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Objective To determine the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of subcutaneously administered mosunetuzumab, a CD20xCD3 T-cell-engaging bispecific antibody, in participants with systemic lupus erythematosus (SLE).Methods This phase Ib, multicentre, open-label, dose-escalation study enrolled 15 participants diagnosed with active autoantibody-positive SLE, demonstrated by an SLE Disease Activity Index 2000 (SLEDAI-2K) score ≥4 at screening. The study included two fixed-dosing dose-finding cohorts (1.6 mg or 5 mg of mosunetuzumab on day 1) and three step-up dose-escalation cohorts (day 1 dose of mosunetuzumab established by dose finding, followed by 15 mg, 45 mg or 60 mg of mosunetuzumab on day 8). The primary objective was evaluation of safety; other key objectives were evaluating the PK and PD of mosunetuzumab. Peripheral B-cell counts and T-cell phenotyping were performed using flow cytometry.Results Fifteen participants were enrolled from January 2022 through December 2023. Two participants discontinued treatment due to treatment-emergent adverse events (AEs). No immune effector cell-associated neurotoxicity syndrome events or high-grade cytokine release syndrome events were reported. The frequency of grade ≥3 AEs and serious AEs was 13.3% and 6.7%, respectively. Mosunetuzumab depleted peripheral B cells below the lower limit of quantification (0.441 cells/µL) in a dose-dependent manner. CD4+ and CD8+ T-cell activation occurred across all tested doses. SLEDAI-2K scores improved, especially among participants with higher baseline SLEDAI-2K scores and those receiving higher doses. The PK profile of mosunetuzumab was consistent with that observed in the relapsed or refractory follicular lymphoma population.Conclusions Mosunetuzumab demonstrated dose-dependent peripheral B-cell depletion and a safety profile consistent with prior studies in follicular lymphoma. Based on these data, mosunetuzumab is currently being evaluated in a phase II study in severe SLE ( NCT07598396).Trial registration number NCT05155345.