Target Information

Target General Information

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Target ID

T25726 (Former ID: TTDI02084)

Target Name

Glypican-3 (GPC3)

Synonyms

Secreted glypican3; OCI5; MXR7; Intestinal protein OCI5; Intestinal protein OCI-5; GTR22; GTR2-2

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Gene Name

GPC3

Target Type

Clinical trial target

[1]

Disease

[+] 4 Target-related Diseases

Metastatic liver/bile duct neoplasm [ICD-11: 2D80]

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Lung cancer [ICD-11: 2C25]

Liver cancer [ICD-11: 2C12]

Function

Negatively regulates the hedgehog signaling pathway when attached via the GPI-anchor to the cell surface by competing with the hedgehog receptor PTC1 for binding to hedgehog proteins. Binding to the hedgehog protein SHH triggers internalization of the complex by endocytosis and its subsequent lysosomal degradation. Positively regulates the canonical Wnt signaling pathway by binding to the Wnt receptor Frizzled and stimulating the binding of the Frizzled receptor to Wnt ligands. Positively regulates the non-canonical Wnt signaling pathway. Binds to CD81 which decreases the availability of free CD81 for binding to the transcriptional repressor HHEX, resulting in nuclear translocation of HHEX and transcriptional repression. Inhibits the dipeptidyl peptidase activity of DPP4. Plays a role in limb patterning and skeletal development by controlling the cellular response to BMP4. Modulates the effects of growth factors BMP2, BMP7 and FGF7 on renal branching morphogenesis. Required for coronary vascular development. Plays a role in regulating cell movements during gastrulation. Cell surface proteoglycan that bears heparan sulfate.

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UniProt ID

GPC3_HUMAN

Sequence

MAGTVRTACLVVAMLLSLDFPGQAQPPPPPPDATCHQVRSFFQRLQPGLKWVPETPVPGS
DLQVCLPKGPTCCSRKMEEKYQLTARLNMEQLLQSASMELKFLIIQNAAVFQEAFEIVVR
HAKNYTNAMFKNNYPSLTPQAFEFVGEFFTDVSLYILGSDINVDDMVNELFDSLFPVIYT
QLMNPGLPDSALDINECLRGARRDLKVFGNFPKLIMTQVSKSLQVTRIFLQALNLGIEVI
NTTDHLKFSKDCGRMLTRMWYCSYCQGLMMVKPCGGYCNVVMQGCMAGVVEIDKYWREYI
LSLEELVNGMYRIYDMENVLLGLFSTIHDSIQYVQKNAGKLTTTIGKLCAHSQQRQYRSA
YYPEDLFIDKKVLKVAHVEHEETLSSRRRELIQKLKSFISFYSALPGYICSHSPVAENDT
LCWNGQELVERYSQKAARNGMKNQFNLHELKMKGPEPVVSQIIDKLKHINQLLRTMSMPK
GRVLDKNLDEEGFESGDCGDDEDECIGGSGDGMIKVKNQLRFLAELAYDLDVDDAPGNSQ
QATPKDNEISTFHNLGNVHSPLKLLTSMAISVVCFFFLVH

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3D Structure

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AlphaFold

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 19 Clinical Trial Drugs

Codrituzumab

Drug Info

Phase 2

Hepatic metastasis

[2]

GC33

Drug Info

Phase 2

Hepatocellular carcinoma

[3]

GPC-3298306

Drug Info

Phase 2

Hepatocellular carcinoma

[4]

RG7686

Drug Info

Phase 2

Hepatocellular carcinoma

[3], [5]

SAR444200

Drug Info

Phase 2

Aggressive cancer

[6]

CAR-T cells targeting Glypican-3 (GPC3)

Drug Info

Phase 1/2

Hepatocellular carcinoma

[7]

CAR-T cells targeting GPC3

Drug Info

Phase 1/2

Hepatocellular carcinoma

[8]

GPC3-CART cells

Drug Info

Phase 1/2

Hepatocellular carcinoma

[9]

Retroviral vector-transduced autologous T cells to express anti-GPC3 CARs

Drug Info

Phase 1/2

Hepatocellular carcinoma

[10]

TAI-GPC3-CART cells

Drug Info

Phase 1/2

Hepatocellular carcinoma

[11]

Anti-GPC3 CAR T

Drug Info

Phase 1

Hepatocellular carcinoma

[12]

CAR-GPC3 T Cells

Drug Info

Phase 1

Lung squamous cell carcinoma

[13]

ERY974

Drug Info

Phase 1

Solid tumour/cancer

[14]

GAP T cells

Drug Info

Phase 1

Solid tumour/cancer

[15]

GLYCAR T cells

Drug Info

Phase 1

Hepatocellular carcinoma

[16]

GPC3 targeting CAR-T cells

Drug Info

Phase 1

Hepatocellular carcinoma

[17]

TAK-102

Drug Info

Phase 1

Solid tumour/cancer

[18]

CAR-GPC3 T cell

Drug Info

Clinical trial

Hepatocellular carcinoma

[19]

CAR-GPC3 T cells

Drug Info

Clinical trial

Hepatocellular carcinoma

[20]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 3 Inhibitor drugs

Codrituzumab

Drug Info

[2]

