Microfabricated cantilever methods as nanoscale screens for early indicators of protein aggregation; a feasibility study

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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.