Public Funding for Lonza Biologics PLC

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Awaiting Public Project Summary

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Awaiting Public Project Summary

Production of biopharmaceuticals that are toxic or have detrimental effects on the growth of the host cell line is very challenging. To overcome this challenge researchers have developed a number of promoters allowing control of protein expression during the bioproduction process. The primary aim of that research was to enable a 2-step bioprocessing platform to be developed whereby the expression of the gene of interest is switched on after sufficient biomass has been obtained or a gene that has negative effects on DSP or product quality can be silenced. This type of process is particularly attractive for the production of difficult to express or toxic proteins where expression is deleterious to the cell or where host cell protens co-purify with the final product and complicate purification strategies. However, to date these promoters have proven to have insufficient control for the task with leaky expression observed or the need for multiple rounds of transfection and cell line selection to achieve the requisite control. Ideally the activity of those promoters should be inducible/repressible by a stress stimulus (chemical or physical) during the production process and allow tight control over the expression levels to ensure maximum productivity and high quality of the final product. To this end Synpromics has used its proprietary technology to develop new synthetic inducible/repressible systems that have demonstrated exquisite control of gene expression. These systems offer significant advantages over the currently available systems as they are small in size, can be driven from one plasmid, offer fine tuning of gene expression, are driven by physiological or chemical stimulus that are non-toxic and are therefore ideal for improving productivity and minimising costs during bioproduction in CHO cells. Using these novel gene expression control tools Synpromics and Lonza will embark on an 18 month exemplification program to validate the use of these control tools in a GMP environment using well characterized model proteins. Once validated in an industrially relevant situation, these tools will then be used to design a process for a therapeutic construct and a manufacturing process will be developed. In addition to this outcome, the validation of Synpromics's control tools will increase the flexibility of bioproduction and offer the industry new powerful tools with which to increase the number and type of proteins that can be produced from CHO cells.

Chinese hamster ovary (CHO) cells are the main production host for >US$145billion/yr of protein biologics used as medicines for a range of diseases. The CHO platform is mature when considering production of monoclonal antibodies, but new format non-native molecules such as fusion proteins, antibody fragments and other exotic molecules remain difficult to express (DTE) in this, or any other host. This project builds upon proof of concept work demonstrating that engineering the CHO chassis, together with growth media manipulation, increases both the yield and quality of a number of DTE proteins that are in development for application to unmet clinical needs and diseases with no current treatments. The project will advance the technology readiness level of our preliminary findings beyond proof-of-concept to deliver the commercialization of new CHO cell systems for DTE proteins and associated bioprocesses ready for industrial application to produce these important new medicines.

To develop novel selection systems generating more productive cell lines with better quality and higher yield, reducing risk in the development of new therapeutic proteins.

This project will aim to develop proof-of-principle approaches for improving CHO cell platforms for recombinant protein expression and bioproduction, based on combining: (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.

This project will establish a world-class consortium to innovatively address a critical step in administering cellular products for the cell therapy industry (CTI) – a robust validated platform technology to enable post-manufacturing process steps to be carried out at the point of care (PoC). This Closed-point-of-care-Preparation device will increase patient safety and enable a new generation of cell therapies that would otherwise have to be shipped fresh with its inherent logistics problems. This will address every step after a cell therapy leaves the central GMP facility through to the completion of the loading of the clinical implantation device at the PoC. Presently no such integrated closed PoC technology exists. Requirement for such a device is well recognised by CTI.

To configure, specify and apply a Science Data Management system for cell culture, molecular biology, purification development. Support integration with corporate systems and GMP validation. To configure SDM system for analytical chemistry, integration with laboratory instrumentation and instrument software.

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The British Regen Industry Tool Set (BRITS) is an industry driven project aimed at establishing reliable market data and creating both detailed bioprocess economics models and higher level business models for integration into a highly valuable and timely set of decisional tools. The individual components will themselves be highly novel, and the final integrated tool set will be a major step change for the cell therapy industry. BRITS will encompass the entire supply chain. This will including direct links through the main innovation routes available within the NHS. Via its wider business benefit activities BRITS will interact with all the UK stakeholders to facilitate the uptake of the outputs of the project and build and maintain the vital linkages between the diverse stakeholders in order to promote the joined-up approach that will be required if the UK is to be at the international forefront of cell therapy, not just scientifically but also commercially.

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