New soluble interferon-beta with increased pharmacokinetic stability
Interferon-beta is used for therapy of multiple sclerosis. A major problem, however, poses the low solubility of the protein. A new method of enhancing its solubility is now presented by Fraunhofer IGB on the Trade Fair Biotechnica, Hannover: By hydrophobicity engineering the scientist have developed a variant which is more soluble and furthermore, pharmacokinetically more stable than wildtype Interferon-beta.
Interferons are proteins produced by the human body which can be used to treat various diseases. For example, interferon-beta is one of the few substances which can be used to treat multiple sclerosis. But the low solubility of the protein poses a major problem. Scientists at the Fraunhofer IGB have found a new method of enhancing the protein's solubility which will now be presented on the International Trade Fair Biotechnica in Hannover, October 5-7 1999, in Hall 4, Stand H12.
Using a new concept of protein design, the so-called hydrophobicity engineering, the scientists have succeeded to replace the hydrophobic (water-repelling) portions of the molecule by soluble ones. The goal was to reduce clustering between the molecules in order to increase the protein yield and thus pharmacological effectiveness. The variant molecules are constructed by means of genetic engineering methods: they are produced in bacteria cells, then all traces of bacterial protein is removed until ultra-pure interferon beta remains.
The researchers' first step was to determine a structural model for human interferon beta. They based this on the three-dimensional crystalline structure of mouse interferon beta – the make-up of the proteins is very similar in the two species. “By means of homology-based modelling we were then able to reproduce the model of the human interferon-beta protein”, reports Christian Schneider-Fresenius of the IGB. “We had to take that course because when we started work nobody knew the crystalline structure of human interferon beta”. In the meantime scientists in the USA have determined its structure; a comparison with the model revealed the same underlying structure. Then the IGB researchers had to identify the amino acids responsible for low solubility, in order to replace them with more soluble ones. This improved the basic biophysical properties of the protein, without affecting its biological activity.
Furthermore, the researchers could demonstrate in animal tests, that the new Interferon-beta variant is not only more soluble but – which is even more important for its application – pharmacokinetically more stable. Thus, the protein becomes better bioavailable than wildtype IFN-beta. Pharmaceutic companies have already shown interest in bringing the new interferon to the clinical phase.