Development of a novel inducible expression system for the manufacture of therapeutic proteins from CHO cells.

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.