Automated optimisation of solubility and conformational stability of antibodies and proteins.

Autor: Rosace A; Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield road, CB2 1EW, Cambridge, UK.; Master in Bioinformatics for Health Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.; Institute for Research in Biomedicine (IRB), The Barcelona Institute of Science and Technology, Barcelona, Catalonia, Spain., Bennett A; Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield road, CB2 1EW, Cambridge, UK.; Department of Mammalian Expression, Global Research Technologies, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark.; BRIC, Faculty of Health and Medical Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark., Oeller M; Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield road, CB2 1EW, Cambridge, UK., Mortensen MM; Department of Purification Technologies, Global Research Technologies, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark.; Faculty of Engineering and Science, Department of Biotechnology, Chemistry and Environmental Engineering, University of Aalborg, Fredrik Bajers Vej 7H, 9220, Aalborg, Denmark., Sakhnini L; Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield road, CB2 1EW, Cambridge, UK.; Department of Biophysics and Injectable Formulation 2, Global Research Technologies, Novo Nordisk A/S, Måløv, 2760, Denmark., Lorenzen N; Department of Biophysics and Injectable Formulation 2, Global Research Technologies, Novo Nordisk A/S, Måløv, 2760, Denmark., Poulsen C; Department of Mammalian Expression, Global Research Technologies, Novo Nordisk A/S, Novo Nordisk Park 1, 2760, Måløv, Denmark., Sormanni P; Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield road, CB2 1EW, Cambridge, UK. ps589@cam.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Apr 06; Vol. 14 (1), pp. 1937. Date of Electronic Publication: 2023 Apr 06.
DOI: 10.1038/s41467-023-37668-6
Abstrakt: Biologics, such as antibodies and enzymes, are crucial in research, biotechnology, diagnostics, and therapeutics. Often, biologics with suitable functionality are discovered, but their development is impeded by developability issues. Stability and solubility are key biophysical traits underpinning developability potential, as they determine aggregation, correlate with production yield and poly-specificity, and are essential to access parenteral and oral delivery. While advances for the optimisation of individual traits have been made, the co-optimization of multiple traits remains highly problematic and time-consuming, as mutations that improve one property often negatively impact others. In this work, we introduce a fully automated computational strategy for the simultaneous optimisation of conformational stability and solubility, which we experimentally validate on six antibodies, including two approved therapeutics. Our results on 42 designs demonstrate that the computational procedure is highly effective at improving developability potential, while not affecting antigen-binding. We make the method available as a webserver at www-cohsoftware.ch.cam.ac.uk.
(© 2023. The Author(s).)
Databáze: MEDLINE
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