Award details

Genome engineering and synthetic biology approaches for improving industrial CHO cell production of biologics

Reference	BB/M028933/1
Principal Investigator / Supervisor	Professor Mark Isalan
Co-Investigators / Co-Supervisors
Institution	Imperial College London
Department	Life Sciences
Funding type	Research
Value (£)	98,504
Status	Completed
Type	Research Grant
Start date	01/08/2015
End date	31/10/2016
Duration	15 months

Abstract

The production of biopharmaceuticals is part of a growing multi-billion dollar industry. The current standard for mammalian CHO recombinant (rP) production relies on constitutive promoters to control rP transcription. While this has long formed part of a platform process suitable for non-engineered monoclonal antibodies (mAbs), issues regarding productivity and stability are increasingly being faced as the diversity of rP proteins increases.This 12-month project will aim to develop proof-of-principle approaches for an innovative, universal, cell line platform for the expression of recombinant proteins that are characterized as "difficult-to-express" or that exhibit cellular toxicity. Using Lonza's proprietary CHOK1SV cell line and GS Gene Expression system, the project will combine: (i) rational site-targeted genome engineering (ii) gene circuit design, employing elements of genetic feedback regulation and conditional regulation. In this way, difficult-to-express proteins will be tested against a benchmark gold-standard expression protein, with the aim of improving protein production in a self-regulating, widely-applicable manner.

Summary

Biologics are protein-based biopharmaceutical drugs that are used in a variety of diseases. The overall market for biopharmaceuticals is steadily increasing and in 2013 generated sales in excess of $140 billion. The Lonza GS platform is considered industry leading with 18 marketed products, and over 100 in active human trials. Despite this success, there are increasing numbers of "difficult-to-express" biologics reaching the pipeline. The new technologies of rational genome and gene circuit engineering promise new ways of regulating biologic expression to maximise production, while reducing toxicity. The aim is to build "genetic thermostats" to prevent toxic proteins from shutting down cellular production altogether, using genetic feedback. The final goal of this feasibility study is to pave the way for the development of a robust and one-fits-all cell line platform for the production of "difficult-to-express" biologics.

Impact Summary

As described in proposal submitted to IUK

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Industrial Biotechnology, Pharmaceuticals, Synthetic Biology, Technology and Methods Development
Research Priority	X – Research Priority information not available
Research Initiative	Industrial Biotechnology Catalyst (IBCAT) [2014-2015]
Funding Scheme	X – not Funded via a specific Funding Scheme

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