Our Science

Legumain is a cysteine protease and lysosomal enzyme in normal tissues of mammals.  It is found to be highly overexpressed and active in most human solid tumors including breast, ovarian, colon and prostate.  In contrast to normal cells, legumain expression is induced by hypoxia in solid tumors and its catalytic activity is great enhanced by forming a legumain/integrin complex on the cancer cell surface and in acidic solid tumor microenvironments.  Furthermore, it is expressed by intratumoral blood vessels and on tumor-associated macrophages (TAMs) and is involved in promoting cell migration and invasion.

As a catalytic protease, legumain has a highly restricted substrate specificity, cleaving peptides on the C-terminal side of an asparagine residue.  Legumain is the only known human asparaginyl endopeptidase and therefore cleavage will be specific to a peptide-drug-conjugate containing an asparagine linker.  This is opposed to other linkers, which might also be cleaved by non-specific endogenous proteases.  The expression and biochemical properties of legumain collectively represent an opportunity to exploit legumain as an attractive target for tumor-selective drug delivery.

Legumain activation of a peptide-drug-conjugate carrying a cytotoxic payload should result in tumor-selective exposure of the toxic active drug. Using this mechanism, the incidence of nonspecific targeting and adverse drug effects will be reduced.  The cytotoxic payload is a clinically approved anticancer drug and is marketed as anti-cancer drug administered intravenously to treat various types of cancers.