Site-selective Antibody-Drug Conjugates by Cysteine-to-Lysine Transfer

Monoclonal antibodies (mAbs) are the fastest growing class of therapeutics, with over 30 approved for clinical use to date. They have the potential to provide effective treatments across a range of clinical areas including inflammatory diseases, oncology, infectious diseases and cardiovascular medicine. The chemical modification of antibodies is a key technological challenge in the area, as it allows the attachment of functional moieties that enable optimisation of the in vivo properties of the antibody (e.g. improved pharmacokinetics) or confer upon it new functions and activities (e.g. the attachment of a drug or imaging agent).
The ideal strategy for antibody conjugation would involve the site-selective modification of native lysines. This would avoid detrimental changes to the antibody structure, producing fully active conjugates whilst negating the need for mutagenesis. The central hypothesis behind this PhD project is that this can be achieved by the development of new bioconjugation methodology, which utilises proximal cysteine residues as ligating 'hooks'. This cysteine-to-lysine transfer (CLT) reaction would allow the construction of highly homogenous antibody conjugates, incorporating serum stable amide linkages.