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Drug Target Encyclopedia Series (20) —GPC3

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Release Time：

2025-12-05 14:29

 

  GPC3 (Glypican-3) is a cell-surface heparan sulfate proteoglycan that regulates cell growth, differentiation, and Wnt/β-catenin signaling.

It is highly expressed in hepatocellular carcinoma (HCC) and several embryonal tumors, while being absent in most normal adult tissues—making it an attractive tumor-specific target for precision oncology.

GPC3 is overexpressed in:

• Hepatocellular carcinoma (HCC) — seen in >70% of cases

• Hepatoblastoma

• Yolk sac tumors and certain lung cancers (subset)

Targeting GPC3 in oncology:

  • Monoclonal antibodies (mAbs) – Humanized antibodies such as GC33 demonstrated selective binding and antitumor activity in GPC3+ HCC.
  • Antibody-drug conjugates (ADCs) – GPC3-targeted ADCs deliver cytotoxic payloads directly to tumor cells, offering enhanced specificity.
  • CAR-T and CAR-NK cell therapies – GPC3-directed CAR-Ts have shown early clinical promise in advanced liver cancer.
  • Bispecific antibodies – GPC3/CD3 bispecifics recruit T cells to mediate potent tumor cell killing.
  • RNA-based and vaccine approaches – Emerging modalities aim to trigger immune recognition against GPC3-expressing tumors.

Challenges include:

• Heterogeneous GPC3 expression within liver tumors

• Limited efficacy in solid tumor microenvironments

• On-target toxicity management in normal hepatic tissues

🔬 Ongoing research focuses on next-generation ADC payloads, dual-target CAR constructs (e.g., GPC3+AFP), and combination strategies integrating GPC3-targeted immunotherapy with checkpoint inhibitors or kinase inhibitors.

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