Direct-from-tumour discovery of next-generation antibody-drug conjugate (ADC) linkers

Antibody-drug conjugates (ADCs) are a promising cancer therapy that precisely deliver potent drugs to cancer cells by linking them to engineered antibodies, minimising damage to healthy tissues. While 14 ADCs are FDA-approved and over 140 are in clinical trials, challenges persist. Current ADC linkers often lack specificity, resulting in off-target drug release and clinical trial setbacks, exemplified by the withdrawal of Mylotarg due to an unstable linker. Improved linker chemistry is crucial to unleash the full potential of ADCs.

Most clinical ADCs rely on dipeptide substrates cleaved by cathepsin B (cat B), a protease abundant in tumours. Unfortunately, these linkers can also degrade in healthy tissues and by less selective proteases, causing drug release in unintended locations. Neutrophil-secreted serine proteases can lead to premature payload release, causing myelosuppression, a significant concern.

Balancing circulatory stability and tumour-specific release remains a challenge for chemical payload release mechanisms.

Developing ADC linkers targeting one of the hundreds of potential tumour-associated proteases (TAPs) is challenging due to tight regulation of proteolytic activity, rendering traditional abundance measures (mRNA, protein) ineffective. Innovative approaches are required to determine protease activity directly in relevant tissues, enabling design of linkers with enhanced tumour specificity for next-generation ADCs.

This advancement is crucial for improving clinical efficacy and reducing side effects associated with ADC therapy.

Our multidisciplinary team has a bold vision: to establish the first universal discovery platform (Substrate Identification From Tissue Resection, SIFTR) for ADC linkers by identifying chemically novel TAP substrates and probes directly from human patient tissue. By directly linking specific protease activity in tumours to discovery of selective linker chemistry, our platform will provide the foundation for a comprehensive discovery pipeline for next-generation ADC linkers.