Development of novel thiol-bridging chemistry for the production of protein conjugates

Lead Research Organisation: University of Bath
Department Name: Pharmacy and Pharmacology

Abstract

The ability to directly target and deliver drug therapies to diseased cells over healthy tissues presents an opportunity to significantly increase specificity, and thereby reduce off-target toxicity, of many highly potent drug compounds. Antibody drug conjugates (ADCs) utilize the biologically selective antibody-antigen recognition system to deliver conjugated drug molecules directly to targeted cancer cells. A typical ADC is comprised of a monoclonal antibody (mAb) bound to a highly pharmacologically active, cytotoxic drug molecule via a chemical linker. ADCs represent one of the fastest growing areas of pharmaceutical research, with over 20 new drugs currently in late stage clinical trials. Recently, however, the nature of chemical linker used to attach the cytotoxic drug to the antibody has been identified as one of the key factors influencing the efficacy of ADCs in clinical trials. In particular, lack of linker stability is one of single biggest contributors to the failure of ADCs in clinic trials.
Recently, novel chemical linkers capable of rapid, selective and stable conjugation to monoclonal antibodies have been developed. These linkers act by bridging the inter-chain disulphide bonds in mAbs, to create a highly stable protein conjugate. During this PhD, I aim to further develop and optimise this class of thiol-bridging linker. To begin, I will synthesise a series of linker derivatives to identify key chemical properties contributing to both thiol-reactivity (conjugation) and hydrolysis (degradation). The target linkers identified will then be characterised in terms of relative reaction rates with thiols (peptides vs proteins) and aqueous stability of the conjugation products over a variety of conditions (time, temperature, pH). Finally, the linkers will be used to generate antibody- conjugates with the immune evasion protein Sbi, which has been characterised in the van den Elsen lab. These antibody-Sbi conjugates will then be evaluated in vitro for their ability to kill a number of cancer cell lines.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/R512424/1 01/10/2017 30/09/2022
1942300 Studentship EP/R512424/1 01/10/2017 30/09/2021 Rebecca MARTIN
 
Title Bake your Doctorate submission 
Description A cake demonstrating my research. 
Type Of Art Artistic/Creative Exhibition 
Year Produced 2018 
Impact The cake was exhibited alongside an abstract summarising my research. The exhibition was open to the University and the public and I explained the principles of my research to attendees. 
URL https://www.bath.ac.uk/announcements/bake-your-doctorate-showcase-2018/