Award details

13 ERA IB: Investigating NOvel VAluable bio-Therapeutics and Expression systems

Reference	BB/M001164/1
Principal Investigator / Supervisor	Professor Alan Dickson
Co-Investigators / Co-Supervisors	Professor David Thornton
Institution	The University of Manchester
Department	Chem Eng and Analytical Science
Funding type	Research
Value (£)	288,078
Status	Completed
Type	Research Grant
Start date	14/07/2014
End date	13/11/2017
Duration	40 months

Abstract

The production of IgG's has revolutionized the biotech industry with products used for the treatment of cancer and immune disorders. The success of standard IgG's built over years of optimization, has led to high expectations for novel recombinant proteins (rPs), "third generation" biopharmaceuticals. Timeframes, stakeholders and commercial pressures are different to those of a decade ago and the manufacture of new rPs is challenging. The promise of commercial and clinical returns from new rPs such as fusion proteins (for novel disease targeting), IgA (the most abundant Ig isoform, for treatment of IgA deficiencies, cancer) and secreted mucins (for disease therapy, vaccines) is obvious but these are unexpectedly difficult to manufacture, with unpredictable failures to generate any (or enough) product. Studies accessible to scrutiny indicate unpredictable limitations occur at the level of translation, folding and post-translational processing (especially N- and O-glycosylation). This project will develop new animal (Chinese hamster ovary, CHO) and plant (tobacco) cell expression technologies, and establish bioprocesses, for the production of difficult to express and novel rPs. Objectives are to (1) define the molecular events linked to production of difficult to express rPs; (2) engineer new expression technologies for enhanced synthesis, folding and assembly of such molecules via manipulation of translational and secretory machinery; (3) engineer CHO cell lines for the efficent N- and O-glycosylation of IgAs; (4) engineer and establish plant cell lines capable of producing industrially relevant amounts of IgAs with bespoke glycosylation; (5) develop an understanding of the metabolic load on the cell expressing challenging rPs; and (6) establish upstream and downstream processes for the new expression technologies and rPs and evaluate the potential for scale-up.

Summary

The production of IgG's has revolutionized the biotech industry with products used for the treatment of cancer and immune disorders. The success of standard IgG's built over years of optimization, has led to high expectations for novel recombinant proteins (rPs), "third generation" biopharmaceuticals. Timeframes, stakeholders and commercial pressures are different to those of a decade ago and the manufacture of new rPs is challenging. The promise of commercial and clinical returns from new rPs such as fusion proteins (for novel disease targeting), IgA (the most abundant Ig isoform, for treatment of IgA deficiencies, cancer) and secreted mucins (for disease therapy, vaccines) is obvious but these are unexpectedly difficult to manufacture, with unpredictable failures to generate any (or enough) product. Studies accessible to scrutiny indicate unpredictable limitations occur at the level of translation, folding and post-translational processing (especially N- and O-glycosylation). This project will develop new animal (CHO) and plant (tobacco) cell expression technologies, and establish bioprocesses, for the production of difficult to express and novel rPs. Objectives are to (1) define the molecular events linked to production of difficult to express rPs; (2) engineer new expression technologies for enhanced synthesis, folding and assembly of such molecules via manipulation of translational and secretory machinery; (3) engineer CHO cell lines for the efficent N- and O-glycosylation of IgAs; (4) engineer and establish plant cell lines capable of producing industrially relevant amounts of IgAs with bespoke glycosylation; (5) develop an understanding of the metabolic load on the cell expressing challenging rPs; and (6) establish upstream and downstream processes for the new expression technologies and rPs and evaluate the potential for scale-up. The consortium will seek protection of IP for the new expression technologies, as these will be of immense interest to industry.

Impact Summary

Who will benefit from this research? In terms of research findings, the primary beneficiaries will be researchers in the academic and biopharmaceutical sectors who are interested in understanding the limitations upon the production of difficult to express recombinant proteins in mammalian and plant expression systems with respect to product yield and quality in industrially relevant systems. As such, this proposal is relevant to all those academics and industrialists who are interested in the process and/or manufacturing of proteins and wish to deliver them at increased yield in a functionally active form at lower cost. The impacts of this research will therefore be national and international. They will benefit the following: (1) those in the research fields of recombinant protein synthesis, purification and development; (2) the academic and industrial bioprocessing and scientific communities; (3) the biopharmaceutical sector; ultimately the National Health Service (and thus the wider public, its patients); (4) the UK economy through the development of new methods to produce novel and larger amounts of increasingly important 'bio-drugs' (i.e. recombinant proteins) more efficiently and thus at lower cost thereby, (v) benefitting health-care providers and their patients. How will they benefit? The major impact of this work will be to provide both industry and academia (i) with a much better understanding of the biology underpinning difficult to express proteins (particularly heavily glycosylated proteins) and their control in an industrial sense with respect to cell growth and the production and quality of recombinant proteins in mammalian and plant cells, and (ii) the subsequent application of this information to generate new tools and methodologies (engineered cell lines and downstream processing methodology). This will generate expression systems with an increased capacity for recombinant protein production and facilitate the faster development of cell lines expressing novel recombinant proteins, specifically IgA and mucin type molecules that can then be used for the treatment of novel disease indications. The ability to produce these high cost drugs will ultimately allow the development of new therapies base upon such molecules and access to these drugs to a wider sector of the population both nationally and internationally, thus contributing to health and quality of life. In order to ensure that this is delivered, our results will be published in peer-reviewed high-quality journals and presented at relevant academic and industrial conferences. We will publicise our findings through our websites, press releases, BBSRC Business and via the local media and our own public engagement activities, including national and local science fairs and working with local schools. We will build upon our industrial links to translate our findings into applications in the recombinant protein production field. Regular teleconferences and meetings between the applicants and PDRAs, and the use of a sharepoint for all data generated in the project, will ensure close coordination between the activities at the institutions, such that findings in one lab are rapidly conveyed to the others to inform and develop the project in a timely and efficient way.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Industrial Biotechnology, Pharmaceuticals, Synthetic Biology
Research Priority	X – Research Priority information not available
Research Initiative	ERA Industrial Biotechnology (ERA-IB) [2013-2014]
Funding Scheme	X – not Funded via a specific Funding Scheme

Associated awards:

BB/M000699/1 13 ERA IB: Investigating NOvel VAluable bio-Therapeutics and Expression systems

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