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

Authors

Jamie Thomas, Gang Xu, Hannah Lock, Qin Song, Yumei Yin, Wanying Luo, Kyu Hong, Liguang Lou, Changyu Wang, Leslie Chinn, Neelufar Mozaffarian, Jaideep Dudani, Paul Bessette, Charlie Zhou, Ruth Lan, Bo Chen, Nishant Mehta

Published in

mAbs. Volume 18. Issue 1. Pages 2718587. Epub Aug 19, 2026.

Abstract

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.

PMID:
42619408
Bibliographic data and abstract were imported from PubMed on 20 Aug 2026.

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