Target: GPC3 (Glypican-3)

Indication: Hepatocellular carcinoma (TCGA LIHC)

1️⃣ Surface Eligibility (hard requirement)

UniProt (P51654) evidence:
- Subcellular location: Cell membrane
- Topology: GPI-anchor
- Transmembrane domains: 0 (GPI-anchored protein)

Reasoning:
GPC3 is a GPI-anchored cell-surface proteoglycan, tethered to the extracellular leaflet of the plasma membrane. This configuration presents the entire protein ectodomain extracellularly and makes it fully accessible to:

• CAR-T cells
• Monoclonal antibodies
• ADCs
• T-cell engagers

There is no intracellular-only restriction.

✅ Surface eligibility: ELIGIBLE

2️⃣ On-Tumor Signal (TCGA LIHC)

• LIHC median tumor expression: 80.0 TPM

This is a very strong tumor signal. For context, this is high relative to many cell-surface targets and suggests robust antigen density in a substantial fraction of HCC tumors.

3️⃣ Tumor-vs-Normal Specificity (dominant criterion)

GTEx normal tissue medians (TPM):

Vital tissues:
- Liver: 0.3
- Lung: 1.0
- Heart - Left Ventricle: 0.2
- Brain - Cortex: 0.3
- Kidney - Cortex: 0.5
- Colon - Transverse: 0.2
- Pancreas: 0.2
- Spleen: 0.2
- Whole Blood: 0.1
- Stomach: 0.3
- Nerve - Tibial: 0.3

Other notable tissues:
- Testis: 2.0
- Ovary: 1.0

Tumor vs normal contrast:

• LIHC tumor: 80.0 TPM
• Adult liver (normal): 0.3 TPM

This is ~267-fold higher in tumor vs normal liver.
Across vital organs, expression remains ≤1 TPM.

Interpretation:
This is an excellent tumor-to-normal differential, particularly important given the hepatic indication. Minimal expression in normal adult liver is critical for safety in HCC-directed therapy.

The slightly higher expression in testis (2.0 TPM) is notable but testis is generally considered an immune-privileged site, often tolerable for oncology targeting.

4️⃣ Safety Assessment (on-target/off-tumor risk)

Key considerations:

• Normal liver: 0.3 TPM → very low baseline hepatic risk
• Other vital organs: ≤1 TPM → low predicted systemic toxicity
• Whole blood: 0.1 TPM → minimal hematologic liability
• No strong expression in heart, brain, lung, kidney

Given:
- Very high tumor expression (80 TPM)
- Very low vital-organ expression

Predicted therapeutic window appears wide.

FINAL ASSESSMENT

Target: GPC3
Indication: Hepatocellular carcinoma (LIHC)

Surface eligibility

✅ Eligible — GPI-anchored cell-membrane protein (UniProt P51654), fully extracellular and accessible to CAR-T, ADC, and bispecific modalities.

On-tumor signal

• LIHC median: 80.0 TPM

Specificity (dominant criterion)

• Normal liver: 0.3 TPM
• Lung: 1.0 TPM
• Heart: 0.2 TPM
• Brain: 0.3 TPM
• Whole blood: 0.1 TPM
• Testis (highest normal): 2.0 TPM

Tumor-to-normal liver differential ≈ 267×.

Safety

• Very low expression across vital tissues.
• Minor expression in testis (2.0 TPM) — likely manageable.
• Low predicted on-target/off-tumor toxicity profile.

Tier

✅ Tier 1 — Strong candidate

Rationale & Recommendation

GPC3 demonstrates high tumor expression in LIHC (80 TPM) with minimal expression across adult vital tissues, including normal liver (0.3 TPM). As a GPI-anchored cell-surface protein, it is fully accessible to extracellular targeting modalities. The tumor-to-normal differential is substantial and supports a favorable therapeutic window. Based strictly on the expression and localization evidence retrieved here, GPC3 is a highly attractive tumor-associated antigen for hepatocellular carcinoma and strongly suitable for CAR-T, ADC, and bispecific development.