+Open data
-Basic information
Entry | Database: PDB / ID: 8ucd | ||||||
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Title | Cryo-EM structure of human STEAP1 in complex with AMG 509 Fab | ||||||
Components |
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Keywords | membrane protein/immune system / membrane protein / antibody / cancer / membrane protein-immune system complex | ||||||
Function / homology | Function and homology information cell-cell junction / endosome membrane / endosome / heme binding / membrane / metal ion binding / plasma membrane Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å | ||||||
Authors | Li, F. / Bailis, J.M. / Zhang, H. | ||||||
Funding support | United States, 1items
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Citation | Journal: Cancer Discov / Year: 2024 Title: AMG 509 (Xaluritamig), an Anti-STEAP1 XmAb 2+1 T-cell Redirecting Immune Therapy with Avidity-Dependent Activity against Prostate Cancer. Authors: Olivier Nolan-Stevaux / Cong Li / Lingming Liang / Jinghui Zhan / Juan Estrada / Tao Osgood / Fei Li / Hanzhi Zhang / Ryan Case / Christopher M Murawsky / Bram Estes / Gregory L Moore / ...Authors: Olivier Nolan-Stevaux / Cong Li / Lingming Liang / Jinghui Zhan / Juan Estrada / Tao Osgood / Fei Li / Hanzhi Zhang / Ryan Case / Christopher M Murawsky / Bram Estes / Gregory L Moore / Matthew J Bernett / Umesh Muchhal / John R Desjarlais / Binnaz K Staley / Jennitte Stevens / Keegan S Cooke / Famke Aeffner / Oliver Thomas / Julia Stieglmaier / Jae-Lyun Lee / Angela Coxon / Julie M Bailis / Abstract: The tumor-associated antigen STEAP1 is a potential therapeutic target that is expressed in most prostate tumors and at increased levels in metastatic castration-resistant prostate cancer (mCRPC). We ...The tumor-associated antigen STEAP1 is a potential therapeutic target that is expressed in most prostate tumors and at increased levels in metastatic castration-resistant prostate cancer (mCRPC). We developed a STEAP1-targeted XmAb 2+1 T-cell engager (TCE) molecule, AMG 509 (also designated xaluritamig), that is designed to redirect T cells to kill prostate cancer cells that express STEAP1. AMG 509 mediates potent T cell-dependent cytotoxicity of prostate cancer cell lines in vitro and promotes tumor regression in xenograft and syngeneic mouse models of prostate cancer in vivo. The avidity-driven activity of AMG 509 enables selectivity for tumor cells with high STEAP1 expression compared with normal cells. AMG 509 is the first STEAP1 TCE to advance to clinical testing, and we report a case study of a patient with mCRPC who achieved an objective response on AMG 509 treatment. SIGNIFICANCE: Immunotherapy in prostate cancer has met with limited success due to the immunosuppressive microenvironment and lack of tumor-specific targets. AMG 509 provides a targeted immunotherapy ...SIGNIFICANCE: Immunotherapy in prostate cancer has met with limited success due to the immunosuppressive microenvironment and lack of tumor-specific targets. AMG 509 provides a targeted immunotherapy approach to engage a patient's T cells to kill STEAP1-expressing tumor cells and represents a new treatment option for mCRPC and potentially more broadly for prostate cancer. See related commentary by Hage Chehade et al., p. 20. See related article by Kelly et al., p. 76. This article is featured in Selected Articles from This Issue, p. 5. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8ucd.cif.gz | 196.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8ucd.ent.gz | 152.1 KB | Display | PDB format |
PDBx/mmJSON format | 8ucd.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8ucd_validation.pdf.gz | 1.8 MB | Display | wwPDB validaton report |
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Full document | 8ucd_full_validation.pdf.gz | 1.8 MB | Display | |
Data in XML | 8ucd_validation.xml.gz | 52.7 KB | Display | |
Data in CIF | 8ucd_validation.cif.gz | 73 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/uc/8ucd ftp://data.pdbj.org/pub/pdb/validation_reports/uc/8ucd | HTTPS FTP |
-Related structure data
Related structure data | 42124MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 1 types, 3 molecules ABC
#1: Protein | Mass: 41215.270 Da / Num. of mol.: 3 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: STEAP1 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q9UHE8 |
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-Antibody , 2 types, 2 molecules HL
#2: Antibody | Mass: 20227.457 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) |
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#3: Antibody | Mass: 23391.014 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) |
-Non-polymers , 4 types, 10 molecules
#4: Chemical | #5: Chemical | #6: Chemical | #7: Water | ChemComp-HOH / | |
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-Details
Has ligand of interest | N |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: complex of human STEAP1 with AMG 509 Fab / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT |
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Molecular weight | Value: 0.168 MDa / Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.5 |
Specimen | Conc.: 2.3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: GOLD / Grid mesh size: 200 divisions/in. |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm |
Image recording | Electron dose: 47 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k) |
-Processing
EM software | Name: PHENIX / Version: 1.19.2_4158: / Category: model refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 203530 / Symmetry type: POINT | ||||||||||||||||||||||||
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