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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 Protein-basierte Medikamente im Menschen zu testen. Es wird untersucht, wie effizient die Methode in diesem Kontext tatsächlich ist.
Lay summary

Die Entwicklung Protein-basierter Medikamente ähnelt typischerweise einem Trichter. Eine grosse Anzahl von Medikamentkandidaten wird in vitro in High-throughput-Verfahren getestet, gefolgt von einer kleineren Anzahl Tests in Modellorganismen. Der Tansfer von Erkenntnissen aus in vitro Tests in Modellorganismen und danach in Patienten hat zur Zeit zwei fundamentale Limiten: 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 die neue NestLink-Technologie beide erwähnten Limiten der Protein-basierten Medikamentenentwicklung überwinden kann. Ausserdem werden weitere mögliche Anwendungsgebiete von NestLink, insbesondere die Detektion von Antikörpern auf Zelloberflächen, erforscht.
Direct link to Lay Summary Last update: 14.06.2017

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Employees

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. 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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