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Automated optimisation of solubility and conformational stability of antibodies and proteins

Author

Listed:
  • Angelo Rosace

    (University of Cambridge
    Universitat Pompeu Fabra
    The Barcelona Institute of Science and Technology)

  • Anja Bennett

    (University of Cambridge
    Global Research Technologies, Novo Nordisk A/S
    BRIC, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Marc Oeller

    (University of Cambridge)

  • Mie M. Mortensen

    (Global Research Technologies, Novo Nordisk A/S
    University of Aalborg)

  • Laila Sakhnini

    (University of Cambridge
    Global Research Technologies, Novo Nordisk A/S)

  • Nikolai Lorenzen

    (Global Research Technologies, Novo Nordisk A/S)

  • Christian Poulsen

    (Global Research Technologies, Novo Nordisk A/S)

  • Pietro Sormanni

    (University of Cambridge)

Abstract

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.

Suggested Citation

  • Angelo Rosace & Anja Bennett & Marc Oeller & Mie M. Mortensen & Laila Sakhnini & Nikolai Lorenzen & Christian Poulsen & Pietro Sormanni, 2023. "Automated optimisation of solubility and conformational stability of antibodies and proteins," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37668-6
    DOI: 10.1038/s41467-023-37668-6
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    1. Jessica S. Ebo & Janet C. Saunders & Paul W. A. Devine & Alice M. Gordon & Amy S. Warwick & Bob Schiffrin & Stacey E. Chin & Elizabeth England & James D. Button & Christopher Lloyd & Nicholas J. Bond , 2020. "An in vivo platform to select and evolve aggregation-resistant proteins," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
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