Next-generation antibody-drug conjugate linkers for colorectal cancer treatment

Antibody-drug conjugates (ADCs) are an emerging class of therapeutic agents that enable the delivery of potent cytotoxic drugs to cancer cells via engineered antibodies that selectively bind to antigens on the cell surface. Most clinically approved ADCs use protease-cleavable linkers between the antibody and the drug, so the drug remains inactive until its cleavage by tumour-associated proteases (TAPs), enabling targeted cancer-cell killing while avoiding systemic toxicity. Despite recent progress, the lack of specificity in current ADC linkers can cause unwanted payload release in healthy tissue, leading to toxicity, intolerable dosing, and high clinical attrition rates. Particularly for colorectal cancer (CRC), one of the leading causes of cancer-related deaths worldwide, no CRC-specific ADC has yet been approved.Here, we propose to develop ADC(s) bearing novel TAP-selective linkers that release the drug in the tumour microenvironment of CRC. To achieve this ambitious goal, this project builds on the powerful “Substrate Identification From Tissue Resection” (SIFTR) platform recently developed in the Tate lab, which enables the de novo discovery of novel TAP substrates directly from human patient tissue. The novel TAP- selective substrate sequence(s) will form the basis for the design of activity-based probes (ABPs) to identify the TAP(s) involved via chemical proteomics and orthogonal methods. Finally, the TAP-selective substrate(s) will inform the design of innovative ADC linker(s). The ADC(s) will be constructed and validated as a proof-of-concept in CRC-relevant cellular disease models. Novel linkers developed in this proposal will provide much-needed innovation in ADC linker technology and help ensure ADCs reach their therapeutic potential in CRC. Notably, newly identified TAPs may also have applications as therapeutic targets in their own right.