GC33

Drug Info

[21]

ERY974

Drug Info

[2]

CAR-T-Cell-Therapy

[+] 12 CAR-T-Cell-Therapy drugs

CAR-T cells targeting Glypican-3 (GPC3)

Drug Info

[7]

CAR-T cells targeting GPC3

Drug Info

[8]

GPC3-CART cells

Drug Info

[9]

Retroviral vector-transduced autologous T cells to express anti-GPC3 CARs

Drug Info

[10]

TAI-GPC3-CART cells

Drug Info

[11]

Anti-GPC3 CAR T

Drug Info

[12]

CAR-GPC3 T Cells

Drug Info

[13]

GAP T cells

Drug Info

[15]

GLYCAR T cells

Drug Info

[16]

GPC3 targeting CAR-T cells

Drug Info

[17]

CAR-GPC3 T cell

Drug Info

[19]

CAR-GPC3 T cells

Drug Info

[20]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Biological Network Descriptors

There is no similarity protein (E value < 0.005) for this target

Degree	6	Degree centrality	6.45E-04	Betweenness centrality	1.30E-04
Closeness centrality	1.93E-01	Radiality	1.33E+01	Clustering coefficient	6.67E-02
Neighborhood connectivity	1.05E+01	Topological coefficient	2.34E-01	Eccentricity	13
Download	Click to Download the Full PPI Network of This Target

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 1 KEGG Pathways

Proteoglycans in cancer

NetPath Pathway

[+] 1 NetPath Pathways

IL2 Signaling Pathway

PID Pathway

[+] 2 PID Pathways

Glypican pathway

Glypican 3 network

Reactome

[+] 3 Reactome Pathways

A tetrasaccharide linker sequence is required for GAG synthesis

HS-GAG degradation

Retinoid metabolism and transport

WikiPathways

[+] 1 WikiPathways

Visual phototransduction

References

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REF 1

Usefulness of a novel oncofetal antigen, glypican-3, for diagnosis and immunotherapy of hepatocellular carcinoma. Nihon Rinsho Meneki Gakkai Kaishi. 2008 Oct;31(5):383-91.

REF 2

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 3

ClinicalTrials.gov (NCT01507168) A Study of RO5137382 (GC33) in Patients With Advanced or Metastatic Hepatocellular Carcinoma. U.S. National Institutes of Health.

REF 4

Glypican-3 is a biomarker and a therapeutic target of hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2015 Aug;14(4):361-6.

REF 5

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8406).

REF 6

ClinicalTrials.gov (NCT05450562) A Phase 1/2 Open-label, First-in-human, Dose Escalation and Expansion Study for the Evaluation of Safety, Pharmacokinetics, Pharmacodynamics, and Anti-tumor Activity of SAR444200-based Regimen in Participants With Advanced Solid Tumors. U.S.National Institutes of Health.

REF 7

ClinicalTrials.gov (NCT02723942) CAR-T Cell Immunotherapy for HCC Targeting GPC3

REF 8

ClinicalTrials.gov (NCT02959151) A Study of Chimeric Antigen Receptor T Cells Combined With Interventional Therapy in Advanced Liver Malignancy

REF 9

ClinicalTrials.gov (NCT03130712) A Study of GPC3-targeted T Cells by Intratumor Injection for Advanced HCC (GPC3-CART)

REF 10

ClinicalTrials.gov (NCT03084380) Anti-GPC3 CAR-T for Treating GPC3-positive Advanced Hepatocellular Carcinoma (HCC)

REF 11

ClinicalTrials.gov (NCT02715362) A Study of GPC3 Redirected Autologous T Cells for Advanced HCC

REF 12

ClinicalTrials.gov (NCT02395250) Anti-GPC3 CAR T for Treating Patients With Advanced HCC

REF 13

ClinicalTrials.gov (NCT02876978) Anti-GPC3 CAR T for Recurrent or Refractory Lung Squamous Cell Carcinoma

REF 14

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 15

ClinicalTrials.gov (NCT02932956) Glypican 3-specific Chimeric Antigen Receptor Expressed in T Cells for Patients With Pediatric Solid Tumors (GAP)

REF 16

ClinicalTrials.gov (NCT02905188) Glypican 3-specific Chimeric Antigen Receptor Expressing T Cells for Hepatocellular Carcinoma (GLYCAR)

REF 17

ClinicalTrials.gov (NCT03198546) GPC3-T2-CAR-T Cells for Immunotherapy of Cancer With GPC3 Expression

REF 18

ClinicalTrials.gov (NCT04405778) A Study of TAK-102 in Adult With Previously-Treated Solid Tumors. U.S. National Institutes of Health.

REF 19

ClinicalTrials.gov (NCT03302403) Clinical Study of Redirected Autologous T Cells With a Chimeric Antigen Receptor in Patients With Malignant Tumors

REF 20

ClinicalTrials.gov (NCT03146234) CAR-GPC3 T Cells in Patients With Refractory Hepatocellular Carcinoma

REF 21

First-in-man phase I study of GC33, a novel recombinant humanized antibody against glypican-3, in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2013 Feb 15;19(4):920-8.

REF 22

Clinical pipeline report, company report or official report of Sanofi

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