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

Abstract

Abstract In 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.