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Details of Grant 

EPSRC Reference: EP/R034621/1
Title: Site-selective antibody modification by cysteine-to-lysine transfer (CLT)
Principal Investigator: Baker, Dr JR
Other Investigators:
Chudasama, Professor V
Researcher Co-Investigators:
Project Partners:
Department: Chemistry
Organisation: UCL
Scheme: Standard Research
Starts: 16 July 2018 Ends: 15 December 2021 Value (£): 411,777
EPSRC Research Topic Classifications:
Chemical Biology
EPSRC Industrial Sector Classifications:
Pharmaceuticals and Biotechnology
Related Grants:
Panel History:
Panel DatePanel NameOutcome
24 Jan 2018 EPSRC Physical Sciences - January 2018 Announced
Summary on Grant Application Form
With CRUK recently highlighting that 1 in 2 of us will have cancer in our lifetimes, the requirement for progress in developing new medicines and improved diagnostics for oncology is a high priority for our society. The current state of the art in chemotherapeutics still relies heavily on untargeted cytotoxins, leading to severe side-effects which are intolerable in many cases. In contrast, the attachment of cytotoxins to a delivery agent, which targets the 'warhead' specifically to the tumor, offers the enticing possibility of 'magic-bullet' chemotherapies. Antibody-Drug Conjugates (ADCs) represent amongst the most promising class of such drugs in development, with 3 ADCs achieving clinical approval in the last few years. However, it is widely considered that the molecular construction of ADCs currently is still far from optimal, and that new technologies in this area are urgently required to help enable them to achieve their clinical potential. Most notably current approaches employed to attach the cytotoxic drugs to the antibodies lead to a highly complex mixture of products. The result is a drug which contains a vast number of distinct species, each with a different pharmacological profile.

In this project we are proposing to pioneer a new chemical approach for the generation of ADCs, which attaches the drugs at specific locations on the antibody, 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.

We will achieve goal this by targeting specific lysine amino-acids on the surface of the antibodies. This is a challenging aim as there are numerous lysines present; and as such we are proposing to develop new methodology, in which the conjugation reagent is guided to a specific location by a neighbouring cysteine amino-acid. This unprecedented cysteine-to-lysine transfer (CLT) approach will generate amide linkages between the antibody and the drug which are already extremely well characterised and known to be robustly stable in vivo. This will afford a high-level of confidence which will facilitate rapid uptake in the field.

Overall this CLT platform will represent an optimum approach for producing ADCs and facilitate the wider success of these exciting targeted therapies.

Key Findings
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