Dimer Interfering peptides (DIPs): A novel platform for targeting the immunosuppressive functions of prototypic galectins

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Completed Project of $264,000 over 2 years

• Supported by CQDM through:
  • Pfizer
  • GSK
  • Janssen
  • Norvartis
  • MESI
  • RCE-E

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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.