Glycopolymer immunomodulators by design: synthetic tools for exploiting the glycocode

Context: 'Sweet' therapeutics - why are they important?
Carbohydrate-protein interactions mediate a plethora of key events in Nature, spanning from fertilisation to parasitisation and the mounting of immune responses. Simple monosaccharides (e.g. glucose and fructose) often bind their corresponding protein receptors too weakly to trigger any these in vivo events. Nature overcomes this problem by utilising larger and often extremely complex carbohydrates with higher and more selective affinity to their corresponding protein receptors. However, while being extremely valuable potential therapeutics, these naturally occurring protein-binding sugars are often impossible to isolate on a large scale and high purity from natural sources, while their preparation in synthetic laboratories can be hampered by extremely expensive and complex procedures. Synthetic glycopolymers - a class of polymers which display multiple copies of "simpler" sugars in their structure - have just now started to emerge as extremely valuable mimics for complex naturally occurring protein-binding complex sugars.

What do novel sugar polymer-protein hybrid materials have to offer?
These materials are an optimal test platform for proof-of-concept studies described in this application. The PI has previously designed an innovative and extremely efficient route to a range of novel glycopolymers. He also has engineered novel a new class of hybrid materials composed by a protein and an appropriate glycopolymer with dual properties: the glycopolymer can direct these materials to specific therapeutic targets in plasma, cells, and tissues, while the protein component can provide further therapeutic activity, e.g. harnessing the immune system to treat diseases. Immune responses stem from extremely complex yet precisely coordinated cascades of processes which the human body utilises for as a protection against foreign pathogens or to avoid neoplastic development. Dendritic cells (DCs) are the sentinels of the immune system, and bring news of the invasion of pathogens or development of other diseases to other immune cells to trigger an appropriate immune response. DCs possess a number of receptors, a great proportion of which recognise specific complex carbohydrates and use them to trigger their biological functions. Cost-effective and efficacious therapeutics that could efficiently activate DC to trigger an immune response against cancer cells or to control autoimmune diseases would have a tremendous impact on medicine and healthcare applications both in developing nations and for ageing populations. Within this context polymer-protein hybrid materials are tools that hold great potential for probing of a range of biological pathways and ultimately contribute to develop safer and more cost-effective therapeutics.

Impact.
Elicitation of protective immunity against cancer or infection, and the amelioration of diseases caused by the harmful activation of the immune system are amongst the biggest global goals in healthcare and medicine. The lack of effective immunomodulators at an affordable price is one of the major obstacles to the development of immunotherapies. This is a major long term objective of this application and progress here could have widespread implications for academia, industry and the society alike. An obvious commercial application would be a hybrid therapeutic assembled with tumour markers which could instruct our immune system to recognise and ultimately eradicate specific cancers.
Longer-term development could generate impact through the development of immunomodulator therapeutics including cancer vaccines. With over 3 million people diagnosed with cancer every year in the EU alone - and the ageing of the European population will cause these numbers to continue to increase even if age-specific rates remain constant - is very clear how significant development in cancer immunotherapy would have a dramatic positive impact our society.

Carbohydrates are information-rich materials which, when included within appropriate molecular structures, can mediate a number of in vivo events in Nature, including the mounting of an immune response. Harnessing the immune system to recognise and eradicate tumour cells or to control autoimmune diseases and transplant rejection is amongst the significant current needs in medicine. Within this context sugar-containing therapeutics hold great potential to become a new, selective and more cost-effective class of immunomodulators, provided that their mechanisms of action are understood and the full potential of our underlying knowledge of disease processes can be translated to effective therapies. Proving that the polymer- and sugar-based materials that will be engineered in this project could control and direct immunological responses may pave the way for the development of better therapeutics able to enhance quality of life for patients. Accordingly, efficient immunomodulation will have a dramatic impact across the academic and industrial sectors, and in turn benefit society through better healthcare technologies.

A number of industries in the healthcare sector, ranging from specialist drug delivery start-ups to large pharmaceutical companies could potentially directly benefit from novel routes to potent and selective immunomodulators generated from this proof-of-concept proposed research. The importance of these industries to UK and wider society is recognised formally via EPSRC Priorities in Diagnostics and Therapeutic Technologies. Impact for these sectors can originate directly from exploitable IP and through supply of trained personnel.
This project will train a research staff in multidisciplinary skills essential for future career either in universities or in high added-value businesses. Increased focus in the pharmaceutical sector on targeted drugs and biopharmatherapeutics, has meant that post-doctoral-level scientists who are more and more familiar with advanced materials and biological science methods are now needed. The impact of such scientists will therefore be very high, especially when considering that the current number of specialists trained across the necessary physical and life science backgrounds is still very low. The pathway to impact is accordingly well-defined for industry beneficiaries, since the work will enhance the pool of highly-trained scientists from which they can recruit.
Engagement with non-academic beneficiaries will be conducted via industry-focused conferences, publications, events, websites and, where appropriate, PDRA secondments. Further societal impact will come from active participation in After-Schools clubs (e.g. the Nottingham School of Pharmacy's award-winning After School Science Club for Year 5 and 6 primary school children) public lectures and exhibitions (Royal Society, Café Scientifique and others) and press/media interactions.