12ES
Cryo-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
Summary for 12ES
| Entry DOI | 10.2210/pdb12es/pdb |
| EMDB information | 76385 |
| Descriptor | Heavy chain of the Fab fragment of an anti-kappa light chain antibody REGN654, Light chain of the Fab fragment of an anti-kappa light chain antibody REGN654, Tumor necrosis factor receptor superfamily member 17, ... (5 entities in total) |
| Functional Keywords | bcma, linvoseltamab, antibody, cryo-em, membrane protein |
| Biological source | Mus musculus More |
| Total number of polymer chains | 5 |
| Total formula weight | 104757.40 |
| Authors | |
| Primary citation | Zhou, Y.,Sineshchekova, O.,Lee, K.,Doshi, A.,Brown, K.,Franklin, M.C.,Ullman, E.,Hermann, A.,Kroog, G.S.,Boyapati, A.,Smith, E.,Lin, J.C.,Olson, W.C.,Olson, K. DISTINCT EPITOPE ENGAGEMENT CONFERS DIFFERENTIAL ACTIVITY OF LINVOSELTAMAB VERSUS TECLISTAMAB ACROSS BCMA MUTATIONS. Blood Adv, 2026 Cited by PubMed 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 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. PubMed: 42509021DOI: 10.1182/bloodadvances.2026020381 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.43 Å) |
Structure validation
Download full validation report
