Global spending on medicines is expected to grow to nearly $1.2 trillion by 2016 and biologics are predicted to contribute an ever-increasing proportion of this ($200-$220 billion, IMS Health Figures: The Global Use of Medicines: Outlook Through 2016). Biologics can be large complex proteins such as hormones (e.g. insulin) or antibodies (e.g. the anti-arthritic blockbuster agent Remicade) or smaller antibody fragments (e.g. anti-TNF mAB fragment, Cimzia). Biologics have been highly successful both as therapeutics and as diagnostics. However, large complex molecules like monoclonal antibodies are costly to manufacture; the biopharmaceutical industry is therefore interested in new strategies and production platforms to reduce cost. Indeed, the exceptionally high cost of many biologics has resulted in restricted prescribing in humans and limited transfer of biologic treatment options to companion and livestock animals. This project represents an opportunity to harness the novel techniques of synthetic cell bioengineering to establish a UK platform for the optimisation and manufacture of biologics that is robust, flexible/adaptable yet more affordable with the impact of making currently prohibitively expensive therapeutics more widely available and expanding the market into animal health.
Current technology relies on the biologic expressing transgenes integrating randomly into the host chromosome resulting in highly variable protein expression between transfectants. It has been shown that site of integration has more influence on expression level than gene copy number. In order to optimize insertion site targeting and expression we will develop “safe haven” landing pads for highly efficient site specific recombinase mediated insertion of genetic constructs into sites within the CHO chromosome identified as stable, free of silencing and high expression.
A key issue with CHO cells is genome plasticity, rearrangement and instability that often result in the loss of the transgenes. In parallel we will use the recently BBSRC funded Edinburgh Genome Foundry (Rosser PI and co-director) to design and synthesise novel mammalian neochromosomes for orthogonal expression of transgenes in CHO cells providing enhanced predictability and stability. These neochromosomes will be able to carry advanced synthetic biology circuits for control of cellular processes.
We will develop a series of orthogonal synthetic promoters for high level, tightly controlled or inducible regulation of host pathways and transgenes to minimize metabolic and transcriptional burden for improved production.
This collaborative project involves the Rosser lab along with the labs in the University of York -
Prof Bob White
Prof Nia Bryant
Dr Daniel Ungar
