An in vivo T cell engager platform induces deep plasma cell depletion in autoimmune dry eye

The BCMA×CD3 bispecific T cell engager (TCE) transforms targeted immunotherapy but remains constrained by ex vivo manufacturing and systemic delivery, limiting its application in autoimmune disorders. Here, we use a T cell-targeted integration-deficient lentiviral vector (T-IDLE) to program endogenous T cells to secrete BCMA×CD3 TCEs directly in vivo. In a murine model of Sjögren's syndrome-associated dry eye, a single intravenous administration of T-IDLE_STCE achieves deep but time-limited depletion of plasmablasts and plasma cells, reverses lacrimal gland inflammation, and restores tear production without detectable off-target transduction. Longitudinal studies in cynomolgus monkeys demonstrate plasma cell clearance and a favorable safety profile. Mechanistic analyses show that secreted TCEs redirect nearby non-activated T cells against BCMA-expressing targets in vitro and that the treatment attenuates T helper 1 (Th1)/Th17-mediated inflammation while eliciting controlled cytokine responses in vivo. This approach avoids individualized ex vivo T cell manufacturing and represents a scalable immunotherapy strategy for autoantibody-mediated diseases.