|Challenge: Galectins are a family of lectin proteins implicated in tumor progression and immune evasion. When produced in excess by cancer cells, galectins can form homodimers and bind glycans on the surface of T cells. This suppresses the local and systemic immune response in patients, helping tumors to escape immune surveillance and limiting the efficacy of immuno-oncology treatments. To date, most efforts to identify anti-galectin therapeutics have focused on drugs that inhibit binding of galectins to cell surface receptors via their carbohydrate recognition domain (CRD). Unfortunately, most of these attempts have failed.
Solution: This project aims to develop a novel class of anti-cancer drugs that specifically inhibit the dimerization of galectins as a means to disrupt their protumorigenic activity. This new mechanism of action is an alternative and/or complementary solution to CRD inhibitors for cancer treatment. As proof of concept, the project has focused on Galectin-7 (Gal-7), a validated target expressed at high levels in aggressive forms of triple-negative breast cancer. Using a rational design approach, the team has developed two classes of inhibitors: “dimer interfering peptides” (DIPs) and camelid nanobodies (Nbs) to selectively target Gal-7 dimerization and consequently, its functional activity in vitro.
Achievements/Impact: The team has identified four distinct DIP hits and improved their pharmacokinetic properties and potency. In parallel, a platform was used to develop Gal-7-specific single domain nanobodies that have been humanized. Twelve Nbs were identified as hits following an initial screening of a non-immune recombinant camelid antibody synthetic library. Like DIPs, these Nbs are highly specific and have the potential to inhibit Gal-7 via at least two mechanisms of actions, including dimer-interference.
Once validated in animal tumor models, the approach could serve as a template to generate inhibitors against a broad range of galectins implicated in the initiation and progression of cancer, including triple-negative breast cancer.