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

Abstract:

:Protein biopharmaceuticals are highly successful, but their utility is compromised by their propensity to aggregate during manufacture and storage. As aggregation can be triggered by non-native states, whose population is not necessarily related to thermodynamic stability, prediction of poorly-behaving biologics is difficult, and searching for sequences with desired properties is labour-intensive and time-consuming. Here we show that an assay in the periplasm of E. coli linking aggregation directly to antibiotic resistance acts as a sensor for the innate (un-accelerated) aggregation of antibody fragments. Using this assay as a directed evolution screen, we demonstrate the generation of aggregation resistant scFv sequences when reformatted as IgGs. This powerful tool can thus screen and evolve 'manufacturable' biopharmaceuticals early in industrial development. By comparing the mutational profiles of three different immunoglobulin scaffolds, we show the applicability of this method to investigate protein aggregation mechanisms important to both industrial manufacture and amyloid disease.

journal_name

Nat Commun

journal_title

Nature communications

authors

Ebo JS,Saunders JC,Devine PWA,Gordon AM,Warwick AS,Schiffrin B,Chin SE,England E,Button JD,Lloyd C,Bond NJ,Ashcroft AE,Radford SE,Lowe DC,Brockwell DJ

doi

10.1038/s41467-020-15667-1

subject

Has Abstract

pub_date

2020-04-14 00:00:00

pages

1816

issue

1

issn

2041-1723

pii

10.1038/s41467-020-15667-1

journal_volume

11

pub_type

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