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- PDB-9ntq: Identification and non-clinical characterization of SAR444200, a ... -

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Basic information

Entry
Database: PDB / ID: 9ntq
TitleIdentification and non-clinical characterization of SAR444200, a novel anti-GPC3 T-cell engager, for the treatment of GPC3+ solid tumors
Components
  • A0226015A08
  • Glypican-3
KeywordsONCOPROTEIN/IMMUNE SYSTEM / GRIPS / ONCOPROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


peptidyl-dipeptidase inhibitor activity / mesonephric duct morphogenesis / regulation of protein localization to membrane / body morphogenesis / cell proliferation involved in kidney development / regulation of non-canonical Wnt signaling pathway / mesenchymal cell proliferation involved in ureteric bud development / Defective B3GALT6 causes EDSP2 and SEMDJL1 / Defective B4GALT7 causes EDS, progeroid type / Defective B3GAT3 causes JDSSDHD ...peptidyl-dipeptidase inhibitor activity / mesonephric duct morphogenesis / regulation of protein localization to membrane / body morphogenesis / cell proliferation involved in kidney development / regulation of non-canonical Wnt signaling pathway / mesenchymal cell proliferation involved in ureteric bud development / Defective B3GALT6 causes EDSP2 and SEMDJL1 / Defective B4GALT7 causes EDS, progeroid type / Defective B3GAT3 causes JDSSDHD / Defective EXT2 causes exostoses 2 / Defective EXT1 causes exostoses 1, TRPS2 and CHDS / cell proliferation involved in metanephros development / Glycosaminoglycan-protein linkage region biosynthesis / HS-GAG biosynthesis / cell migration involved in gastrulation / HS-GAG degradation / negative regulation of growth / positive regulation of Wnt signaling pathway, planar cell polarity pathway / positive regulation of BMP signaling pathway / coronary vasculature development / positive regulation of smoothened signaling pathway / embryonic hindlimb morphogenesis / regulation of canonical Wnt signaling pathway / anterior/posterior axis specification / Wnt signaling pathway, planar cell polarity pathway / branching involved in ureteric bud morphogenesis / smoothened signaling pathway / RSV-host interactions / bone mineralization / Respiratory syncytial virus (RSV) attachment and entry / positive regulation of endocytosis / anatomical structure morphogenesis / canonical Wnt signaling pathway / Retinoid metabolism and transport / side of membrane / lysosomal lumen / lung development / osteoclast differentiation / epithelial cell proliferation / positive regulation of D-glucose import / negative regulation of smoothened signaling pathway / response to bacterium / Post-translational protein phosphorylation / negative regulation of canonical Wnt signaling pathway / Golgi lumen / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / negative regulation of epithelial cell proliferation / positive regulation of protein catabolic process / positive regulation of canonical Wnt signaling pathway / cell migration / Attachment and Entry / endoplasmic reticulum lumen / cell surface / plasma membrane
Similarity search - Function
Glypican, conserved site / Glypicans signature. / Glypican / Glypican
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.04 Å
AuthorsBatchelor, J.D. / Svidritskiy, E.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Mol Cancer Ther / Year: 2025
Title: Identification and non-clinical characterization of SAR444200, a novel anti-GPC3 NANOBODY® T-cell engager, for the treatment of GPC3+ solid tumors.
Authors: Paolo Meoni / Ana Paula B Vintém / Virna F Cortez-Retamozo / Jasper Jacobs / Evelyn De Tavernier / Paola Fiorentini / Diane Van Hoorick / Joseph D Batchelor / Egor Svidritskiy / Yu Qiu / ...Authors: Paolo Meoni / Ana Paula B Vintém / Virna F Cortez-Retamozo / Jasper Jacobs / Evelyn De Tavernier / Paola Fiorentini / Diane Van Hoorick / Joseph D Batchelor / Egor Svidritskiy / Yu Qiu / Eline Dejonckheere / Aiqun Li / Lily I Pao / Marie-Ange Buyse /
Abstract: T-cell engager (TCE) immunotherapy has demonstrated significant clinical activity in multiple cancers by inducing co-engagement of T-cells and tumor cells, resulting in T-cell activation and T-cell- ...T-cell engager (TCE) immunotherapy has demonstrated significant clinical activity in multiple cancers by inducing co-engagement of T-cells and tumor cells, resulting in T-cell activation and T-cell-dependent cellular cytotoxicity (TDCC) against tumor cells. Current-generation TCEs are predominantly composed of antibody-based binding domains targeting the CD3e molecule of the T-cell antigen receptor (TCR)/CD3 complex on T-cells and a tumor-associated antigen on tumor cells. However, limitations of this approach include cytokine release syndrome and a limited therapeutic window. Here, we report the generation and preclinical evaluation of SAR444200, the first NANOBODY®-based TCE clinical candidate binding to TCRαβ and GPC3 to co-engage T-cells and GPC3+ tumor cells, causing TDCC. SAR444200 bound with nanomolar to picomolar affinity to TCRαβ and GPC3 respectively and induced in vitro TDCC against multiple human tumor cell lines with differential GPC3 expression with picomolar potency. In vivo analysis using human cancer cell line-derived (HuH-7 and HepG2) xenografts in immunodeficient mice showed complete tumor regression at doses starting from 0.7 mg/kg. In exploratory non-human primate studies, intravenous administration of SAR444200 was well tolerated up to 8 mg/kg and exhibited greater than dose-proportional clearances and dose-proportional maximum concentrations across the tested dose range. The highly potent and efficacious activity of SAR444200 in diverse models of GPC3+ tumors and the extremely wide tolerated dose range merits further development of this compound. Furthermore, NANOBODY®-based TCEs developed using an anti-TCRαβ moiety may have specific advantages for the development of TCEs.
History
DepositionMar 18, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 15, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Glypican-3
B: A0226015A08
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,7933
Polymers63,5722
Non-polymers2211
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Glypican-3 / GTR2-2 / Intestinal protein OCI-5 / MXR7 / GPC3


Mass: 50961.965 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GPC3, OCI5 / Production host: Homo sapiens (human) / References: UniProt: P51654
#2: Protein A0226015A08


Mass: 12610.134 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#3: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: 2D ARRAY / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: GPC3_A0026015A08 complex / Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 80 e/Å2 / Film or detector model: GATAN K2 IS (4k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 4.04 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 88803 / Symmetry type: POINT

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