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Immunoproteasome Drug Targeting: Immunoproteasome inhibitors allow control of autoimmune diseases

Marcus Groettrup is the chair of immunology at the University of Konstanz and has been active in the field of immunology for many years. In 2009, Groettrup made a discovery that led to him setting up a company. His analysis of immunoproteasomes, whose main function is to degrade unneeded or damaged proteins, showed that these protein complexes also play a major role in the development of autoimmune diseases. Based on this knowledge, Groettrup established the Steinbeis Transfer Centre “Immunoproteasome Drug Targeting”, which supports pharmaceutical companies in the development of drugs that target immunoproteasomes.

Marcus Groettrup, scientist at the University of Konstanz, established his own company to exploit the use of immunoproteasomes for therapeutic purposes in 2011. © Marcus Groettrup

Proteasomes are large protein complexes that are found in the cytoplasm and nucleus of cells. “The major role of proteasomes is to break down proteins into peptides, a process that never stops due to the short half-life of some proteins,” Groettrup says. In contrast to normal, so-called constitutive proteasomes, immunoproteasomes contain some subunits that are key in the fight against viruses and bacteria. Proteins of viruses and bacteria that enter the cells of the human body are degraded just like any other cellular proteins. The immunoproteasome cuts down proteins into peptides that are subsequently presented on the cellular surface. T lymphocytes recognise these viral peptides as 'non-self' and kill the infected cells. “It has been known for quite some time that immunoproteasomes break down viruses and bacteria,” said Groettrup. “In addition, we discovered that immunoproteasomes control the production of pro-inflammatory signalling substances. Special immune cells, i.e. macrophages, need to release pro-inflammatory signaling substances in order to trigger the immune response of T lymphocytes. This process is impaired when fewer immunoproteasomes are present.”

Immunoproteasome inhibitors can be used for therapeutic applications

Groettrup and his team were able to put their new finding to good use in cooperation with an American pharmaceutical company. The company had previously developed an immunoproteasome inhibitor that was aimed at specifically killing cancer cells. The development was unsuccessful, but Groettrup was able to show that the company’s inhibitor could be used for the treatment of autoimmune diseases such as rheumatism and diabetes in mouse models. The inhibitor also proved effective in the treatment of Crohn’s disease in preclinical models. Groettrup is currently testing the inhibitor for its suitability for the treatment of multiple sclerosis. “In such cases, the immune system acts against its own body,” Groettrup explains. “The inhibition of the activity of immunoproteasomes prevents the release of pro-inflammatory signalling substances, and disease symptoms and progression can be suppressed.” In 2009, Groettrup published a paper on the use of immunoproteasomes as targets for the treatment of autoimmune diseases in the renowned journal Nature Medicine. The article attracted such huge interest from the pharmaceutical industry that Groettrup decided to establish his own company and focus on targeting immunoproteasomes for therapeutic purposes.

Steinbeis Transfer Centres – between university and industry

In 2011, Groettrup founded the company “Immunoproteasome Drug Targeting” with the status of a Steinbeis Transfer Centre. Company establishment was made possible through the Steinbeis Foundation, an institute headquartered in Stuttgart that is dedicated to the transfer of academic findings to industry, for example by supporting university professors in establishing a company. The foundation carries out the administrative tasks such as cost monitoring and controlling. He uses immunoproteasomes to provide his clients with services related to drug development, including immunoproteasome purification, assay development and the validation of substances developed.

The figure shows a model of the three-dimensional immunoproteasome structure identified by the groups of M. Groettrup and M. Groll in 2012 (Cell 148: 727-738). Groettrup’s company purifies human and mouse immunoproteasomes that are subsequently used by the company’s clients for drug development. © Marcus Groettrup

From purification to assay development

In order to purify immunoproteasomes from human cell cultures, the scientists need to separate them from the other 20,000 cellular proteins. Groettrup uses a chromatography system that exploits the physical and chemical characteristics of immunoproteasomes to separate them from the other proteins. Groettrup also develops assays that visualize immunoproteasome activity: the substrate of immunoproteasomes carries a fluorescent label, which lights up when a peptide is split off. The assay can therefore visualize the activity of immunoproteasomes.

As well as companies benefitting from the cooperation between the university and the industry, Groettrup himself is also delighted to be able to exchange information and experiences with his industrial partners. “I can learn a lot from working in cooperation with my clients,” Groettrup comments.

Further information:
Steinbeis Transfer Centre
Immunoproteasome Drug Targeting at the University of Konstanz
Prof. Dr. Marcus Groettrup
Universitätsstr. 10
78457 Konstanz
Tel.: +49 (0)7531/ 882130
Fax: +49 (0)7531/ 883102
E-mail: SU1520(at)stw.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/immunoproteasome-drug-targeting-immunoproteasome-inhibitors-allow-control-of-autoimmune-diseases/