EPSRC logo

Details of Grant 

EPSRC Reference: EP/T016043/1
Title: C-Terminal Selective Ligation to Access Homogeneous Antibody Conjugates
Principal Investigator: Baker, Dr JR
Other Investigators:
Chudasama, Dr V
Researcher Co-Investigators:
Project Partners:
Department: Chemistry
Organisation: UCL
Scheme: Standard Research
Starts: 01 March 2020 Ends: 28 February 2023 Value (£): 444,295
EPSRC Research Topic Classifications:
Chemical Biology
EPSRC Industrial Sector Classifications:
No relevance to Underpinning Sectors
Related Grants:
Panel History:
Panel DatePanel NameOutcome
05 Dec 2019 EPSRC Physical Sciences - December 2019 Announced
Summary on Grant Application Form
Antibody-Drug Conjugates (ADCs) represent one of the most exciting classes of new targeted anti-cancer therapeutics, with 4 ADCs achieving clinical approval over the last 8 years. They consist of an antibody, which is a protein macromolecule that specifically binds to an antigen overexpressed on a cancer cell surface, attached to a cytotoxic chemical 'warhead'. They aim to overcome the limitations of existing chemotherapeutics by delivering the cytotoxic drug specifically to the cancer cells, and thus reducing the side-effects associated with damaging healthy tissue. To maximise the chances for ADCs achieving their therapeutic potential, their design and chemical construction must be improved. Critically, current approaches for the attachment of the drug to the antibody have relied on unselective chemistries, which generate highly complex mixtures of conjugates with variable pharmacological profiles. Instead, it is now widely accepted that the attachment method for the next generation of optimised ADCs must be site-selective.

In this project we are proposing to pioneer a new approach for the generation of ADCs, which attaches the drugs at specific locations on the antibody by extending the protein chain, generating superior homogeneous conjugates. Our strategy, crucially, will not require genetic engineering of the antibodies to incorporate reactive handles, and is thus applicable directly to native 'off-the-shelf' antibodies. This will maximise the accessibility of homogenous ADCs to researchers across the world and ensure that the production yields are maintained as high as possible, ultimately reducing the cost of these relatively complex biopharmaceuticals. Moreover, it will form ADCs with a controlled loading of 2 drugs, which is timely as many of the new ultra-potent warheads can only be tolerated at such loadings as they are so hydrophobic.

We will achieve this goal by targeting the C-terminal cysteines present on the vast majority of clinically validated antibodies. This is a challenging aim as whilst a wide variety of methods have been established for the selective modification of various amino acids on peptides/proteins, there is an absence of a reliable strategy for modification at the C-terminus. As such, the development of a C-terminal modification strategy would also provide a fundamental advance in the broader field of bioconjugation. Our strategy exploits cysteine reactive reagents, which will be designed to transfer from Cys-to-C-terminus via highly favourable 6-membered ring intermediates. The reactions will result in the formation of amide linkages, which are already extremely well characterised and known to be robustly stable in vivo. Overall this C-terminal modification strategy will represent an optimum approach for producing next generation ADCs and facilitate the wider success of these exciting targeted therapies.





Key Findings
This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
Potential use in non-academic contexts
This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
Impacts
Description This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
Summary
Date Materialised
Sectors submitted by the Researcher
This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
Project URL:  
Further Information:  
Organisation Website: