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- EMDB-71128: Cryo-EM structure of CD73 in complex with antibody Sym024 -

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Basic information

Entry
Database: EMDB / ID: EMD-71128
TitleCryo-EM structure of CD73 in complex with antibody Sym024
Map dataComposite map
Sample
  • Complex: CD73 dimer bound to antibody Sym024
    • Protein or peptide: 5'-nucleotidase
    • Protein or peptide: Antibody Light Chain
    • Protein or peptide: Antibody Heavy Chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: ZINC ION
KeywordsAntigen-Antibody Complex / Drug Target / HYDROLASE
Function / homology
Function and homology information


thymidylate 5'-phosphatase / : / ADP catabolic process / 5'-deoxynucleotidase / 5'-deoxynucleotidase activity / 7-methylguanosine nucleotidase / adenosine biosynthetic process / inhibition of non-skeletal tissue mineralization / Pyrimidine catabolism / AMP catabolic process ...thymidylate 5'-phosphatase / : / ADP catabolic process / 5'-deoxynucleotidase / 5'-deoxynucleotidase activity / 7-methylguanosine nucleotidase / adenosine biosynthetic process / inhibition of non-skeletal tissue mineralization / Pyrimidine catabolism / AMP catabolic process / : / IMP-specific 5'-nucleotidase / : / Nicotinate metabolism / 5'-nucleotidase / Purine catabolism / 5'-nucleotidase activity / leukocyte cell-cell adhesion / DNA metabolic process / response to ATP / ATP metabolic process / Purinergic signaling in leishmaniasis infection / calcium ion homeostasis / negative regulation of inflammatory response / external side of plasma membrane / nucleotide binding / cell surface / extracellular exosome / zinc ion binding / nucleoplasm / identical protein binding / membrane / plasma membrane / cytosol
Similarity search - Function
5'-nucleotidase signature 1. / 5'-Nucleotidase, conserved site / 5'-nucleotidase signature 2. / 5'-Nucleotidase, C-terminal / 5'-nucleotidase, C-terminal domain / 5'-Nucleotidase/apyrase / 5'-Nucleotidase, C-terminal domain superfamily / Calcineurin-like phosphoesterase domain, ApaH type / Calcineurin-like phosphoesterase / Metallo-dependent phosphatase-like
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsArmbruster E / Bansia H / Des Georges A
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: Clin Cancer Res / Year: 2026
Title: Sym024 interacts with a unique epitope on the CD73 homodimer, favoring effective bivalent binding to improve anti-PD1 therapy.
Authors: Janus S Jakobsen / Michael M Grandal / Randi W Hansen / Harsh Bansia / Emily Armbruster / Isabelle Theret / Niels Jørgen Ø Skartved / Rikke Hald / Maria C Melander / Anne Worsaae / Matteo ...Authors: Janus S Jakobsen / Michael M Grandal / Randi W Hansen / Harsh Bansia / Emily Armbruster / Isabelle Theret / Niels Jørgen Ø Skartved / Rikke Hald / Maria C Melander / Anne Worsaae / Matteo Riva / Kristian Reckzeh / Laurent Vuillard / Johan Lantto / Amedee des Georges / Camilla Fröhlich /
Abstract: PURPOSE: Adenosine signaling may be a central immune suppressive mechanism in several cancers, and blockade of the rate-limiting CD73 AMP-to-adenosine enzyme has been demonstrated to improve clinical ...PURPOSE: Adenosine signaling may be a central immune suppressive mechanism in several cancers, and blockade of the rate-limiting CD73 AMP-to-adenosine enzyme has been demonstrated to improve clinical efficacy of PD(L)-1 immune therapy. However, deep inhibition of CD73 activity could prove difficult in tumor environments with a constant AMP supply and high CD73 levels. Here, we sought to identify, characterize, and benchmark a novel antagonistic anti-CD73 antibody, Sym024 (S95024), and to structurally decode its mode of action.
EXPERIMENTAL DESIGN: Sym024, selected via functional antibody repertoire screening, was tested against benchmark anti-CD73 antibodies in primary cell, cell line in vitro binding, CD73 enzymatic ...EXPERIMENTAL DESIGN: Sym024, selected via functional antibody repertoire screening, was tested against benchmark anti-CD73 antibodies in primary cell, cell line in vitro binding, CD73 enzymatic activity, and T cell activation assays. Its in vivo tumor growth inhibition was examined in transplanted human or mouse tumors in immunocompetent or immunodeficient mice, and intra-tumoral enzymatic inhibition and immune cell recruitment were assessed. We investigated Sym024-CD73 interaction using surface plasmon resonance, cryo-electron microscopy, site-directed mutagenesis, and population level complex formation through size-exclusion-chromatography with light scatter mass detection. Preclinical safety and pharmacokinetics were assessed in monkeys.
RESULTS: Sym024 effectively blocked CD73 across a large range of enzyme expression levels, comparing favorably to benchmark anti-CD73 antibodies; it improved the efficacy of PD-1 blockade in vitro as ...RESULTS: Sym024 effectively blocked CD73 across a large range of enzyme expression levels, comparing favorably to benchmark anti-CD73 antibodies; it improved the efficacy of PD-1 blockade in vitro as well as in vivo. Our structural data indicate that a unique one-to-one Sym024-CD73 interaction engenders this comprehensive inhibition. No pre-clinical safety flags were observed, and the pharmacokinetics profile of Sym024 supported a standard clinical dosing regimen.
CONCLUSIONS: The comprehensive CD73 inhibition exhibited by Sym024 may improve the efficacy of anti-PD(L)-1/anti-CD73 combination treatment.
History
DepositionJun 10, 2025-
Header (metadata) releaseDec 24, 2025-
Map releaseDec 24, 2025-
UpdateJan 21, 2026-
Current statusJan 21, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_71128.png

