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

• 1. Ramantamig binds CD3 on T cells, and BCMA and GPRC5D on myeloma cells, enhancing tumor binding due to avidity

• 2. Ramantamig induced potent T-cell mediated cytotoxicity against single and dual target-expressing myeloma cells and in vivo xenografts

In multiple myeloma (MM), cell-specific antigens are valuable targets for developing effective T-cell-engaging therapeutics which could provide good immune responses. Achieving a sustained immune response in recurrent MM, however, remains challenging. Ramantamig (JNJ-79635322) is a trispecific antibody targeting B-cell maturation antigen (BCMA) and G-protein-coupled receptor class 5 member D (GPRC5D), both of which are highly expressed on plasmablasts and plasma cells in myeloma patient samples. 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 sub nM 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. Additionally, it induced dose-dependent depletion of malignant plasma cells both in MM patient samples in an ex-vivo T-cell co-culture assay and in healthy fresh whole blood co-cultured 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 two 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 (NCT05652335, NCT06768489).