Modify-catch-release-repeat: Reversible bioconjugations for controlled release of small molecules from antibodies and their fragments

Protein based drugs are revolutionising the precision treatment of cancer and other complex disease, and often consist of large macromolecules like antibody proteins, that can act when they are attached to a small molecule drug. An example of this new type of "biologic" medicine are antibody-drug conjugates (ADCs) which are leading the way in personalised chemotherapy treatments for cancer, with >100 such drugs in clinical trials or pharmaceutical pipeline all over the world. However, the bottleneck in progressing this field further is not the antibodies, or the drugs available, but the chemistry required to stitch these two components together, and developments in this area of chemistry lag decades behind other branches of small molecule organic chemistry. A major challenge in the construction of these medicines is the difficulty in building linkages between small molecules and proteins that are stable enough to survive in the body during circulation, but then also labile enough to break-down inside the targeted cancer cells, which is required for full activity. An ideal solution to this problem would be the development of a reversible linkage which is stable until exposed to an external small molecule trigger which would then catalyse break-down of the linkage. A reversible method such as this would also have a wide ranging cost-effective application in the in vitro purification of therapeutic proteins, including 'fishing' antibodies and other proteins out of complex mixtures before preparing them for clinical applications- akin to a 'catch-and-release' strategy. Nature makes abundant use of similar reversible modifications including glycosylation, phosphorylation, acetylation and lipidation, which all act as dynamic switches, as yet however our ability as chemists to emulate these enzymatic modifications pales in comparison. In this project we will take inspiration from Nature and address this limitation by developing a new chemical method which will allow the reversible attachment of small molecules to protein scaffolds. We ultimately aim to deploy this method, both in vitro and in vivo, for the tandem purification and modification of antibody fragments, and the subsequent controlled release of a drug inside bladder cancer cells- a disease which results in 15 deaths every day in the UK. To achieve this goal we will assemble a team with multidisciplinary expertise at the University of York, working at the interface of small molecule and protein chemistry, glycoscience, bladder cancer cell biology, and antibody production. We will also establish a collaborative relationship with a UK biotech specialising in the development of antibody-drug conjugates (ADCs). This unique combination will facilitate the development of a novel reversible protein bioconjugation platform method, which will be used to overcome the challenges presented in the production of these 21st century therapeutics.

This project will support an emerging area of UK science, the development of biotherapeutics using a new reversible platform technology. The underpinning protein bioconjugation chemistry which the team will develop during this project has the potential to transform small molecule organic chemistry methods into innovative chemical tools that will drive advances in personalised medicine and diagnostics, and impact diverse fields including personalised cancer chemical medicine, cell biology and immunology.

Impact on the economy

The research proposed in this application has great potential impact on the UK pharmaceutical and 'biologic start-up' companies working in the area of biologic immunoconjugate therapies, including novel chemotherapy treatments. The UK is at the forefront of the developments in Antibody-Drug Conjugates (ADCs) therapy, which has revolutionised cancer treatment in the last decade and has a global market value projected to exceed £7bn annually by 2024. Yet the need for new linker, and protein conjugation methodology to construct ADCs is constant, and arguably a bottleneck in the progression of the field. This proposal will have a direct impact on the development of new methods for ADC construction, which will provide a stimulus to the UK personalised medicine market. We will explore the development of our own methodology in this area at the University of York, and in collaboration with a UK biotech specialist.

Impact on society

The NHS initial decision not to fund the regular treatment of advanced breast cancer patients with biologic drug Kadcyla made headline national news this year. This is because despite its expense, Kadcyla can extend the lives of patients by many months, but due to the complexity of its constitution and synthesis, not every patient who was eligible for the drug in the UK received it. Such are the devastating societal impacts of diseases such as cancer on families and individuals both nationally and worldwide, cost and resources should play no role in the decisions made by policy makers- but they still do. The aim of this research is to use novel strategies for protein conjugation to improve and invigorate the methods currently used to make these biologic drugs, thus removing the barriers to treatment for UK patients. Indeed, we will also focus specifically on developing new strategies to combat bladder cancer, of which there are 10,000 new sufferers each year in the UK, with a 50% mortality rate, or 15 deaths every day. Therefore, high quality research published in this field will create significant public interest in the area because it has a direct impact on quality of people's lives and health, and will highlight the role chemistry plays in the construction of new medicines, just as it has continued to do over the last century, albeit on much smaller molecules.

Impact on people

Alongside individual research team members who will benefit from the opportunities to establish research collaborations with emerging UK industrial specialists in antibody bioconjugation, the impact of this research could also be measured upon new developing scientists. The Department of Chemistry at the University of York is nationally renowned not only for its research excellence, but also for its inspirational teaching, exemplified by a commitment to include cutting edge, research driven scientific content in both undergraduate and postgraduate lecture courses. In a continuation of this philosophy, the staff and student cohort at York will benefit from the project as the research results arising will be incorporated into lectures, and also shared with undergraduate research students on placement in the lab.