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- EMDB-49761: Identification and non-clinical characterization of SAR444200, a ... -

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Entry
Database: EMDB / ID: EMD-49761
TitleIdentification and non-clinical characterization of SAR444200, a novel anti-GPC3 T-cell engager, for the treatment of GPC3+ solid tumors
Map data
Sample
  • Complex: GPC3_A0026015A08 complex
    • Protein or peptide: Glypican-3
    • Protein or peptide: A0226015A08
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsGRIPS / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.04 Å
AuthorsBatchelor JD / Svidritskiy E
Funding support1 items
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, 2025-
Header (metadata) releaseOct 15, 2025-
Map releaseOct 15, 2025-
UpdateOct 15, 2025-
Current statusOct 15, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_49761.png

Downloads & links

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Map

FileDownload / File: emd_49761.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Contrast
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AxesZ (Sec.)Y (Row.)X (Col.)
0.89 Å/pix.
x 400 pix.
= 354. Å		0.89 Å/pix.
x 400 pix.
= 354. Å		0.89 Å/pix.
x 400 pix.
= 354. Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.885 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-1.2078433 - 1.2021663
Average (Standard dev.)-0.00041432178 (±0.026539868)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 354.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_49761_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_49761_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : GPC3_A0026015A08 complex

EntireName: GPC3_A0026015A08 complex
Components
  • Complex: GPC3_A0026015A08 complex
    • Protein or peptide: Glypican-3
    • Protein or peptide: A0226015A08
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: GPC3_A0026015A08 complex

SupramoleculeName: GPC3_A0026015A08 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Glypican-3

MacromoleculeName: Glypican-3 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50.961965 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: CHQVRSFFQR LQPGLKWVPE TPVPGSDLQV CLPKGPTCCS RKMEEKYQLT ARLNMEQLLQ SASMELKFLI IQNAAVFQEA FEIVVRHAK NYTNAMFKNN YPSLTPQAFE FVGEFFTDVS LYILGSDINV DDMVNELFDS LFPVIYTQLM NPGLPDSALD I NECLRGAR ...String:
CHQVRSFFQR LQPGLKWVPE TPVPGSDLQV CLPKGPTCCS RKMEEKYQLT ARLNMEQLLQ SASMELKFLI IQNAAVFQEA FEIVVRHAK NYTNAMFKNN YPSLTPQAFE FVGEFFTDVS LYILGSDINV DDMVNELFDS LFPVIYTQLM NPGLPDSALD I NECLRGAR RDLKVFGNFP KLIMTQVSKS LQVTRIFLQA LNLGIEVINT TDHLKFSKDC GRMLTRMWYC SYCQGLMMVK PC GGYCNVV MQGCMAGVVE IDKYWREYIL SLEELVNGMY RIYDMENVLL GLFSTIHDSI QYVQKNAGKL TTTIGKLCAH SQQ RQYRSA YYPEDLFIDK KVLKVAHVEH EETLSSRRRE LIQKLKSFIS FYSALPGYIC SHSPVAENDT LCWNGQELVE RYSQ KAARN GMKNQFNLHE LKMKGPEPVV SQIIDKLKHI NQLLRTMS

UniProtKB: Glypican-3

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Macromolecule #2: A0226015A08

MacromoleculeName: A0226015A08 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 12.610134 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
DVQLVESGGG LVQPGGSLRL SCVASGS(UNK)FR SVFSSSTMEW YRQPPGKKRE LVARIAPGDG TNYGALYADS VKGRFT ISR DDAKKTVDLQ MNSLKPEDTG VYFCASGVAW GQGTLVTVSS

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 1 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation state2D array

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K2 IS (4k x 4k) / Average electron dose: 80.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.04 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 88803
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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