GPC3 (glypican-3) x 4-1BB (CD137)

Class

Bispecific antibody (tumor-conditional 4-1BB agonist)

Pathway

Tumor-localized T-cell costimulation, activated only in presence of GPC3-expressing tumor cells

GPC3 (glypican-3) is a glycosylphosphatidylinositol-anchored cell-surface proteoglycan expressed at high density on hepatocellular carcinoma cells and largely absent from normal adult tissue, making it a tumor-selective anchor point for targeted therapies. 4-1BB (CD137) is a costimulatory receptor found on activated T cells; when clustered, it delivers a second signal that amplifies T-cell proliferation, survival, and cytotoxic activity, complementing the primary signal delivered through the T-cell receptor. Because 4-1BB belongs to the tumor necrosis factor receptor superfamily, its activation requires multimeric clustering. Antibodies designed to engage it directly and systemically have produced immune activation but are limited by liver inflammation, a recurring toxicity linked to background 4-1BB expression on hepatic immune cells. A bispecific antibody that binds both GPC3 and 4-1BB is designed to cluster 4-1BB receptors only in the vicinity of GPC3-expressing tumor cells, restricting costimulatory signaling to the tumor microenvironment. This tumor-conditional design aims to preserve the antitumor immune benefits of 4-1BB agonism in hepatocellular carcinoma and other GPC3-positive cancers while limiting the systemic, liver-directed toxicity associated with untargeted 4-1BB agonists.