DISTINCT EPITOPE ENGAGEMENT CONFERS DIFFERENTIAL ACTIVITY OF LINVOSELTAMAB VERSUS TECLISTAMAB ACROSS BCMA MUTATIONS

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• B-cell maturation antigen (BCMA) is a key target for multiple myeloma therapies.
• BCMA mutations are emerging as a resistance mechanism against BCMA×CD3 bispecific antibodies (bsAbs).
• Linvoseltamab is a recently approved BCMA×CD3 bsAb for relapsed/refractory multiple myeloma.

Purpose of the Study:

• To compare the activity of linvoseltamab and teclistamab against BCMA mutations associated with treatment resistance.
• To investigate the binding and functional activity of linvoseltamab on cell lines with specific BCMA mutations.

Main Methods:

• In vitro assessment of bsAb binding to cell lines expressing BCMA mutations (R27P, S30del, P34del, P33S).
• Functional assays including Jurkat-NFAT reporter and primary T-cell activation.
• Cytotoxicity assays against mutated BCMA targets.
• Cryogenic electron microscopy to determine binding orientations.

Main Results:

• Linvoseltamab maintained binding and cytotoxic activity against BCMA R27P and S30del mutations, unlike teclistamab.
• Both bsAbs showed reduced activity against the P34del mutation.
• Both bsAbs retained activity against the P33S variant.
• Structural analysis revealed distinct binding modes, explaining differential sensitivity to mutations.

Conclusions:

• Linvoseltamab demonstrates broader activity across certain BCMA resistance mutations compared to teclistamab.
• Linvoseltamab may be less susceptible to resistance mechanisms involving BCMA R27P and S30del mutations.
• Further clinical studies are needed to establish the relevance of these findings in patients.