Unleashing the Potential of BT8009: Targeting Nectin-4 in Cancer Therapy

A novel peptide has been discovered that specifically targets Nectin-4, a molecule prevalent in various cancer types such as bladder, triple-negative breast, and non-small cell lung cancers, but scarce in healthy tissues. This peptide is part of a class of compact, synthetic drugs known as Bicycles, which are designed to have the targeting precision of antibodies and the favorable pharmacokinetics of small molecules. Utilizing a phage display platform, researchers have developed a peptide with high affinity and selectivity for Nectin-4. Further synthetic enhancements have improved its binding capabilities, solubility, and stability.

The refined peptide is linked to a toxin, MMAE, through an inert spacer and a cleavable bond to create a Bicycle Toxin Conjugate named BT8009. This conjugate is designed to bind to Nectin-4 on cancer cells and then be cleaved by enzymes overexpressed in the tumor microenvironment, releasing the toxin. The complete structure of BT8009 will be detailed in an upcoming presentation.

Assessment through fluorescence polarization and surface plasmon resonance confirmed BT8009's high affinity and selectivity for Nectin-4 over other similar proteins. In vitro studies showed effective binding to cancer cells, and in vivo studies in mice and rats demonstrated that BT8009 is well-tolerated and induces tumor regression across different cancer models. The effectiveness of BT8009 is linked to the level of Nectin-4 expression and the administered dose. Notably, complete tumor regression was observed in certain models with weekly intravenous administration.

As a small peptide, BT8009 is rapidly cleared from the bloodstream, minimizing exposure to non-target tissues. However, the toxin MMAE has been found to persist in tumor tissues for over 60 hours post-dose, at significantly higher levels than in plasma or other tissues. The research suggests that Bicycle Toxin Conjugates like BT8009 offer a promising therapeutic approach for cancers that express Nectin-4, with significant efficacy demonstrated in multiple preclinical models.

The study was authored by Mike Rigby, Paul Beswick, Gemma Mudd, Katerine Van Rietschoten, Liuhong Chen, Sophie M. Watcham, Heather Allen, Amy Brown, Helen Harrison, Gavin Bennett, Phil Jeffrey, Peter U. Park, Maria Koehler, and Nicholas Keen. The findings were presented at the American Association for Cancer Research Annual Meeting in 2019.