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Klaus Pfizenmaier: bridging the fields between immunology and biomedicine

Prof. Dr. Klaus Pfizenmaier has been focusing on cytokines, and in particular on the tumour necrosis factor TNF, for the last 25 years. Pfizenmaier and his team of researchers at the Institute of Cell Biology and Immunology at the University of Stuttgart have unravelled numerous facets of TNF, which is a key and versatile signalling molecule. These discoveries have led to the development of groundbreaking therapy concepts and drug candidates for the treatment of cancer and neurodegenerative diseases. Pfizenmaier is also involved in systems biology research at the University of Stuttgart.

Cytokines are Prof. Dr. Klaus Pfizenmaier’s specialty. © Institute of Cell Biology and Immunology, University of Stuttgart
As a student of biology at the Technical University of Darmstadt, Pfizenmaier chose microbiology as his main subject. In 1974, he began his doctorate on antiviral, cell-mediated immunity at the Institute of Medical Microbiology at the University of Mainz and became fascinated with cellular immunology, a field he has been attracted to ever since and to which he has made important contributions. Pfizenmaier spent a one-year postdoctoral period at the Wistar Institute in Philadelphia, USA, which was highly successful and resulted in three publications in renowned scientific journals. He then returned to Germany for two reasons. “Before I moved to the States, I promised the director of the Institute of Medical Microbiology that I would return to the institute and continue my work. And returning to Germany fitted in a lot better with my personal life,” said Pfizenmaier who stayed in Mainz until 1983, heading up his own research group from 1980 and habilitating in immunology in 1982.

Pfizenmaier then became a principal investigator and was looking for new challenges, which he found at the Göttingen University Hospital where he led a clinical research group of the Max Planck Society. This was his first independent position and was equivalent to a professorship. “In the 1980s, the Max Planck Society established clinical research groups of this kind with the aim of advancing clinical research in Germany. During the first five years, the group was financed with funds from the VW Foundation, the Max Planck Society gave us the required administrative support and Göttingen University Hospital provided us with the rooms and the scientific environment,” explained Pfizenmaier.

Research priority: cytokines

Pfizenmaier originally focused particularly on mice and the resolution of immunological issues, but his move to Göttingen brought him into contact with human biology and cancer research. The position did not require him too much of his time for university obligations, which meant that he could concentrate fully on research. Pfizenmaier initially concentrated on basic research into the immunostimulatory and anti-tumour effect of interferons. He was specifically interested in the mechanisms of action of gamma interferon and in the characterisation of its receptor on the membrane of tumour cells, which is important for interferon to exert an anti-tumour effect. The interferons soon entered clinical testing. The tumour necrosis factor (TNF), whose gene was sequenced in 1985, also quickly entered clinical testing, and Göttingen became involved in TNF research at a very early stage.

“My Max Planck research group had close links with Göttingen University Hospital. We worked alongside the hospital’s Department of Oncology. It is a hospital with an excellent international reputation due to its involvement in many clinical trials. As such, it also has quick access to new drugs. The hospital was also part of clinical trials testing the effect of biologics, including recombinant interferons and TNF. The close links with Göttingen University Hospital enabled us to carry out basic research as closely as possible to patients and alongside clinical trials,” said Pfizenmaier. With the discovery of a large structurally related gene family of TNF-like ligands and with TNF as lead substance, an important research focus on immunomodulatory cytokines was emerging on the international level. Although TNF could not fulfil early expectations and did not turn out to be a universal remedy against cancer, the researchers slowly but surely became aware of the wide range of therapeutic uses of this cytokine and its key role in many diseases. Pfizenmaier made this exciting field of research one of his major priorities when he accepted the position of professor and institute director at the University of Stuttgart in 1990.

Successful establishment of the Institute of Cell Biology and Immunology

Atrosab is an antagonistic TNFR1-specific humanised antibody. It prevents TNF from binding to TNFR1 and hence stops the production of receptor-ligand complexes in the plasma membrane that are able to transmit signals. © Institute of Cell Biology and Immunology, University of Stuttgart
Pfizenmaier established the new Institute of Cell Biology and Immunology at the University of Stuttgart as well as a research group at the Fraunhofer Institute of Interfacial Engineering and Biotechnology IGB. “During my first two years in Stuttgart, I established a cell biology laboratory at the IGB that focused specifically on the use of the hybridoma technology for the production of monoclonal antibodies,” said Pfizenmaier. As the number of university obligations grew and the institute relocated to the Centre for Bioprocess Engineering, Pfizenmaier now found he had to focus entirely on university work. Pfizenmaier’s institute now has more than 60 employees and four departments and professorships. Pfizenmaier pointed out that their everyday work does not necessarily follow established departmental structures, with individual research groups focusing instead on specific topics. “This means that a particular project might involve researchers from several departments and the project is usually managed by the person who has the greatest skills in the particular topic,” said Pfizenmaier also highlighting the excellent chemistry between professors and scientists. “We get on with each other very well. And this enables us to work together very effectively. I find this very rewarding and it makes things a lot easier and more effective.” The second professorship was established shortly after the institute was set up and was part of Pfizenmaier’s conditions for accepting his current position. This professorship is held by Prof. Dr. Peter Scheurich, who began a successful working relationship with Pfizenmaier when he was still in Mainz. According to Pfizenmaier, this cooperation has made a huge contribution to driving forward their research on cytokines. The third professorship was established in 2004 with funds from German Cancer Aid; the post was taken by Prof. Dr. Roland Kontermann and will become part of the university in 2015 when the Dr. Mildred Scheel Foundation for Cancer Research’s (German Cancer Aid) funding comes to an end in 10 years’ time. Kontermann works in biomedical engineering and uses basic research findings to develop therapeutic products, including recombinant antibodies, fusion proteins and nanoparticulate systems. The institute’s fourth professorship was taken in 2011 by Prof. Dr. Monilola Olayioye, who works on molecular tumour cell biology. “Before her current position, Olayioye headed up a DFG-funded junior research group, at which she was outstandingly successful to the extent that the DFG decided to award her a Heisenberg professorship,” said Pfizenmaier who was delighted with this achievement.

