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An in vivo platform to select and evolve aggregation-resistant proteins.

Jessica S Ebo1,2, Janet C Saunders1,2,3,3, Paul W A Devine1,2,3

  • 1Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.

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Scientists developed a new assay to detect and prevent protein aggregation in biopharmaceuticals. This method aids in creating more stable antibody fragments, improving drug manufacturing and potentially treating diseases like amyloidosis.

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Area of Science:

  • Biochemistry
  • Biotechnology
  • Protein Engineering

Background:

  • Protein biopharmaceuticals are crucial but prone to aggregation during production and storage.
  • Predicting aggregation is challenging as it's linked to non-native states, not just thermodynamic stability.
  • Current methods for identifying stable protein sequences are inefficient.

Purpose of the Study:

  • To develop a novel screening method for identifying and engineering aggregation-resistant protein sequences.
  • To create a tool for early-stage industrial development of 'manufacturable' biopharmaceuticals.
  • To investigate protein aggregation mechanisms relevant to biopharmaceutical manufacturing and amyloid diseases.

Main Methods:

  • An assay was engineered in E. coli periplasm linking protein aggregation to antibiotic resistance.
  • This assay functions as a direct sensor for the innate aggregation of antibody fragments.
  • Directed evolution was employed using this assay to screen for aggregation-resistant single-chain variable fragments (scFvs).

Main Results:

  • The assay successfully identified and facilitated the evolution of aggregation-resistant scFv sequences.
  • Engineered aggregation-resistant sequences were confirmed when reformatted as immunoglobulin Gs (IgGs).
  • Comparative analysis of mutational profiles across different immunoglobulin scaffolds provided insights into aggregation mechanisms.

Conclusions:

  • The developed assay is a powerful tool for screening and evolving aggregation-resistant biopharmaceuticals.
  • This method enables early-stage identification of 'manufacturable' protein therapeutics.
  • The approach is applicable to understanding protein aggregation in both industrial contexts and diseases like amyloidosis.