Design and Synthesis of Novel Sequence-dependent Bioconjugation Linkers for Antibody-Drug Conjugates (ADCs)
Lead Research Organisation:
University of Cambridge
Department Name: Chemistry
Abstract
Theme: Industrial Biotechnology and Bioenergy
The 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.
The 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.
Publications
Iegre J
(2018)
Two-Component Stapling of Biologically Active and Conformationally Constrained Peptides: Past, Present, and Future
in Advanced Therapeutics
Iegre J
(2018)
Stapled peptides as a new technology to investigate protein-protein interactions in human platelets.
in Chemical science
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
BB/M011194/1 | 30/09/2015 | 31/03/2024 | |||
1800637 | Studentship | BB/M011194/1 | 30/09/2016 | 30/08/2020 | Josephine Gaynord |
Description | -Discovered the application of macrocyclic peptides as tools for investigating protein-protein interactions in human platelets for the first time. These findings have been published and are being followed up by myself and the other authors of the paper. |
Exploitation Route | The research into the use of macrocyclic peptides as inhibitors for protein-protein interactions in human platelets can be taken forward and a platelet-specific therapeutic can be developed, for either the treatment of cardiac events or cancer. In this work one family of proteins was investigated in platelets; the work could be used by others to investigate other families of proteins. |
Sectors | Pharmaceuticals and Medical Biotechnology |
URL | https://pubs.rsc.org/en/content/articlepdf/2018/sc/c8sc00284c |