TNF and its receptors as therapeutic targets

Asked about which achievements were most important to him personally, Pfizenmaier cites the results on TNF, naming one of his scientists’ key findings as an example: there are two forms of TNF, a transmembrane form and a soluble form that arises from the transmembrane form by way of proteolytic cleavage. The researchers from Stuttgart have shown that these two forms differ in their activity. “The two different forms address two different receptors, namely TNFR1 and 2, which convey different signals, which in turn leads to different cellular reactions. There are still quite a number of questions relating to the molecular mechanisms and the physiological/pathophysiological importance of the two TNFRs which we need to investigate in more detail. In addition, we are also looking for possibilities to use these findings for therapeutic applications,” said Pfizenmaier.

Pfizenmaier believes in the great potential of fusion proteins in the treatment of cancer. His group has fused a shortened soluble variant of the TNF ligand TRAIL (TNF-related apoptosis-inducing ligand) with antibody fragments that bind selectively to the surface proteins of tumour cells. The binding reinforces the effect of TRAIL, which then induces apoptosis, i.e. the programmed death of the tumour cells. The researchers have already been able to show that the principle works, but they still have to put a lot more work into the development of effective fusion proteins. One thing that is highly interesting in this respect is the use of specific peptide linkers for producing specific di- and trimers, which have a higher specific activity than monomers. In addition to tumour cell markers, the researchers from Stuttgart are also focusing on surface proteins of tumour stroma and tumour blood vessels that provide the tumour with nutrients. “We hope to be able to induce the apoptosis of the tumour cells by interfering with the tumour’s blood and nutrient supply. The tumour starves and eventually dies. This might be another option for cancer treatment.

As specific TNF ligands are not only able to induce apoptosis, but also have an immunostimulatory effect, other research groups in Pfizenmaier’s institute are focusing on the development of immunotherapies in which bifunctional fusion proteins recognise specific surface markers on immune system and tumour cells. “We hope that this will be used to activate a patient’s immune system, for example after the patient has undergone chemo- or radiation therapy, in order to get it to recognise and eliminate any tumour cells that may still be there,” said Pfizenmaier.

A major finding of the Stuttgart researchers is that the activity of soluble and membrane-bound TNF ligands differs. © Institute of Cell Biology and Immunology, University of Stuttgart

Thinking cell biology forward towards medicine and biotechnology

As TNF is a cytokine with many functions – it is able to induce apoptotic cell death and inflammation and to inhibit tumourigenesis and viral replication – there is also the potential to target TNF for treating diseases other than cancer. Pfizenmaier and his team are also focusing on chronic inflammatory diseases such as rheumatism and psoriasis as well as neurodegenerative diseases such as multiple sclerosis, Parkinson’s and Alzheimer’s. The team has already developed a drug candidate called Atrosab, an antibody that selectively binds to type 1 TNF receptors and is thus expected to increase the safety and efficiency of anti-TNF therapy. “With Atrosab, which we are developing in cooperation with a partner, we are approaching clinical application. We have already been able to demonstrate the therapeutic potential of antibody-mediated specific TNFR1 inhibition in inflammatory disease. We are planning to commence a Phase I trial in July 2012,” Pfizenmaier said.

Pfizenmaier always has the applied aspect in mind. “When we start a project, we initially focus on the principle of action, which soon leads us to questions related to the stability and production of the drug. We deal with all these aspects in our laboratory before they are further pursued in cooperation with the pharmaceutical industry,” said Pfizenmaier highlighting the importance of collaborating with external partners. “We have interdisciplinary collaborations with academic groups and also work closely with the pharmaceutical industry.”

Interdisciplinary collaboration is also crucial in the field of systems biology, a research field that has been emerging over the last few years. Systems biology relates to the combination of computer-assisted data analysis and mathematical modelling with experimental research whose objective is to achieve a holistic understanding of complex biological processes.

Pfizenmaier is one of eight directors of the Centre for Systems Biology (CSB) at the University of Stuttgart that aims to advance this field of research. In close cooperation with engineers, the CSB researchers are developing dynamic mathematical models. “It is no longer possible to intuitively understand the complexity of entire biological systems. Our interdisciplinary projects therefore focus on the development of predictive mathematical models, and in so doing support experimental researchers in the clarification of mechanisms and speeding up the testing of the efficacy of new drugs in clinical research. I am convinced that systems biology will continue to play a key role in biomedical research in the future,” said Pfizenmaier.

Further information:

University of Stuttgart
Institute of Cell Biology and Immunology
Prof. Dr. Klaus Pfizenmaier
Allmandring 31
70569 Stuttgart
Phone: +49(0)711/ 685 66 986
E-mail: klaus.pfizenmaier(at)izi.uni-stuttgart.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/klaus-pfizenmaier-bridging-the-fields-between-immunology-and-biomedicine