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- EMDB-76385: Cryo-EM structure of BCMA in complex with the BCMA-targeted Fab a... -

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Basic information

Entry
Database: EMDB / ID: EMD-76385
TitleCryo-EM structure of BCMA in complex with the BCMA-targeted Fab arm of linvoseltamab and the Fab fragment of an anti-kappa light chain antibody REGN654
Map data
Sample
  • Complex: BCMA extracellular domain in complex with the BCMA-targeted Fab arm of linvoseltamab and the Fab fragment of an anti-kappa light chain antibody REGN654
    • Complex: Human BCMA (TNFRSF17) extracellular domain with a Myc-Myc-His tag
      • Protein or peptide: Tumor necrosis factor receptor superfamily member 17
    • Complex: BCMA-targeted Fab arm of linvoseltamab
      • Protein or peptide: Heavy chain of the BCMA-targeted Fab arm of linvoseltamab
      • Protein or peptide: Light chain of the BCMA-targeted Fab arm of linvoseltamab
    • Complex: Fab fragment of an anti-kappa light chain antibody REGN654
      • Protein or peptide: Heavy chain of the Fab fragment of an anti-kappa light chain antibody REGN654
      • Protein or peptide: Light chain of the Fab fragment of an anti-kappa light chain antibody REGN654
KeywordsBCMA / linvoseltamab / antibody / cryo-EM / MEMBRANE PROTEIN
Function / homology
Function and homology information


TNFs bind their physiological receptors / endomembrane system / tumor necrosis factor-mediated signaling pathway / signaling receptor activity / adaptive immune response / signal transduction / membrane / plasma membrane
Similarity search - Function
BCMA, TALL-1 binding / Tumour necrosis factor receptor 17 / BCMA, TALL-1 binding / Tumor necrosis factor receptor 13C/17
Similarity search - Domain/homology
Tumor necrosis factor receptor superfamily member 17
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.43 Å
AuthorsZhou Y / Franklin MC
Funding support United States, 1 items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Blood Adv / Year: 2026
Title: DISTINCT EPITOPE ENGAGEMENT CONFERS DIFFERENTIAL ACTIVITY OF LINVOSELTAMAB VERSUS TECLISTAMAB ACROSS BCMA MUTATIONS.
Authors: Yi Zhou / Olga Sineshchekova / Ken Lee / Aneesha Doshi / Kyle Brown / Matthew C Franklin / Erica Ullman / Aynur Hermann / Glenn S Kroog / Anita Boyapati / Eric Smith / John C Lin / William C ...Authors: Yi Zhou / Olga Sineshchekova / Ken Lee / Aneesha Doshi / Kyle Brown / Matthew C Franklin / Erica Ullman / Aynur Hermann / Glenn S Kroog / Anita Boyapati / Eric Smith / John C Lin / William C Olson / Kara Olson /
Abstract: B-cell maturation antigen (BCMA) is a well-established therapeutic target in multiple myeloma. BCMA mutations have been identified in patients who relapsed after treatment with approved BCMA×CD3 ...B-cell maturation antigen (BCMA) is a well-established therapeutic target in multiple myeloma. BCMA mutations have been identified in patients who relapsed after treatment with approved BCMA×CD3 bispecific antibodies (bsAbs; eg, teclistamab). BCMA mutations can impair bsAb binding and cytotoxic activity in vitro, suggesting an acquired resistance mechanism leading to clinical relapse. Linvoseltamab (human BCMA×CD3 bsAb) was recently approved for adults with heavily pretreated relapsed/refractory multiple myeloma. Here, we compared the activity of linvoseltamab in the presence of cell lines expressing four BCMA mutations reported in patients treated with teclistamab: R27P, S30del, P34del (associated with resistance), and the germline variant P33S (identified in a relapsed patient but not associated with resistance). Linvoseltamab retained binding to cells expressing BCMA R27P and S30del mutations, and demonstrated robust Jurkat-NFAT reporter and primary T-cell activation, as well as targeted cytotoxicity against mutated BCMA that was comparable to wild-type BCMA. Conversely, teclistamab exhibited reduced binding and functional activity against these mutations. Both linvoseltamab and teclistamab showed impaired binding against P34del, consistent with diminished Jurkat-NFAT reporter, primary T-cell activation, and cytotoxicity. Both bsAbs retained activity against P33S. Cryogenic electron microscopy uncovered distinct binding orientations for linvoseltamab and teclistamab, consistent with the respective sensitivities to the studied BCMA mutations (ie, the selected residues contributed less to linvoseltamab binding than teclistamab binding, consistent with the broader activity of linvoseltamab across BCMA mutations). While linvoseltamab may be less susceptible than teclistamab to resistance mechanisms involving R27P and S30del, the clinical relevance of our findings is to be established.
History
DepositionMar 31, 2026-
Header (metadata) releaseAug 12, 2026-
Map releaseAug 12, 2026-
UpdateAug 12, 2026-
Current statusAug 12, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_76385.png

Downloads & links

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Map

FileDownload / File: emd_76385.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 320 pix.
= 275.2 Å		0.86 Å/pix.
x 320 pix.
= 275.2 Å		0.86 Å/pix.
x 320 pix.
= 275.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.14
Minimum - Maximum-0.44945 - 0.9683564
Average (Standard dev.)-0.00000002865787 (±0.021601679)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 275.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_76385_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_76385_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : BCMA extracellular domain in complex with the BCMA-targeted Fab a...

