Efficacy of the Bispecific Anti‐BAFF/IL‐21 Antibody CZ105 Bis2 in Models of Systemic Lupus Erythematosus

BACKGROUND: Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease. B cells play a crucial role in disease initiation and progression. Clinical trial evidence suggests that intensified B-cell depletion can improve SLE therapeutic outcomes. While efficacy and tolerability of belimumab, the first B-cell-targeted agent approved for SLE, have been demonstrated, around 30-40% of patients still show suboptimal treatment response. Interleukin-21 (IL-21), a regulator of B-cell development, is closely associated with disease activity in SLE, underscoring its potential as a therapeutic target. However, monotherapy targeting IL-21 has yielded limited efficacy in clinical trials. METHODS: We prepared h18B10, a humanized anti-IL-21 monoclonal antibody. Building upon this candidate, we constructed CZ105 Bis2, a bispecific antibody assembled by fusing the variable domains of h18B10 and belimumab, enabling concurrent blockade of IL-21 and BAFF signaling pathways. In vitro functional assays verified that CZ105 Bis2 exhibits binding affinity and cytokine neutralization potency equivalent or superior to its two parent molecules. Compared with selective inhibitors of BAFF or IL-21, CZ105 Bis2 elicited more robust suppression of in vivo B-cell effector functions. In the keyhole limpet hemocyanin (KLH) model, CZ105 Bis2 significantly reduced T-cell-dependent, antigen-specific B-cell responses. In both pristane-induced lupus mouse models and humanized lupus-like models (chronic graft-versus-host disease (GVHD)), CZ105 Bis2 decreased anti-double-stranded DNA (dsDNA) antibody levels, reduced proteinuria, and alleviated renal inflammatory infiltration. CONCLUSION: Our preclinical data confirm that CZ105 Bis2 achieves superior efficacy over single-target biologics across in vitro and in vivo systems, supporting its translational potential to improve clinical outcomes in SLE.