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- EMDB-49735: abTCR bound to SAR444200, a novel anti-GPC3 T-cell engager, for t... -

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Basic information

Entry
Database: EMDB / ID: EMD-49735
TitleabTCR bound to SAR444200, a novel anti-GPC3 T-cell engager, for the treatment of GPC3+ solid tumors
Map data
Sample
  • Complex: TCRab
    • Protein or peptide: M1-specific T cell receptor alpha chain
    • Protein or peptide: M1-specific T cell receptor beta chain
    • Protein or peptide: 2C04
    • Protein or peptide: TCE01
KeywordsTCR / T-cell receptor / NANOBODY / IMMUNE SYSTEM
Function / homology
Function and homology information


T cell activation involved in immune response / T cell receptor complex / adaptive immune response / cell surface
Similarity search - Function
: / : / T-cell receptor alpha chain, constant domain / Domain of unknown function (DUF1968) / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / Immunoglobulin C-Type ...: / : / T-cell receptor alpha chain, constant domain / Domain of unknown function (DUF1968) / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
M1-specific T cell receptor alpha chain / M1-specific T cell receptor beta chain
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsSvidritskiy E / Qiu Y / Yanfeng Z
Funding support1 items
OrganizationGrant numberCountry
Not fundedNone
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 14, 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_49735.png

Downloads & links

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Map

FileDownload / File: emd_49735.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 200 pix.
= 166. Å		0.83 Å/pix.
x 200 pix.
= 166. Å		0.83 Å/pix.
x 200 pix.
= 166. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.03
Minimum - Maximum-0.11968331 - 0.17545629
Average (Standard dev.)0.0002136498 (±0.004383225)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 166.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_49735_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_49735_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : TCRab

EntireName: TCRab
Components
  • Complex: TCRab
    • Protein or peptide: M1-specific T cell receptor alpha chain
    • Protein or peptide: M1-specific T cell receptor beta chain
    • Protein or peptide: 2C04
    • Protein or peptide: TCE01

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Supramolecule #1: TCRab

SupramoleculeName: TCRab / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: M1-specific T cell receptor alpha chain

MacromoleculeName: M1-specific T cell receptor alpha chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 21.782236 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QLLEQSPQFL SIQEGENLTV YCNSSSVFSS LQWYRQEPGE GPVLLVTVVT GGEVKKLKRL TFQFGDARKD SSLHITAAQP GDTGLYLCA GAGSQGNLIF GKGTKLSVKP NIQNPDPAVY QLRDSKSSDK SVCLFTDFDS QTNVSQSKDS DVYITDKCVL D MRSMDFKS ...String:
QLLEQSPQFL SIQEGENLTV YCNSSSVFSS LQWYRQEPGE GPVLLVTVVT GGEVKKLKRL TFQFGDARKD SSLHITAAQP GDTGLYLCA GAGSQGNLIF GKGTKLSVKP NIQNPDPAVY QLRDSKSSDK SVCLFTDFDS QTNVSQSKDS DVYITDKCVL D MRSMDFKS NSAVAWSNKS DFACANAFNN SIIPEDTFFP S

UniProtKB: M1-specific T cell receptor alpha chain

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Macromolecule #2: M1-specific T cell receptor beta chain

MacromoleculeName: M1-specific T cell receptor beta chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 27.555459 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DGGITQSPKY LFRKEGQNVT LSCEQNLNHD AMYWYRQDPG QGLRLIYYSQ IVNDFQKGDI AEGYSVSREK KESFPLTVTS AQKNPTAFY LCASSSRSSY EQYFGPGTRL TVTEDLKNVF PPEVAVFEPS EAEISHTQKA TLVCLATGFY PDHVELSWWV N GKEVHSGV ...String:
DGGITQSPKY LFRKEGQNVT LSCEQNLNHD AMYWYRQDPG QGLRLIYYSQ IVNDFQKGDI AEGYSVSREK KESFPLTVTS AQKNPTAFY LCASSSRSSY EQYFGPGTRL TVTEDLKNVF PPEVAVFEPS EAEISHTQKA TLVCLATGFY PDHVELSWWV N GKEVHSGV CTDPQPLKEQ PALNDSRYSL SSRLRVSATF WQNPRNHFRC QVQFYGLSEN DEWTQDRAKP VTQIVSAEAW GR AD

UniProtKB: M1-specific T cell receptor beta chain

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Macromolecule #3: 2C04

MacromoleculeName: 2C04 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.562209 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
VQLVESGGGL VQAGGSLRLS CAASGSIVGI HSVGWYRQVP GRQRELVATI VTDTGTHYRD FVKGRFTISR DIAKNTLYLQ MNSLQPEDT AVYYCYFNLI RGRYWAQGTL VTVSS

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Macromolecule #4: TCE01

MacromoleculeName: TCE01 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.061505 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
DVQLVESGGG VVQPGGSLRL SCVASGYVHK INFYGWYRQA PGKEREKVAH ISIGDQTDYA DSAKGRFTIS RDESKNTVYL QMNSLRPED TAAYYCRALS RIWPYDYWGQ GTLVTVSS

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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 QUANTUM (4k x 4k) / Average electron dose: 80.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.2 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: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 95366
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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