Beyond Antibodies - Pick 'n' Mix Modified Apoferritin Subunits Harnessing Self-assembly for Targeted Therapy

This project will use both protein engineering and chemical conjugation methods to allow the creation of a portfolio of new functionalized apoferritin (AFt) subunits that have been tailored to target tumours (breast, gastric, ovarian cancer) that overexpress Human epidermal growth factor receptors (HERx/EGFRs/ErbBx). These will gain specific tumour targeting abilities through the attachment of molecules with unique chemical signatures that have very high affinities for the Human epidermal growth factor receptors. The targeting ligands will be introduced using a combination of site-specific un-natural amino acid mutagenesis and subsequent bio-orthogonal 'click' chemistry reactions as well as highly peptide sequence selective enzyme-mediated conjugation reactions. The self-assembly abilities of the engineered nanocarriers will be used to encapsulate a range of drug molecules and the project will investigate the mechanism and rate of release of these by the engineered apoferritin using fluorescence and a range of spectrometry methods. The nanocarriers will be fully characterized using a range of techniques including TEM, DLS, MS, confocal fluorescence microscopy.
This proposal fits the EPSRC Healthcare technologies remit as it involves the creation of new sustainable biomaterial nanocarriers engineered using a combination of synthetic biology and chemical methods. These have significant potential as new nanomaterial platforms for future therapies that will have improved efficacy through significantly better targeting and reduce side effects. The nanocarriers produced will benefit from being homogeneous, having scalable low-cost production and excellent biocompatibility given they are derived from human apoferritin and exploit the unique structural and material properties of this nanocage.
The student will be trained in the site specific manipulation of proteins using a range of advanced chemical and synthetic biology methods to engineer new materials as well as in the use of a range of physical techniques to fully characterize the new materials generated. This will be complemented by practical experience in studying the drug release kinetics and nanocarrier uptake and degradation in suitable human cell lines to allow iterative improvement of the nanocarrier design.

Society needs better medicines and requires scientists trained in new ways to develop these therapies towards the clinic. The pharmaceutical industry demands a culture change in research training to equip the next generation of leaders with the breadth of skills to translate the most innovative scientific concepts. The proposed CDT will deliver these leading scientists, highly-trained in interdisciplinary areas central to the EPSRC Healthcare Technologies priority whilst at the same time generating high impact research data and exploitable results. These outputs will benefit the Pharmaceutical sector, both 'big pharma' and SMEs, as well as underpinning key advances central to EPSRC Themes in Healthcare Technologies such as Diagnostics, Therapeutics and Medicines. Partners in the proposed CDT, including three of the world's largest pharmaceutical companies, have helped to shape this proposal to ensure maximum relevance in a time of rapid change in the industry.
The CDT will specifically address a key need, highlighted by the Association of British Pharmaceutical Industries' (APBI) to reverse 'the decline in skills among young people training for careers in science (which) has a serious effect on the development of a knowledge-based industry'. Impact for university and industry partners also includes generation of IP-protected product opportunities. We anticipate a number of new patent application filings to cover inventions in high throughput material selection, self-assembled drug carriers, engineered in vitro models of diseased tissue, and new properties and therapeutic outcomes of specifically formulated biotherapeutics.
By building multisite, multidisciplinary teams through translation-focused collaborative projects, the CDT will further advance mutual benefits to industry and UK society. In 2007, the Gross Value Added (GVA) contribution per employee within the pharmaceutical industry (£233,000) was ~ 3.5 times than the GVA of other high-tech sectors in the UK. Scientists and engineers comprise 42 % of the pharma workforce, indicating clear economic impacts of high-level PhD training in this area. Transfer of knowledge and technology into the Healthcare sector, enhances treatment options and quality of life for patients and carers. Improvements in pharmaceutical science and enhanced academy / industry pathways to translation are important across many other industry sectors: the UK market for formulated products is worth around £180bn a year, with a potential in emerging overseas markets of around £1,000bn (Chemistry Innovation KTN Strategy Report 2010).
Impact beyond the industry sector is expected via outreach activities and engagement of CDT students and staff, in for example, After-Schools clubs and media activities. The subject base for the proposed Centre i.e. Nanomedicines, and the link between academic and industry partners, offers many opportunities for positive public engagement. The applicants have a track record, (e.g. in the award-winning 'Test-Tube' web videos), of showing how pharmaceutical science is pivotal to the development of new medical breakthroughs. Highly motivated and enthusiastic CDT students have demonstrated, (e.g. at EPSRC Showcase events) that their training enables them to be powerful ambassadors for their universities, industry partners and EPSRC.
Impact activities will be embedded throughout the CDT via continual training, monitored via IP and Knowledge Transfer Review meetings of the CDT Steering Group and Advisory Boards, and further encouraged through consultation with Outreach and Impact Champions appointed in Nottingham and UCL as part of EPSRC Impact Acceleration Accounts (IAA). Prof Alexander is Academic Lead for the IAA in Nottingham and so is well-placed to encourage impact activities in the CDT.
The longer-term impact of the CDT will be a sustainable future for the the UK pharmaceutical science base, leading in turn to wider healthcare and societal gains.