Although the exact etiology of systemic lupus erythematosus (SLE) remains elusive, B‐cell hyperactivity and production of autoantibodies directed to components of the cell nucleus are a well‐established pathogenetic mechanism of the disease. Therefore, the targeted inhibition of DNA‐specific B cells is a logical therapeutic approach. The complement receptor type 1 (CR1, CD35) has been shown to suppress human B‐cell activation and proliferation after co‐cross‐linking with the BCR, and may serve as a mediator for negative signal delivery. In order to evaluate this therapeutic approach in a human‐like system, we used immune‐restricted SCID mice transferred with PBMCs from SLE patients. The tolerance of these humanized SCID mice to native DNA was re‐established after administration of a chimeric molecule consisting of a CR1‐specific mAb coupled to the decapeptide DWEYSVWLSN that mimics dsDNA. The generated protein‐engineered chimera was able to co‐cross‐link selectively native DNA‐specific BCR with the B‐cell inhibitory receptor CR1, thus delivering a strong inhibitory signal.