Targeting hypersialylation via lectin-directed protein aggregation therapy (LPAT) for anti-metastasis applications

Here, we report the development of lectin-directed protein aggregation therapy (LPAT), which combines the strong glycan-targeting capabilities of multivalent lectins with the aggregating propensities of bacterial microcompartment proteins. The design aims to create a system sensitive enough to elicit cell-specific aggregation towards invasive, metastatic tumor cells, while being nontoxic to normal tissues. LPAT agents were screened against a panel of 6 breast cancer cell lines, with the most potent agent showing preferential anti-adhesive and anti-invasive activity against the hypersialylated/MMP9 overexpressing MDA-MB-231 cell line. Furthermore, LPAT agents did not exhibit any propensity for hemagglutination, a principal disadvantage of lectin-based targeting systems. Subsequent studies using a metastatic mouse model showed that LPAT agents could prevent the formation of experimental lung metastases caused by the highly metastatic MDA-MB-231-LM2 isoform cell line. Overall, this work has laid the foundation for a potential glycan-targeting therapy aimed at preventing the onset and progression of metastatic tumors in a safe and selective manner.