Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTJTSX4)

• DTT Name: Glypican-3 (GPC3)
• Synonyms: Secreted glypican3; OCI5; MXR7; Intestinal protein OCI5; Intestinal protein OCI-5; GTR22; GTR2-2
• Gene Name: GPC3
• DTT Type: Clinical trial target; [1]
• UniProt ID: GPC3_HUMAN
• TTD ID: T25726
• Sequence:
  MAGTVRTACLVVAMLLSLDFPGQAQPPPPPPDATCHQVRSFFQRLQPGLKWVPETPVPGS
  DLQVCLPKGPTCCSRKMEEKYQLTARLNMEQLLQSASMELKFLIIQNAAVFQEAFEIVVR
  HAKNYTNAMFKNNYPSLTPQAFEFVGEFFTDVSLYILGSDINVDDMVNELFDSLFPVIYT
  QLMNPGLPDSALDINECLRGARRDLKVFGNFPKLIMTQVSKSLQVTRIFLQALNLGIEVI
  NTTDHLKFSKDCGRMLTRMWYCSYCQGLMMVKPCGGYCNVVMQGCMAGVVEIDKYWREYI
  LSLEELVNGMYRIYDMENVLLGLFSTIHDSIQYVQKNAGKLTTTIGKLCAHSQQRQYRSA
  YYPEDLFIDKKVLKVAHVEHEETLSSRRRELIQKLKSFISFYSALPGYICSHSPVAENDT
  LCWNGQELVERYSQKAARNGMKNQFNLHELKMKGPEPVVSQIIDKLKHINQLLRTMSMPK
  GRVLDKNLDEEGFESGDCGDDEDECIGGSGDGMIKVKNQLRFLAELAYDLDVDDAPGNSQ
  QATPKDNEISTFHNLGNVHSPLKLLTSMAISVVCFFFLVH
• 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.
• KEGG Pathway: Proteoglycans in cancer (hsa05205)
• Reactome Pathway:
  HS-GAG degradation (R-HSA-2024096)
  Retinoid metabolism and transport (R-HSA-975634)
  A tetrasaccharide linker sequence is required for GAG synthesis (R-HSA-1971475)

Molecular Interaction Atlas (MIA) of This DTT

18 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Codrituzumab	DMDWG36	Hepatic metastasis	2D80	Phase 2	[2]
GC33	DMXTD74	Hepatocellular carcinoma	2C12.02	Phase 2	[3]
GPC-3298306	DMOHAS2	Hepatocellular carcinoma	2C12.02	Phase 2	[1]
RG7686	DM6CNFW	Hepatocellular carcinoma	2C12.02	Phase 2	[3]
SAR444200	DM7J5H0	Aggressive cancer	2A00-2F9Z	Phase 2	[4]
CAR-T cells targeting Glypican-3 (GPC3)	DMDSKR2	Hepatocellular carcinoma	2C12.02	Phase 1/2	[5]
CAR-T cells targeting GPC3	DM6H1MQ	Hepatocellular carcinoma	2C12.02	Phase 1/2	[6]
GPC3-CART cells	DMGN679	Hepatocellular carcinoma	2C12.02	Phase 1/2	[7]
Retroviral vector-transduced autologous T cells to express anti-GPC3 CARs	DMDO6J1	Hepatocellular carcinoma	2C12.02	Phase 1/2	[8]
TAI-GPC3-CART cells	DMCFSZ5	Hepatocellular carcinoma	2C12.02	Phase 1/2	[9]
Anti-GPC3 CAR T	DMUMWFK	Hepatocellular carcinoma	2C12.02	Phase 1	[10]
CAR-GPC3 T Cells	DMQH2DK	Lung squamous cell carcinoma	2C25.2	Phase 1	[11]
ERY974	DM9YNTO	Solid tumour/cancer	2A00-2F9Z	Phase 1	[2]
GAP T cells	DMIXMQE	Solid tumour/cancer	2A00-2F9Z	Phase 1	[12]
GLYCAR T cells	DM1PK0T	Hepatocellular carcinoma	2C12.02	Phase 1	[13]
GPC3 targeting CAR-T cells	DMVWHS1	Hepatocellular carcinoma	2C12.02	Phase 1	[14]
TAK-102	DMD79TX	Solid tumour/cancer	2A00-2F9Z	Phase 1	[15]
CAR-GPC3 T cell	DMBDT3V	Hepatocellular carcinoma	2C12.02	Clinical trial	[16]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Liver cancer	2C82	Liver tissue	5.54E-86	3	9.74

References

• [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.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] 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.
• [4] Clinical pipeline report, company report or official report of Sanofi
• [5] ClinicalTrials.gov (NCT02723942) CAR-T Cell Immunotherapy for HCC Targeting GPC3
• [6] ClinicalTrials.gov (NCT02959151) A Study of Chimeric Antigen Receptor T Cells Combined With Interventional Therapy in Advanced Liver Malignancy
• [7] ClinicalTrials.gov (NCT03130712) A Study of GPC3-targeted T Cells by Intratumor Injection for Advanced HCC (GPC3-CART)
• [8] ClinicalTrials.gov (NCT03084380) Anti-GPC3 CAR-T for Treating GPC3-positive Advanced Hepatocellular Carcinoma (HCC)
• [9] ClinicalTrials.gov (NCT02715362) A Study of GPC3 Redirected Autologous T Cells for Advanced HCC
• [10] ClinicalTrials.gov (NCT02395250) Anti-GPC3 CAR T for Treating Patients With Advanced HCC
• [11] ClinicalTrials.gov (NCT03146234) CAR-GPC3 T Cells in Patients With Refractory Hepatocellular Carcinoma
• [12] ClinicalTrials.gov (NCT02932956) Glypican 3-specific Chimeric Antigen Receptor Expressed in T Cells for Patients With Pediatric Solid Tumors (GAP)
• [13] ClinicalTrials.gov (NCT02905188) Glypican 3-specific Chimeric Antigen Receptor Expressing T Cells for Hepatocellular Carcinoma (GLYCAR)
• [14] ClinicalTrials.gov (NCT03198546) GPC3-T2-CAR-T Cells for Immunotherapy of Cancer With GPC3 Expression
• [15] ClinicalTrials.gov (NCT04405778) A Study of TAK-102 in Adult With Previously-Treated Solid Tumors. U.S. National Institutes of Health.
• [16] ClinicalTrials.gov (NCT03302403) Clinical Study of Redirected Autologous T Cells With a Chimeric Antigen Receptor in Patients With Malignant Tumors