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3265 Characterization of Linvoseltamab’s BCMA Binding Epitope and Efficacy Against BCMA Mutations in Relapsed/Refractory Multiple Myeloma

Program: Oral and Poster Abstracts
Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Poster II
Hematology Disease Topics & Pathways:
Research, Assays, Bispecific Antibody Therapy, Translational Research, Plasma Cell Disorders, Diseases, Immunotherapy, Biological therapies, Treatment Considerations, Lymphoid Malignancies, Technology and Procedures
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Ken Lee1*, Yi Zhou1*, Matthew Franklin1*, Erica Ullman2*, Aynur Hermann2*, Glenn S. Kroog1*, Anita Boyapati3*, Karen Rodriguez Lorenc1, Eric Smith, PhD4*, John Lin, MD, PhD1*, William Olson2*, Leonardo Andres Sirulnik, MD, PhD1 and Kara Olson, MS5*

1Regeneron Pharmaceuticals, Inc, Tarrytown, NY
2Therapeutic Proteins, Regeneron Pharmaceuticals, Inc, Tarrytown, NY
3Regeneron Pharmaceuticals, Inc., Tarrytown, NY
4Bispecifics, Regeneron Pharmaceuticals, Inc, Tarrytown, NY
5Regeneron Pharmaceuticals, Inc, White Plains, NY

Patient outcomes in relapsed/refractory multiple myeloma (RRMM) have improved significantly with the adoption of BCMA targeted CAR-T and CD3 bispecific antibodies (bsAb). However, despite improvements in MM therapies, relapse remains an issue. Recent data from patients who relapsed following treatment with approved BCMAxCD3 bsAbs led to the identification of rare mutations in the extracellular domain of BCMA that can negatively impact the binding and cytotoxic activity of these molecules in vitro (Lee, H., et al, Nat Med. 2024). Linvoseltamab is a fully human BCMAxCD3 bsAb that demonstrated high and durable responses in RRMM. Here we characterize the binding epitope of linvoseltamab and evaluate its binding and activity on cells with identified BCMA mutations.

A 3.4 Å cryo-EM structure of the linvoseltamab Fab fragment bound to the BCMA extracellular domain shows that linvoseltamab features a long heavy chain CDR3, stabilized by a disulfide bond, which plays a major role in binding by inserting into a groove on the surface of BCMA. Linvoseltamab contacts a total of 16 BCMA residues which largely overlap with the reported epitopes of teclistamab and elranatamab (Lee, H., et al, Nat Med. 2024; Josic, M., et al, ASCO 2024). However, linvoseltamab also binds to the very N-terminal end of BCMA, suggesting that it is tilted toward the BCMA N-terminus with a distinct binding orientation.

Binding assays on cells expressing wild-type or mutant BCMA variants demonstrated that, unlike teclistamab and elranatamab, the BCMA R27P mutation had minimal impact on linvoseltamab binding. Additionally, utilizing a Jurkat NFAT-luc reporter assay system which measures BCMAxCD3 specific activation of T-cells, linvoseltamab mediated potent NFAT-luc activation in the presence of cells expressing BCMA-R27P. While the structural analysis showed linvoseltamab contacts BCMA R27, it is located at the edge of the binding interface and thus appears to not be crucial for binding. In addition, BCMA P33 does not contact linvoseltamab, consistent with the observation that the P33S mutation has no effect on linvoseltamab binding or activity. Cell binding and functional reporter bioassay and primary T cell cytotoxicity studies are underway for additional reported BCMA mutations.

This study identified a unique binding orientation for linvoseltamab and demonstrated that linvoseltamab retains its binding and functional activity even in the presence of an identified BCMA mutation (R27P) that negatively impacts other BCMAxCD3 bispecific antibodies. This suggests that linvoseltamab may be less susceptible to resistance mechanisms that involve these mutations, resulting in improved patient outcomes.

Disclosures: Lee: Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Zhou: Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Franklin: Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Ullman: Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Hermann: Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Kroog: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Boyapati: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Rodriguez Lorenc: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Smith: Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Lin: Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Olson: Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Sirulnik: Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Olson: Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

*signifies non-member of ASH