Ramantamig (JNJ-79635322), a novel T-cell-engaging trispecific antibody targeting BCMA, GPRC5D, and CD3, in multiple myeloma models.

abstractIn multiple myeloma (MM), cell-specific antigens are valuable targets for developing effective T-cell-engaging therapeutics that can provide good immune responses. Achieving a sustained immune response in recurrent MM, however, remains challenging. Ramantamig (JNJ-79635322) is a trispecific antibody targeting BCMA (B-cell maturation antigen) and GPRC5D (G-protein-coupled receptor family C group 5 member D), both of which are highly expressed on plasmablasts and plasma cells in samples from patients with myeloma. Dual antigen recognition on malignant plasma cells by a trispecific T-cell-engaging antibody could potentially enhance tumor binding through increased avidity, resulting in efficient depletion of the malignant clonal populations, targeting of tumor heterogeneity, and prevention of tumor antigen loss-mediated resistance. At subnanomolar ranges, ramantamig induced potent cytotoxicity in cancer cell lines with concomitant T-cell activation. Ramantamig efficiently depleted both dual- and single-target-expressing MM cell lines. In addition, it induced dose-dependent depletion of malignant plasma cells in samples from patients with MM both in an ex vivo T-cell coculture assay and in healthy fresh whole blood cocultured with H929 MM cells to mimic physiological conditions. Ramantamig exhibited potent antitumor activity in a murine xenograft prevention model (single-target-expressing clonal cells) and 2 tumor regression models. The potent and selective antitumor activity of ramantamig, with a clonal-depleting ability in vitro, ex vivo, and in vivo, warrants clinical evaluation of its ability to induce durable responses in myeloma. Phase 1 clinical trials are ongoing for patients with relapsed/refractory MM. These trials are registered at www.clinicaltrials.gov as NCT05652335 and NCT06768489.