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Objectives Plasma cells have emerged as a promising therapeutic target in SLE, as confirmed by the successful treatment of refractory SLE patients with bortezomib, anti-CD38 antibodies, BCMA T-cell engagers, and BCMA or CD19 CAR-T cells. However, this generic ablation of plasma cells compromises humoral immunity as such and increases the risk of infection. We have developed an alternative therapeutic strategy that selectively ablates plasma cells that secrete pathogenic anti-dsDNA antibodies, which has been tested in NZB/W mice.Methods An antibody-mediated cytotoxicity engager (ACE) consisting of a 100 base pair long dsDNA oligonucleotide and an anti-mouse CD138 antibody with a constant region of the heavy chain of human IgG1 (clone: REA104; Miltenyi Biotec), was prepared using a biotin-streptavidin interaction. The in vivo labeling of this ACE on plasma cells and its ablation were examined by flow cytometry after intraperitoneal (i.p.) administration to NZB/W mice (200 µg/mouse). Long-term treatment was initiated in 20-week-old NZB/W mice by i.p. administration of ACE and continued every two weeks. Proteinuria, a biomarker for nephritis, and antibody levels detected by ELISA were monitored.Results Flow cytometric analysis showed that the ACE selectively labeled plasma cells in both the spleen and bone marrow, while B or T cells were not labeled at all. The labeling peaked after 2 hours and then gradually decreased and disappeared completely after 48 hours.Two days after injection of the ACE, up to 80% of the dsDNA-specific plasma cells in spleen, bone marrow and kidneys of the mice were ablated, presumably by complement or cellular cytotoxicity, targeted to them by their own secreted antibodies. Plasma cells secreting antibodies of different specificities were not affected. Treated mice showed a sustained reduction of dsDNA-specific antibodies in the serum and a significant improvement in proteinuria.Conclusions In a mouse model for lupus nephritis, we show for the first time that selective ablation of plasma cells that secrete pathogenic anti-dsDNA autoantibodies can halt the disease. This concept of antigen-specific ablation of pathogenic plasma cells while preserving humoral immunity offers a promising therapeutic perspective for (auto)antibody-mediated diseases.