Downloads & links

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Map

FileDownload / File: emd_71128.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationComposite map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 320 pix.
= 270.88 Å		0.85 Å/pix.
x 320 pix.
= 270.88 Å		0.85 Å/pix.
x 320 pix.
= 270.88 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8465 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.735
Minimum - Maximum-0.14208432 - 4.0800376
Average (Standard dev.)0.02404532 (±0.07942011)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 270.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : CD73 dimer bound to antibody Sym024

EntireName: CD73 dimer bound to antibody Sym024
Components
  • Complex: CD73 dimer bound to antibody Sym024
    • Protein or peptide: 5'-nucleotidase
    • Protein or peptide: Antibody Light Chain
    • Protein or peptide: Antibody Heavy Chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: ZINC ION

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Supramolecule #1: CD73 dimer bound to antibody Sym024

SupramoleculeName: CD73 dimer bound to antibody Sym024 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: 5'-nucleotidase

MacromoleculeName: 5'-nucleotidase / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: thymidylate 5'-phosphatase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 59.514633 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: AWELTILHTN DVHSRLEQTS EDSSKCVNAS RCMGGVARLF TKVQQIRRAE PNVLLLDAGD QYQGTIWFTV YKGAEVAHFM NALRYDAMA LGNHEFDNGV EGLIEPLLKE AKFPILSANI KAKGPLASQI SGLYLPYKVL PVGDEVVGIV GYTSKETPFL S NPGTNLVF ...String:
AWELTILHTN DVHSRLEQTS EDSSKCVNAS RCMGGVARLF TKVQQIRRAE PNVLLLDAGD QYQGTIWFTV YKGAEVAHFM NALRYDAMA LGNHEFDNGV EGLIEPLLKE AKFPILSANI KAKGPLASQI SGLYLPYKVL PVGDEVVGIV GYTSKETPFL S NPGTNLVF EDEITALQPE VDKLKTLNVN KIIALGHSGF EMDKLIAQKV RGVDVVVGGH SNTFLYTGNP PSKEVPAGKY PF IVTSDDG RKVPVVQAYA FGKYLGYLKI EFDERGNVIS SHGNPILLNS SIPEDPSIKA DINKWRIKLD NYSTQELGKT IVY LDGSSQ SCRFRECNMG NLICDAMINN NLRHTDEMFW NHVSMCILNG GGIRSPIDER NNGTITWENL AAVLPFGGTF DLVQ LKGST LKKAFEHSVH RYGQSTGEFL QVGGIHVVYD LSRKPGDRVV KLDVLCTKCR VPSYDPLKMD EVYKVILPNF LANGG DGFQ MIKDELLRHD SGDQDINVVS TYISKMKVIY PAVEGRIKFS LEGSGSHHHH HH

UniProtKB: 5'-nucleotidase

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Macromolecule #2: Antibody Light Chain

MacromoleculeName: Antibody Light Chain / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.200814 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIQMTQSPSS VSASVGDRVT ITCRATQGIS RRLAWYQQKP GKAPKLLIYA ASSLQSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQ QANSFPLTFG GGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
DIQMTQSPSS VSASVGDRVT ITCRATQGIS RRLAWYQQKP GKAPKLLIYA ASSLQSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQ QANSFPLTFG GGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #3: Antibody Heavy Chain

MacromoleculeName: Antibody Heavy Chain / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 49.603695 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLVESGGG LVQPGRSLRL SCAASGFTFD DFAMHWVRQA PGKGLEWVSG ISWNSGNIGY ADSVKGRFTI SRDNAKNSLY LQMNSLRAE DTALYYCAKD KSGSPYYYYG MDVWGQGTMV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP V TVSWNSGA ...String:
EVQLVESGGG LVQPGRSLRL SCAASGFTFD DFAMHWVRQA PGKGLEWVSG ISWNSGNIGY ADSVKGRFTI SRDNAKNSLY LQMNSLRAE DTALYYCAKD KSGSPYYYYG MDVWGQGTMV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP V TVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS LGTQTYICNV NHKPSNTKVD KRVEPKSCDK THTCPPCPAP EA AGGPSVF LFPPKPKDTL MISRTPEVTC VVVDVSHEDP EVKFNWYVDG VEVHNAKTKP REEQYNSTYR VVSVLTVLHQ DWL NGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTT PPVLD SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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Macromolecule #5: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 5 / Number of copies: 4 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.5 mg/mL
BufferpH: 5.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS TITAN THEMIS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 0.8 µm

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 286779
Initial angle assignmentType: COMMON LINE
Final angle assignmentType: MAXIMUM LIKELIHOOD

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