Design and Synthesis of Novel Sequence-dependent Bioconjugation Linkers for Antibody-Drug Conjugates (ADCs)

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Theme: Industrial Biotechnology and BioenergyThe discovery and development of new therapeutic agents has recently moved into a key new area, looking to combine two distinct classes of chemical or biological agents into a single entity. Bringing two different agents together provides the opportunity for synergistic effects, most notably when one of the components acts as a targeting agent and the other interacting with the desired biological system. One of the leading areas for new synergistic therapeutic modalities is Antibody Drug Conjugates (ADCs). Recent years have witnessed tremendous interest in ADCs; two are already on the market as anticancer agents (Roche's Kadcyla and Seattle Genetics' Adcetris) and there are now a further 54 ADCs in clinical trials. Linker technology is a crucial aspect of ADC chemotherapeutics and can be split into two aspects; (1) 'conjugation chemistry' (the chemical method of attachment of the linker to the antibody and to the warhead) and (2) 'linker composition' (the structure, and thus properties of the linker, including the warhead release mechanism). The linker not only provides a functional handle for efficient conjugation of the warhead to the antibody (ideally without compromising antibody binding or cytotoxic activity), but it also impacts significantly upon the behaviour of the resultant ADC construct. The stability of the linker plays a key role in regulating the release of the warhead and thus the therapeutic index of the ADC. In addition, the nature of the linker can have a profound effect on the physico-chemical and pharmacokinetic properties of the overall ADC.This research aims to develop enhanced linker technologies capable of overcoming current shortcomings.