Project

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Biodistribution analysis of 1’000 antibody drug candidates in one single mouse

English title Biodistribution analysis of 1’000 antibody drug candidates in one single mouse
Applicant Egloff Pascal
Number 175192
Funding scheme Bridge - Proof of Concept
Research institution
Institution of higher education University of Zurich - ZH
Main discipline Biochemistry
Start/End 01.01.2018 - 31.12.2018
Approved amount 129'800.00
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All Disciplines (4)

Discipline
Biochemistry
Molecular Biology
Pharmacology, Pharmacy
Experimental Cancer Research

Keywords (4)

Phage display; Tumor targeting; Protein therapeutics; Protein library

Lay Summary (German)

Lead
Eine neue Methode zur Bindeproteingenerierung für pharmazeutische Anwendungen, genannt NestLink, wurde kürzlich entwickelt. Die Methode hat das Potenzial die Anzahl Tierversuche signifikant zu reduzieren, die man benötigt, um gewisse Medikamente im Menschen zu testen. Es wird untersucht, wie effizient die Methode in diesem Kontext tatsächlich ist.
Lay summary

Für die Entwicklung Protein-basierter Medikamente wird typischerweise eine grosse Anzahl von Medikamentkandidaten in High-throughput-Verfahren in vitro getestet. Danach wird die Kandidatenanzahl stark eingeschränkt und Tests an Modellorganismen werden durchgeführt. Der Tansfer von Erkenntnissen aus in vitro Tests zu den Modellorganismen und danach in Patienten hat zur Zeit zwei fundamentale Probleme: 1) Es ist in in vitro Tests unmöglich zu sehen, ob sich Medikamentkandidaten in die relevanten Gewebe eines Körpers verteilen. 2) Studien an Modellorganismen haben grundsätzlich einen sehr geringen Durchsatz.

In diesem Projekt wird untersucht, ob eine neue Technologie beide erwähnten Probleme der Protein-basierten Medikamentenentwicklung überwinden kann. Ausserdem werden weitere mögliche Anwendungsgebiete der Technologie, insbesondere die Detektion von Antikörpern auf Zelloberflächen, erforscht.
Direct link to Lay Summary Last update: 11.06.2019

Responsible applicant and co-applicants

Employees

Publications

Publication
Engineered peptide barcodes for in-depth analyses of binding protein libraries
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.
Engineered Peptide Barcodes for In-Depth Analyses of Binding Protein Ensembles
EgloffPascal (2018), Engineered Peptide Barcodes for In-Depth Analyses of Binding Protein Ensembles, in bioarxiv, 1-2.
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Datasets

Engineered Peptide Barcodes for Binding Protein Generation

Author Roschitzki, Bernd
Publication date 15.01.2019
Persistent Identifier (PID) PXD009301
Repository Proteomexchange


Engineered Peptide Barcodes for In-Depth Analyses of Binding Protein Ensembles

Author Egloff, Pascal
Publication date 01.08.2019
Persistent Identifier (PID) PRJEB25673
Repository European Nucleotide Archive


Collaboration

Group / person Country
Types of collaboration
Institute of Laboratory Animal Science University of Zurich/Dr. Johannes vom Berg Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Institute of Medical Microbiology/Dr. Iwan Zimmermann Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Abstract

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.
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