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

Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disease in which B cells play a crucial role. Although belimumab, the first B cell-targeted biologic approved for SLE, has demonstrated efficacy and tolerability, approximately 30%-40% of patients show suboptimal responses. Interleukin-21 (IL-21), a key regulator of B cell differentiation and function, is closely associated with SLE disease activity, but IL-21-targeted monotherapy has shown limited clinical efficacy. This study aimed to develop and characterize a bispecific antibody targeting both IL-21 and B cell-activating factor (BAFF) and to determine whether dual blockade provides greater therapeutic efficacy than inhibition of either pathway alone.

We prepared humanized 18B10 (h18B10), an anti-IL-21 monoclonal antibody. Building on 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 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-vs-host disease), CZ105 Bis2 decreased anti-double-stranded DNA antibody levels, reduced proteinuria, and alleviated renal inflammatory infiltration.

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.