Engineering a TACI × CD3 bispecific antibody to redirect T cells against multiple myeloma.

abstractImmunotherapies targeting B-cell maturation antigen (BCMA), a member of the tumor necrosis factor receptor (TNFR) superfamily, have demonstrated remarkable clinical efficacy in treating relapsed/refractory multiple myeloma (MM). However, a major challenge is the frequent downregulation or loss of BCMA expression in patients receiving BCMA-targeted immunotherapies, which substantially diminishes therapeutic efficacy and contributes to disease progression and treatment resistance after an initial positive response. In this study, we developed a T-cell-redirecting bispecific antibody (bsAb) targeting transmembrane activator and CAML interactor (TACI), another TNFR superfamily member expressed on MM cells. The TACI × CD3 bsAb induced robust T-cell activation, proliferation, and potent cytotoxicity against MM cells. Importantly, it also effectively inhibited the growth of MM cells with downregulated BCMA expression that were unresponsive to BCMA × CD3 bsAb treatment. Moreover, the TACI × CD3 bsAb mediated effective cytotoxicity against primary MM cells derived from patients. Collectively, these findings suggest that TACI-targeted T-cell-redirecting bsAb may represent a promising therapeutic strategy for MM, with the potential of overcoming resistance associated with BCMA downregulation in MM.