EntireName: BCMA extracellular domain in complex with the BCMA-targeted Fab arm of linvoseltamab and the Fab fragment of an anti-kappa light chain antibody REGN654
Components
  • Complex: BCMA extracellular domain in complex with the BCMA-targeted Fab arm of linvoseltamab and the Fab fragment of an anti-kappa light chain antibody REGN654
    • Complex: Human BCMA (TNFRSF17) extracellular domain with a Myc-Myc-His tag
      • Protein or peptide: Tumor necrosis factor receptor superfamily member 17
    • Complex: BCMA-targeted Fab arm of linvoseltamab
      • Protein or peptide: Heavy chain of the BCMA-targeted Fab arm of linvoseltamab
      • Protein or peptide: Light chain of the BCMA-targeted Fab arm of linvoseltamab
    • Complex: Fab fragment of an anti-kappa light chain antibody REGN654
      • Protein or peptide: Heavy chain of the Fab fragment of an anti-kappa light chain antibody REGN654
      • Protein or peptide: Light chain of the Fab fragment of an anti-kappa light chain antibody REGN654

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Supramolecule #1: BCMA extracellular domain in complex with the BCMA-targeted Fab a...

SupramoleculeName: BCMA extracellular domain in complex with the BCMA-targeted Fab arm of linvoseltamab and the Fab fragment of an anti-kappa light chain antibody REGN654
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: Human BCMA (TNFRSF17) extracellular domain with a Myc-Myc-His tag

SupramoleculeName: Human BCMA (TNFRSF17) extracellular domain with a Myc-Myc-His tag
type: complex / ID: 2 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: BCMA-targeted Fab arm of linvoseltamab

SupramoleculeName: BCMA-targeted Fab arm of linvoseltamab / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #4-#5
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #4: Fab fragment of an anti-kappa light chain antibody REGN654

SupramoleculeName: Fab fragment of an anti-kappa light chain antibody REGN654
type: complex / ID: 4 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Heavy chain of the Fab fragment of an anti-kappa light chain anti...

MacromoleculeName: Heavy chain of the Fab fragment of an anti-kappa light chain antibody REGN654
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.02977 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QVQLQQWGAG LLKPSETLSL TCAVYGGSLS DYYWTWIRQP PEKGLEWIGE INHSGSTNYA PSLKSRVTIS VDTSKNQFSL KLTSVTAAD TAVYYCARTT YGYDYYFDMD VWGQGTTVTV SSAKTTAPSV YPLAPVCGDT TGSSVTLGCL VKGYFPEPVT L TWNSGSLS ...String:
QVQLQQWGAG LLKPSETLSL TCAVYGGSLS DYYWTWIRQP PEKGLEWIGE INHSGSTNYA PSLKSRVTIS VDTSKNQFSL KLTSVTAAD TAVYYCARTT YGYDYYFDMD VWGQGTTVTV SSAKTTAPSV YPLAPVCGDT TGSSVTLGCL VKGYFPEPVT L TWNSGSLS SGVHTFPAVL QSDLYTLSSS VTVTSSTWPS QSITCNVAHP ASSTKVDKKI EPRGP

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Macromolecule #2: Light chain of the Fab fragment of an anti-kappa light chain anti...

MacromoleculeName: Light chain of the Fab fragment of an anti-kappa light chain antibody REGN654
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.404924 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: DIQMTQSPSS LSASVGDRVT ITCRASQVIT NFLAWYQQTP GKVPKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCQ KYNYTPLTFG GGTKVEIKRA DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS ...String:
DIQMTQSPSS LSASVGDRVT ITCRASQVIT NFLAWYQQTP GKVPKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCQ KYNYTPLTFG GGTKVEIKRA DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS KDSTYSMSST LTLTKDEYER HNSYTCEATH KTSTSPIVKS FNRGEC

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Macromolecule #3: Tumor necrosis factor receptor superfamily member 17

MacromoleculeName: Tumor necrosis factor receptor superfamily member 17 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 9.21927 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString:
MLQMAGQCSQ NEYFDSLLHA CIPCQLRCSS NTPPLTCQRY CNASVTNSVK GTNAEQKLIS EEDLGGEQKL ISEEDLHHHH HH

UniProtKB: Tumor necrosis factor receptor superfamily member 17

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Macromolecule #4: Heavy chain of the BCMA-targeted Fab arm of linvoseltamab

MacromoleculeName: Heavy chain of the BCMA-targeted Fab arm of linvoseltamab
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.654453 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: EVQLVESGGG LVQPGGSLRL SCAASGFTFS NFWMTWVRQA PGKGLEWVAN MNQDGSEKYY VDSVKGRFTI SRDNAKSSLY LQMNSLRAE DTAVYYCARD REYCISTSCY DDFDYWGQGT LVTVSSASTK GPSVFPLAPC SRSTSESTAA LGCLVKDYFP E PVTVSWNS ...String:
EVQLVESGGG LVQPGGSLRL SCAASGFTFS NFWMTWVRQA PGKGLEWVAN MNQDGSEKYY VDSVKGRFTI SRDNAKSSLY LQMNSLRAE DTAVYYCARD REYCISTSCY DDFDYWGQGT LVTVSSASTK GPSVFPLAPC SRSTSESTAA LGCLVKDYFP E PVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTKTYTC NVDHKPSNTK VDKRVESKY

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Macromolecule #5: Light chain of the BCMA-targeted Fab arm of linvoseltamab

MacromoleculeName: Light chain of the BCMA-targeted Fab arm of linvoseltamab
type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.448984 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: DIQMTQSPSS LSASVGDRVT ITCRASQSIS SYLNWYQQKP GKAPKLLIYA ASSLHSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQ QSYSTPPITF GQGTRLEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
DIQMTQSPSS LSASVGDRVT ITCRASQSIS SYLNWYQQKP GKAPKLLIYA ASSLHSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQ QSYSTPPITF GQGTRLEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.43 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 85730
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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