Mapping functionally important and stabilising regions in biotherapeutic proteins - GCSF as a model

Building on the collaborative work established between the two laboratories over 3 previous studentships, this project will establish the areas critical to function and stability for the G-CSF biomolecule, concentrating both on regions identified as important for 3-D structural stability (from computer modelling and hydrophobic marker dye binding), and those linked to improved /impaired biological activity. This will continue to expand the knowledge base of the impact of structure and formation on the propensity for protein to aggregate in the liquid state, already developed in Prof Dalby's Group over recent years for a variety of biomolecules. This will then be extrapolated and compared to the freeze-dried state using HDX Mass spectrometry and 2-D NMR to establish whether similar regions of instability apply in the dried state. This will lead to important conclusions for the formulation development of biotherapeutics, a critical area as this group of products are becoming the dominant player in the 21st Century pharmaceutical market.

The benefits of the proposed EPSRC Centre for Doctoral Training (CDT) aligned to the EPSRC Centre for Innovative Manufacture of Emergent Macromolecular Therapies will be significant. The CDT will address an acute skills storage of trained manpower, needed to take this industry forward for the benefit of the UK, and ultimately to improve the levels of healthcare provision nationally. This is a radical new opportunity for the industry which suffers from a lack of joined up thinking and hence tends to operate in discrete silos of expertise. The integrated approach offered by the CDT would pay high dividends. UK companies will benefit from access to highly skilled doctorates who will each have benefited from a wide and interdisciplinary research approach created by the CDT. Macromolecular medicines are complex and labile so that bioprocess development times and costs tend to be high due to unforeseen issues that occur during scale-up of the manufacturing process. Currently there is little scope to alter a manufacturing process because the effect of changes cannot be readily predicted. This is compounded by lack of individuals skilled in the methods needed. Our transformative CDT research training agenda will allow for the first time engineers and scientists to create the methods and approaches needed for UK companies to genuinely understand and control directly, for the first time, the quality of output during manufacture, in spite of biological variability. By creating and then testing manufacturing models and methods for whole bioprocesses using the resources of a national EPSRC Centre we shall gain fundamental engineering insights crucial for the more effective direction of acquisitions of experimental data and also the improved design and operation of whole bioprocesses. Manufacturing efficiencies will be raised and waste reduced. Such a vision is consistent with recent efforts by the regulatory authorities, and in particular the Quality by Design (QbD) initiative of the International Committee on Harmonisation (ICH), to develop science-based regulatory submissions for approval to manufacture new biological products. The CDT will create a network to provide a conduit for effective knowledge exchange from the very best academic groups in the UK. A key metric of success will be retention of CDT graduates within the industry where they will be effective in the application of Centre concepts with industrial practice and the adoption of the methods created. Potential patients will benefit as the innovations created by the CDT research will significantly aid reduction in development times of macromolecular medicines, which is particularly crucial for those addressing previously unmet clinical needs and the treatment of severe conditions such as arthritis, cardiovascular disease, viral infections and cancers. By providing industry the capabilities and tools to achieve changes to manufacturing processes we shall open up possibilities for major improvements to processes during production and hence reduce costs to the NHS. The capacity to treat conditions such as rheumatoid arthritis much more effectively in ageing populations is vital but it still poses a problem with respect to stretched NHS budgets. A significantly greater number of drugs will be capable of meeting NICE's thresholds and thus benefit extended patient populations. The UK economy will benefit because the academic research and training offered by the CDT will complement the country's strength in bioscience discovery. Collaboration between bioprocess engineers, process modellers manufacturing experts, regulators and physical scientists will ensure effective knowledge and skills transfer between the science and engineering base and UK industry and the regulating agencies. This will strengthen the UK position in the global healthcare market and attract further R&D investment from global business which recognises the UK as a good place to conduct these activities.