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.
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.
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.
Further information:University of StuttgartInstitute of Cell Biology and ImmunologyProf. Dr. Klaus PfizenmaierAllmandring 3170569 StuttgartPhone: +49(0)711/ 685 66 986E-mail: klaus.pfizenmaier(at)izi.uni-stuttgart.de