The design of miniproteins with enhanced in-vivo stability
The Technology
To achieve high therapeutic effect and potency protein-based drugs must exhibit high serum stability.
Antibodies are highly successful as therapeutic agents since they can bind their targets with high affinity and exhibit very high stability following administration. Thus, therapeutic antibodies can be injected seldom and yet retain high serum levels for long periods of time.
The mechanism allowing high serum stability of antibodies utilizes recycling in a variety of cell types expressing Fc receptors (FcRn) on the cell surface. Antibodies in the serum are non-selectively trapped in the endocytic vesicle together with FcRn. Upon acidification of the endosome, antibodies bind to FcRn through their Fc region and are protected from degradation. These endosomes are then recycled by fusion to the cell membrane exposing the Fc-FcRn complex to neutral pH leading to the release of the antibody back into the serum.
Our aim is to design miniproteins that can mimic Fc’s recycling pathway and thus extend serum half-life, while incorporating Fc fragment’s pH sensitivity such that it will bind at acidic pH (pH 6) and be released at neutral pH or higher (pH 7.2 or higher). Genetic fusions to these miniproteins will extend the serum half-life of protein therapeutics, making the miniproteins a broad platform for the extension of therapeutic protein’s biological half-life.
The advantages of this designed miniprotein mimic for Fc are its small size, stability, being capable of E. Coli expression and the possibility to further design it for higher order structures including dimers, trimers etc.
Advantages
- Miniprotein with genetic fusion, instead of chemical
- A novel patentable biological half-life extending solution
- Easily expressed in prokaryotic systems like E. coli
Patent Status
Know-how based technology. IP will be filed on the new generated products
Principal Investigator
Prof. Amir Aharoni, Department of Life Sciences and NIBN, Ben-Gurion University of the Negev, Israel