The magic of magic bullets. Paul Ehrlich, noble prize winner and possibly the most visionary of the “grand old immunologists”, had a dream, a dream in which “magic bullets” used the specificity of antigen-antibody reactions to specifically bind and neutralize infected or malignant cells. Today, almost 100 years later, one can safely state that this vision has been realized, at least in part: monoclonal antibodies, such as Rituxan and Herceptin, are capable of recognizing specific molecules on the surface of tumor cells and thereby mediating the destruction of these cells. Such antibodies have considerably improved the treatment of most lymphomas and Her2-positive mammary carcinomas and the side effects of this type of treatment are usually reduced compared to those of conventional chemotherapy.
However, this success story has its limitations: some patients do not respond at all, others for a limited time only. Thus, numerous strategies have been suggested to increase the efficiency of antitumor antibodies. Most of these strategies picture an antibody as a vehicle carrying a toxic effector molecule of some kind to its target. The compounds used as payload include conventional cytostatic drugs, highly effective protein toxins, radio isotopes and cytokines. Suggestive as these approaches may be, most of them fail because at any given time less than 1% of the total body dose is specifically bound. This plain pharmacokinetic fact reduces the specificity an antibody based immunotoxin to almost nothing, unless antibody selectivity is preserved. What does this mean? An antibody exerts its effector functions, the activation of complement or Fc-receptor carrying effector cells, via its constant Fc part. It does so however only after binding to its target antigen. We like to call this property the selectivity of the Fc-part, contrasting it with the specificity of the antibody variable regions. The research activities of the Section of Experimental Antibody Therapy aim at the improvement of antitumor antibodies. Common theme of the different strategies pursued is the preservation and amplification of antibody selectivity as defined above.
Translational research with antibodies, more than a scientific challenge. Currently, it takes more than 10 years for an antibody to reach the clinic as an approved drug. Thus, generating better antibodies is insufficient. They also need to be faster in the clinic. At present, the process of antibody development is almost entirely in the hands of the pharmaceutical industry, that means that it is heavily influenced by non-scientific considerations, such as intellectual property issues. Together with a steadily growing regulatory burden this results in a ponderous developmental process which is often suboptimal with respect to both, the quality of the substances developed and the speed and flexibility with which this is done. We believe that improving this process is a tremendous additional challenge to be met, and one that calls for structures which allow for a more efficient interaction between academic and industrial institutions.
With our translational research project “Preclinical development, production and initial clinical evaluation of optimized antitumor antibodies” we have tried to address this problem. The project was supported by the GoBio programme of the Federal Ministry for Education and Research (BMBF) in the years 2008-2012. It has led to the foundation of the Synimmune GmbH in 2012. The aim of this company is the rapid development of innovative mono- and bispecific antitumor antibodies in close cooperation with the University of Tübingen.
University of Tübingen
Interfaculty Institute for Cell Biology
Department of Immunology
Section of experimental antibody therapy
Auf der Morgenstelle 15
D-72076 Tübingen, Germany
Phone: +49-7071-29 87621
Fax: +49-7071-29 5653
Email: gundram.jung (@) uni-tuebingen.de