Phage display; Tumor targeting; Protein therapeutics; Protein library
Egloff Pascal, Zimmermann Iwan, Arnold Fabian M., Hutter Cedric A. J., Morger Damien, Opitz Lennart, Poveda Lucy, Keserue Hans-Anton, Panse Christian, Roschitzki Bernd, Seeger Markus A. (2019), Engineered peptide barcodes for in-depth analyses of binding protein libraries, in Nature Methods
, 16(5), 421-428.
EgloffPascal (2018), Engineered Peptide Barcodes for In-Depth Analyses of Binding Protein Ensembles, in bioarxiv
The generation of antibodies and their development into approved drugs for the treatment of diseases is a main focus of today’s pharmaceutical industry worldwide and a multi-billion market. Biomolecular drug development is typically a funnel-like process that begins with a large number of binding protein candidates that are subjected to high-throughput in vitro tests, followed by in vivo experiments using disease model organisms. The transfer of in vitro results to model organisms and subsequently into patients is inherently difficult due to two fundamental limitations: 1) in vitro assays cannot test for appropriate biodistribution of binding proteins, and 2) in vivo studies are limited heavily in throughput compared to in vitro experiments, thus they represent an enormous bottleneck of drug development. In the proposed project, our goal is to demonstrate that a recently developed paradigm-shifting technology (patent filed on October 31, 2016) can overcome both of these problems while massively reducing animal consumption for drug development. The potential of our technology, which is termed NestLink, will be shown in the context of glioblastoma, an almost universally lethal brain cancer, frequently accompanied by the overexpression of EGFR (epidermal growth factor receptor), a well-known tumor marker. The research group of Prof. Markus Seeger at the Institute of Medical Microbiology (UZH) recently developed an efficient in vitro display platform for the identification of synthetic nanobodies, so called sybodies. The platform will initially be used to generate a diverse pool of EGFR-binder candidates. Subsequently, NestLink will be applied to systemically inject the pool of anti-EGFR nanobodies into a mouse glioblastoma model bearing an EGFR-overexpressing tumor. This animal experiment will be carried out under the supervision of Dr. Johannes vom Berg at the Institute of Laboratory Animal Sciences (UZH), an expert for animal trials and pre-clinical glioblastoma research. NestLink will then be used to track all individual EGFR-binders at once within various individual mouse tissues.