Design and preclinical characterization of an affinity-tuned BCMA×CD3 bispecific T-cell engager for broad B-cell depletion.

B cell maturation antigen (BCMA) is a validated target for plasma cell depletion; however, T cell-redirecting approaches must balance potent cytotoxicity with controlled T cell activation. Here, we describe the design and preclinical characterization of gamgertamig, an affinity-tuned BCMA×CD3 bispecific T-cell engager engineered to promote target-dependent activity. Gamgertamig is a humanized IgG4-based 1 + 1 bispecific antibody incorporating Fc-silencing mutations and a reduced-affinity CD3-binding arm, resulting in a >50-fold affinity bias toward BCMA relative to CD3. Gamgertamig exhibited high-affinity binding to BCMA and mediated potent, antigen-dependent cytotoxicity across B cell and myeloma cell lines spanning a wide range of target densities, with sub-nanomolar EC50 values. In primary human peripheral blood mononuclear cells (PBMCs), gamgertamig induced robust depletion across B cell subsets, including naïve, memory, and transitional populations. Consistent activity was observed across samples from healthy donors and patients with autoimmune diseases and multiple myeloma. In vivo, gamgertamig produced dose-dependent tumor inhibition in human PBMC-reconstituted xenograft models and sustained depletion of circulating B cells and bone marrow plasma cells in rhesus monkeys, with a serum half-life exceeding five days. Together, these data demonstrate that gamgertamig mediates potent, target-dependent cytotoxicity and broad depletion of disease-relevant B-cell populations, supporting its development as a BCMA×CD3 T-cell engager for autoimmune diseases and B-cell malignancies.