Medical Biotechnology

Mission

The central R&D focus is the development of innovative drug discovery strategies for the rapid identification, optimization and pre-clinical validation of novel synthetic or biological drug candidates and the discovery of drug targets and biomarkers.

Current Research Activities

1. Development of Disease Models and Assays

We are developing in vitro disease models for the cost effective identification and optimization of lead candidates. At present, our portfolio consists of cell- and tissue based models for cancer, immune disorders and skin diseases. The models include conventional two-dimensional (2D) cultures on plastic and filter inserts, three-dimensional (3D) spheroids embedded in natural or synthetic extracellular matrix (ECM) scaffolds, heterotypic 3D cultures consisting of tumor and stromal cells and miniaturized primary tumor tissue obtained from surgical resections and biopsies.

In corresponding biological assays, we are performing multi-parameter physiologic and phenotypic profiling including label-free, fluorescence- and luminescence-based methods to determine cell growth, apoptosis, necrosis, senescence and (de)differentiation. Many methods are compatible with automated high-throughput screening or bioimaging and high-content phenotype-based drug discovery.

For drug target identification, we have established a large panel of pathway-specific reporter cell lines based on luminescence or fluorescence measurements (FRET), e.g. Live BLAzer reporter technology for NFkB, AP1, Forkhead box factors, TCF/LEF, SMADs. To evaluate particular signaling pathways we investigate the dynamics of posttranslational modifications using immunoblotting, ELISA, protein arrays and in situ cell imaging. In addition, we have cell panels exhibiting gain and loss of function mutations in defined signalling pathways. These models are instrumental for studying oncogene addiction and synthetic lethality. They help to understand the mode of action of drugs and facilitate the identification of cellular drug targets. Advanced genomic and proteomic approaches are performed in collaboration with our industrial and academic partners. These technologies facilitate the identification of novel genotype-drug response relationships (biomarkers) and pave the way for personalized medicine in the clinic.

2. Development of Therapeutic Peptides

Protein-protein interactions are underlying almost all mechanisms by which biological systems transmit information and regulate metabolism. The specific inhibition or activation of protein-protein interactions has therapeutic relevance for most human diseases. Peptide-based biopharmaceuticals can modulate protein-protein interactions with high specificity and selectivity. They have demonstrated impressive clinical efficacy and exhibited reduced adverse side effects and toxicity in patients.

In collaboration with our partners, we have developed in-depth technological expertise in peptide drug development. Both rational protein-engineering as well as combinatorial high-throughput screening are presently employed to develop peptides with high stabilities and binding affinities to their targets (Figure 2).

A. Molecular Modeling

In the rational and hypothesis-driven approach, we use computational design methods to identify peptides specifically interacting with the target protein. Starting points are NMR and X-ray data of the targets under consideration, often in combination with their natural ligands (proteins or peptides). We use advanced software tools to translate X-ray and NMR data into first peptide hits. The main types of methods that are used in the design of peptide ligands are (A) computational analysis of the ligand-receptor interaction using protein-ligand interaction fingerprints, (B) in silico mutagenesis studies, (C) conformational analysis of designed peptide ligands and (D) protein-peptide docking.

B. Molecular Screening

The combinatorial screening approaches do not require a priori knowledge of the structures of interacting proteins. For the identification of first peptide hits, we perform large scale screening procedures using yeast two-hybrid (HTS-Y2H) and/or phage display technologies. In integrative and iterative cycles of screening, chemical derivatization (e.g. intramolecular cyclization, insertion of functional groups), molecular modeling and biological testing the hits are converted into high affinity lead peptides (in vitro evolution). The lead candidates serve as templates for the design of high affinity low molecular weight (LMW) drugs (peptidomimetics) using a combination of molecular modeling and medicinal chemistry.

Figure 1: R&D platform for the development of therapeutic peptides

3. Custom Services

We offer specialized and high-quality solutions for immunological, genetic and cell-based testing of biopharmaceuticals, nutrient additives and environmental pollutants. In addition, we offer testing of research instrumentation for cell biology, molecular biology and immunology prior to market launch.