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- PDB-12er: Cryo-EM structure of BCMA in complex with the BCMA-targeted Fab a... -

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Entry
Database: PDB / ID: 12er
TitleCryo-EM structure of BCMA in complex with the BCMA-targeted Fab arm of teclistamab and the Fab fragment of an anti-lambda light chain antibody REGN15499
Components
  • Heavy chain of the BCMA-targeted Fab arm of teclistamab
  • Heavy chain of the Fab fragment of an anti-lambda light chain antibody REGN15499
  • Light chain of the BCMA-targeted Fab arm of teclistamab
  • Light chain of the Fab fragment of an anti-lambda light chain antibody REGN15499
  • Tumor necrosis factor receptor superfamily member 17
KeywordsMEMBRANE PROTEIN / BCMA / teclistamab / antibody / cryo-EM
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 speciesMus musculus (house mouse)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.99 Å
AuthorsZhou, Y. / Franklin, M.C.
Funding support United States, 1items
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, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 12, 2026Provider: repository / Type: Initial release
Revision 1.0Aug 12, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Aug 12, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Aug 12, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Aug 12, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Aug 12, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
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Assembly

Deposited unit
A: Heavy chain of the Fab fragment of an anti-lambda light chain antibody REGN15499
B: Light chain of the Fab fragment of an anti-lambda light chain antibody REGN15499
C: Tumor necrosis factor receptor superfamily member 17
D: Heavy chain of the BCMA-targeted Fab arm of teclistamab
E: Light chain of the BCMA-targeted Fab arm of teclistamab


Theoretical massNumber of molelcules
Total (without water)102,1155
Polymers102,1155
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Antibody Heavy chain of the Fab fragment of an anti-lambda light chain antibody REGN15499


Mass: 23241.957 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Cricetulus griseus (Chinese hamster)
#2: Antibody Light chain of the Fab fragment of an anti-lambda light chain antibody REGN15499


Mass: 23588.006 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Cricetulus griseus (Chinese hamster)
#3: Protein Tumor necrosis factor receptor superfamily member 17 / B-cell maturation protein


Mass: 9219.270 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TNFRSF17, BCM, BCMA / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: Q02223
#4: Antibody Heavy chain of the BCMA-targeted Fab arm of teclistamab


Mass: 23411.160 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#5: Antibody Light chain of the BCMA-targeted Fab arm of teclistamab


Mass: 22654.945 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1BCMA extracellular domain in complex with the BCMA-targeted Fab arm of teclistamab and the Fab fragment of an anti-lambda light chain antibody REGN15499COMPLEXall0MULTIPLE SOURCES
2Human BCMA (TNFRSF17) extracellular domain with a Myc-Myc-His tagCOMPLEX#31RECOMBINANT
3BCMA-targeted Fab arm of teclistamabCOMPLEX#4-#51RECOMBINANT
4Fab fragment of an anti-lambda light chain antibody REGN15499COMPLEX#1-#21RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
44Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Cricetulus griseus (Chinese hamster)10029
33Cricetulus griseus (Chinese hamster)10029
44Cricetulus griseus (Chinese hamster)10029
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.99 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 309709 / Symmetry type: POINT
RefinementHighest resolution: 2.99 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0027011
ELECTRON MICROSCOPYf_angle_d0.4619565
ELECTRON MICROSCOPYf_dihedral_angle_d3.44979
ELECTRON MICROSCOPYf_chiral_restr0.0411087
ELECTRON MICROSCOPYf_plane_restr0.0041224

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