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

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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.