Targeting BCMA in multiple myeloma with a trifunctional NK cell engager.

Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable, highlighting the need for durable therapies. Natural killer (NK) cell engagers (NKCEs) represent a promising alternative to T cell therapies, offering potent anti-tumor activity with limited cytokine release. SAR445514 (SAR'514) is a trifunctional NKCE that co-engages NKp46 and FcγRIIIa to activate NK cells while targeting B cell maturation antigen (BCMA) on MM cells. After exploring several molecular formats with varied BCMA and NKp46 valency, we selected SAR'514, a monovalent format with enhanced antibody-dependent cellular cytotoxicity (ADCC). SAR'514 has potent and selective anti-tumor activity in vitro and in vivo, outperforming other FcγRIIIa-immune cell engagers, while inducing minimal cytokine release compared to T cell engagers targeting the same antigen. Ex vivo, SAR'514 efficiently activates NK cells from MM patients and induces cytotoxicity against autologous malignant cells, including those resistant to standard therapies. These findings support further development of SAR'514.