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Cryo-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
Structural highlights
DiseaseTNR17_HUMAN Note=A chromosomal aberration involving TNFRSF17 is found in a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(4;16)(q26;p13) with IL2. FunctionTNR17_HUMAN Receptor for TNFSF13B/BLyS/BAFF and TNFSF13/APRIL. Promotes B-cell survival and plays a role in the regulation of humoral immunity. Activates NF-kappa-B and JNK.[1] [2] [3] Publication Abstract from PubMedB-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 BCMAxCD3 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 BCMAxCD3 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. DISTINCT EPITOPE ENGAGEMENT CONFERS DIFFERENTIAL ACTIVITY OF LINVOSELTAMAB VERSUS TECLISTAMAB ACROSS BCMA MUTATIONS.,Zhou Y, Sineshchekova O, Lee K, Doshi A, Brown K, Franklin MC, Ullman E, Hermann A, Kroog GS, Boyapati A, Smith E, Lin JC, Olson WC, Olson K Blood Adv. 2026 Jul 27:bloodadvances.2026020381. doi: , 10.1182/bloodadvances.2026020381. PMID:42509021[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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