which are produced in recombinant E.

Coli cells and Avonex and Rebif which are produced in CHO cell lines. This figure here is an Overview of the manufacture of Betaferon, a recombinant human IFN-β produced in E. Coli. E. Coli fermentation is achieved using minimal salts/glucose media. During downstream processing, the Ibs are solubilized in butanol.

After that, it will pass to the purification process. 9 The most notable medical application of IFN- relates to the treatment of CGD, a rare genetic condition. Phagocytic cells of patients suffering from CGD are incapable of ingesting or destroying infectious agents such as bacteria or protozoa. In this case, phagocytic cells have difficulty forming the ROC … This figure shows the production of reactive oxygen species by phagocytes. The ROC are produced by an NADPH oxidase system, the main feature of which is a plasma membrane-based electron transport chain. The electrons are passed via a number of carriers. The cytochrome passes the electrons to oxygen, generating a superoxide anion, which can be converted to hydrogen peroxide at the end.

IFN- can potentiate the ability of phagocytes to generate toxic oxidative products by boosting flux through the NADPH oxidative system, which they then use to kill infectious agents. IFN- also promotes increased expression of IgG Fc receptors on the surface of phagocytes. This would increase a phagocyte’s ability to destroy opsonized infectious agents via phagocytes. IFN- also proves valuable in treating leishmaniasis, a disease common in tropical and subtropical region, caused by a parasitic protozoan of the genus Leishmania. IFN- appears to stimulate the infected macrophage to produce nitric oxide which is toxic for this parasite. Additional studies illustrate that IFN can stimulate … Like most drugs, administration of interferons can also elicit a number of unwanted side effects. This table shows the side-effects of IFN-as.

In most cases, only minor side effects are noted. However, more serious effects may occur in up to 17% of patients. However, the common side effect associated with almost all types of interferons is the characteristic flu-like symptoms. It has been found that a protein called Trophoblastin was closely related to IFN-a.

Functional studies have proven this. These studies show that trophoblastin: … Trophoblastin, therefore, has been named interferon-tau and is classified as a type I interferon. IFN-tau is currently generating considerable clinical interest. It induces effects similar to type I interferon, but it appears to exhibit significantly lower toxicity. Thus, it may prove possible to be an alternative effective interferon.

IFN-w represents an additional member of type I interferon family. This interferon induces its antiviral, and other effects by binding the type I interferon receptor.