Interferon-gamma was discovered during the 1960s as an important response mechanism of the human immune system. By virtue of its intrinsic, versatile anti-viral, anti-proliferative and immuno-stimulating biologic activities the protein gained access to the pharmaceutical market soon after its discovery in several therapeutic applications.
In 1991, interferon-gamma was approved as a drug for the treatment of chronic granulomatosis, a very rare hereditary disease in which the activation of the immune system is defective. After the pharmaceutical industry lost interest in the protein in the 1990s due to a number of failures, new applications with great potential are now emerging and global sales of the only two pharmaceutical products Actimmune® and Imukin® have increased to an estimated US$ 180-200 million annually over the last four years (2004).
In 2000, interferon-gamma received approval for osteopetrosis (Albers-Schönberg disease), a hereditary disease of bone metabolism also known as marble bone disease. However, the greatest potential for the protein appears to lie in diseases that are associated with increased collagen production in connective tissue and lead to pathological scarring of tissue. Interferongamma may, for example, contribute to the slowing down of pulmonary fibrosis, a fatal scarring of lung tissue. A pivotal clinical trial (Phase III) for the use of interferon-gamma in pulmonary fibrosis is currently underway in the United States.
Our research team has been working for more than a decade in the interferon field, with the goal of providing improved molecules with enhanced clinical potential for the pharmaceutical industry.
These “second generation” interferongamma molecules contain innovations affecting stability, solubility, and bioavailability and also fermentation and production processes. Intellectual property rights are claimed in all major pharmaceutical markets. A comprehensive portfolio of five world-wide patent families has been filed.
Through use of computer modeling, new variants of interferon-gamma with improved thermal stability have been developed. In addition, a truncation of the molecule resulted in an increase in bioactivity. Latest data shows the positive impact of a combination of polyethyleneglycol (PEGylation) with interferon- gamma on pharmacokinetics and bioavailability in an animal experiment. The optimization of the fermentation and production process led for the first time to the possibility of obtaining the protein in completely soluble form.
The excellence of this research project was confirmed by research awards from the International Society for Interferon and Cytokine Research (ISICR) and the Fraunhofer-Gesellschaft.
These “second generation” interferongamma molecules, together with the modified fermentation and downstream process, are the basis for new indications and forms of application. Currently, the Fraunhofer IGB is looking for partners from the pharmaceutical industry for licensing and further clinical development of the project.
[1] Sergey E. Perchenov et al. (2002) Mutant analogues of human interferongamma with higher stability and activity. Protein Expression and Purification 24, 173-180
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[3] Waschütza, G.; Dengler, U.; Villmann, C.; Böttinger, H. and
Otto, B. (1998) Interferon-g variants with deletions in the AB-surface loop. Eur. J. Biochem. 256, 303-309
[4] Waschütza, G.; Li, V.; Schäfer, T.; Schomburg, D.; Villmann, C.; Zakaria, H. and Otto, B. (1996) Engineered disulfide bonds in recombinant human interferon-γ: The impact of the N-terminal helix A and the AB-loop on protein stability. Protein Engng. 9, 905-912
[5] Slodowski, O.; Bohm J.; Schöne B.; and Otto, B. (1991) Carboxy-terminal truncated rhuIFN-gamma with a substitution of Gln133 or Ser132 to leucine leads to higher biological activity than in the wild type. Eur. J. Biochem. 18, 1133-1140
Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB