Novel approach cathepsin S-Specific antibody-drug conjugates

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with poor survival rates and no effective early detection methods. Most patients present at an advance stage, where chemotherapy is limited. Antibody-drug conjugates (ADCs) offer targeted delivery of cytotoxic agents, reducing systemic toxicity. However, current ADCs face issues such as non-specific linker cleavage and lysosomal entrapment. This project developed a novel ADC platform using a Cathepsin S (Cat S)-cleavable linker, chosen for its restricted expression in normal tissues, overexpression in tumours, and stability under physiological conditions. A cleavable substrate was linked to SN-38 via various linkers designed to mimic metabolites that promote lysosomal escape. The most active metabolite was then attached to the linker and conjugated to Cetuximab using either acrylamide or bromopyridazinedione (BrPD), with BrPD showing better conjugation efficiency. Future work is needed to identify more selective Cat S substrates and to optimise the conjugation process.

Thesis is embargoed until 31 December 2030.

Date of Award	Dec 2025
Original language	English
Awarding Institution	Queen's University Belfast
Supervisor	Christopher Scott (Supervisor) & Richard Williams (Supervisor)