Abstract
It currently takes over $800 million and around 10-15 years for a new medicinal product to reach the market. Over one third of the products currently under development are biopharmaceuticals; medicines in which the active ingredients are large biological molecules, such as proteins or nucleic acids. Preparations containing monoclonal antibodies (e.g. for the treatment of immune disorders, cancer and infection) are currently the largest, and most important class of biopharmaceutical. The development of biopharmaceuticals is therefore both costly and time intensive. The approaches employed to design/discover new biopharmaceutical agents are very different to traditional synthetic drug-molecule based medicines, with large biological molecules bringing new challenges in terms of development processes during medicine design (formulation), manufacture and storage. At present this is often reflected in the high market price of biopharmaceutical therapeutics, and the pressure to provide cheaper products more quickly has resulted in a demand for new analytical methods/approaches to address issues which conventional drug approaches are struggling to meet. One such issue which directly impacts on protein-based medicines, and which can adversely affect any stage of the development process, is the unpredictable tendency of protein molecules to stick together, to form assemblies of molecules termed aggregates. During medicine manufacture, aggregation can result in highly viscous solutions, causing problems during processing and product packaging. It can also lead to decreased product stability, and hence difficulties in estimating product shelf-life. Within the final medicine, aggregation of the key therapeutic active ingredient can ultimately reduce the efficacy of the medicine and can in extreme cases produce severe unwanted side effects in the patient. By identifying as early as possible within the drug development process, which biomolecules have a tendency to aggregate (and also the conditions which encourage/discourage this aggregation) then the effort, costs and risks to patients associated with development of the therapeutic could therefore be significantly reduced. In this project we aim to explore the feasibility of addressing this difficult challenge, using microcantilever detection approaches (which employ ultrasensitive springs to measure interactions between biological molecules). Ultimately we aim to develop a novel approach to screen potential biological 'active' molecules for their tendency to aggregate through the use of devices capable of detecting the very early stages of aggregation or changes in molecular properties consistent with aggregation behaviour. Within this one year project, our aim is to test and explore the feasibility of a range of potential approaches to achieve this goal. Importantly, our experimental programme will use both model and therapeutically relevant proteins (including monoclonal antibodies). In close collaboration with the pharmaceutical industry the devices identified in these preliminary studies will also be assessed for viability and scale up for use in an industrial context. A sizable and increasing academic and industrial community have identified the occurence of protein aggregation as a critical issue in a number of fields, and have sought new methods to study this phenomenon. This project has the potential to provide an entirely new approach to detecting and investigating the origins of aggregation at its earliest stage. In the longer-term, the work, if built upon will impact upon significant areas of biotechnology and healthcare. Indeed, the methods developed could play an important role in bringing new generation medicines to the market in a cost-efficient and timely manner, and would thus have a very significant impact on public health and quality of life.
Technical Summary
Biopharmaceuticals are medicinal products where the active ingredients are large biological molecues (e.g. proteins or nucleic acids), and they constitute over a third of the medicines currently under development. Despite their increasing number, they continue to present many biomolecule specific challenges during product development - the considerable time and resource required to address these is ultimately reflected in products with high market prices. The vast majority of products have protein/peptide actives, with a large proportion of these based on monoclonal antibodies (mAbs). Aggregation of such molecules can be unpredictable and result in significant difficulties during formulation, manufacture and storage. Due to the severe immune responses that can be observed in patients if aggregates are administered, there is also a stringent regulatory environment associated with the levels of aggregate permissible in a final formulation. Identification of the tendency of a molecule to aggregate - and under what conditions - as early as possible within the development process could therefore help to significantly reduce the time, effort and costs associated with development, and also the potential risks to patients. The urgent need to address this issue is reflected by the support of MedImmune for this feasibility proposal. The proposed 12-month project will investigate the feasibility of using microfabricated cantilever approaches for the detection of protein aggregation propensity early within biopharmaceutical development. Importantly, through the 'development of new enabling tools' and obtaining biophysical data to extend our fundamental understanding of protein aggregation within biopharmaceuticals, the project aligns with the broad themes of BRIC2, and more specifically priority areas 1 (bioprocessing research challenges for protein products) and 4 (analytics for bioprocessing).
Planned Impact
Who will benefit from this research, and how? Statements on global market sizes are in general misleading at early stages in development, such as within this project, as the potential market share cannot easily be assessed. Nevertheless, it is useful to recognize that the biopharmaceutical market is immense (biopharmaceutical products accounted for 10% in 2006 of the total global market and is projected to account for about 15% or US$182.5 billion by 2015 (Biopharmaceuticals: A Global Market Overview, Industry Experts, April 2010)) and represents the one real long-term growth area in pharmaceuticals, a key UK market sector which has suffered major downsizing in recent years. The core project aim is to explore the feasibility of microcantilever detection methods for the early-stage detection of molecules susceptible to aggregation within biopharmaceutical development. The difficulties in predicting which molecules may or may not be prone to aggregation is currently a key barrier to bringing a new generation of biomacromolecular based treatments to the market. This hence represents a potential massive loss in benefits to public health, as well as a financial loss to the UK based biopharmaceutical sector. The urgent need to address this question is reflected by the support of MedImmune for this feasibility proposal, and within the broad themes of BRIC2 (and specifically priority areas 1 and 4). The long-term public benefits are wide ranging. Clearly the methodologies developed could play an important role in helping to bring viable bio-therapeutic formulations to the market in a cost-efficient and timely manner and would thus have a very significant impact on public health and quality of life. The knowledge gained would also have an impact in complementary areas such as sensors, diagnostics and food. What will be done to ensure that they have the opportunity to benefit? Within the proposed one-year project we aim to establish a clear proof-of-principle of the use of microfabricated levers as a viable and scalable approach to aggregation propensity screening. With the aid of our industrial supporters and the School of Pharmacy Business Development Officer, Dr Mark Gilbert (in-kind contribution) we will also carry out a preliminary study of the IP/patent landscape in the application area and collate market potential data. This will enable efforts to attract follow-on funding to be informed by a sound basis of the potential of the IP and the future needs of the healthcare and industrial communities. The ultimate commercial exploitation of the technology will benefit the industries to which it is licensed, or spun in to and hence the economy through the creation of value and new employment. The long-term benefits of this work will be achieved, by preference through follow-on support from the second round of BRIC2 funding, to achieve a level of outputs suitable to attract translation funding (such as from the Wellcome Foundation, TSB, an investment fund or direct industrial support, for example through a KTP). The applicants, supported by the Universities Research Innovation Services will also identify key application advances that have the potential to develop new/extend current IP and the development of an exploitation strategy. We will also aim to help maximise future technology transfer through engagement with regional and national networks (eg. East Midlands Development Agency, bioKneX, Medilink, East Midlands Innovation, iNets and KTNs), Nottingham University's wholly owned TSB funded healthcare-focused technology transfer company, Eminate Ltd and through extensive current industrial contacts. We will through these routes, or through direct contact engage industrial interest to support the project, and ultimately to form a potential partnership database. This process has already begun with support from MedImmune.