Glypican-3 Targeting Strategies in Hepatocellular Carcinoma

Glypican-3 (GPC3) is an oncofetal heparan sulfate proteoglycan tethered to the cell surface by a glycosylphosphatidylinositol anchor. Its restricted expression in normal adult tissues and high prevalence in hepatocellular carcinoma (HCC) render it an attractive therapeutic and diagnostic target. Mechanistically, GPC3 modulates key oncogenic pathways—including Wnt/β-catenin, YAP and hedgehog cascades—to promote tumour proliferation and survival. Targeting approaches encompass monoclonal antibodies, antibody–toxin conjugates, peptide vaccines, chimeric antigen receptor (CAR) T cells, natural killer (NK) cell therapies and combinations with immune checkpoint blockade. These strategies aim not only to ablate GPC3-expressing cells through direct cytotoxicity or immune-mediated mechanisms but also to disrupt growth factor signalling and reprogramme the tumour microenvironment. Advances in antibody engineering, humanisation and bispecific formats have improved selective delivery of cytotoxic payloads while minimising off-target effects. Early-phase clinical studies have demonstrated manageable safety profiles and preliminary antitumour activity, underscoring the global significance of GPC3-directed modalities as precision medicines for HCC.

Research from Nature Portfolio

Innovative immunotoxin constructs combining a functional anti-GPC3 antibody fragment with a fragment of bacterial exotoxin have been shown to induce potent regression of liver tumour xenografts. By simultaneously inactivating Wnt signalling via the antibody and arresting protein synthesis through the toxin moiety, these bioconjugates achieved tumour eradication in preclinical models and synergised with standard chemotherapy. Complementary efforts in antibody humanisation have yielded high-affinity human IgG formats that retain selective binding to GPC3, mediate strong antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, and suppress xenograft growth in vivo. These humanised antibodies serve as platforms for next-generation formats, including bispecific engagers and antibody–drug conjugates, and lay the groundwork for clinical translation.

Glypican-3 Targeting Strategies in Hepatocellular Carcinoma publication trend

The graph below shows the total number of articles in glypican-3 targeting strategies in hepatocellular carcinoma across all publications each year (not limited to Nature Index journals).

Technical terms

Glypican-3: A cell-surface heparan sulfate proteoglycan overexpressed in hepatocellular carcinoma, involved in the modulation of growth factor signalling.

Immunotoxin: A fusion molecule combining a targeting antibody fragment with a cytotoxic protein domain to selectively kill antigen-expressing cells.

Chimeric antigen receptor (CAR) T cell: A genetically engineered T lymphocyte expressing a synthetic receptor that recognises a specific tumour antigen and triggers T cell activation.

Antibody-dependent cellular cytotoxicity: An immune effector mechanism in which Fc receptor-bearing cells lyse target cells coated with specific antibodies.

References

1. Anti-GPC3-CAR T Cells Suppress the Growth of Tumor Cells in Patient-Derived Xenografts of Hepatocellular Carcinoma. Frontiers in Immunology (2017).
2. Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis. Nature Communications (2015).
3. First-in-Man Phase I Study of GC33, a Novel Recombinant Humanized Antibody Against Glypican-3, in Patients with Advanced Hepatocellular Carcinoma. Clinical Cancer Research (2013).
4. Glypican‐3: a marker and a therapeutic target in hepatocellular carcinoma. The FEBS Journal (2013).
5. Programmed death-1 blockade enhances the antitumor effects of peptide vaccine-induced peptide-specific cytotoxic T lymphocytes. International Journal of Oncology (2014).
6. The Role of Glypican-3 in Regulating Wnt, YAP, and Hedgehog in Liver Cancer. Frontiers in Oncology (2019).
7. Glypican-3: A Novel and Promising Target for the Treatment of Hepatocellular Carcinoma. Frontiers in Oncology (2022).
8. Humanization of high-affinity antibodies targeting glypican-3 in hepatocellular carcinoma. Scientific Reports (2016).