Background/Purpose: Dysregulated B-cell activation plays a pivotal role in the pathogenesis of various autoimmune diseases. B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are essential cytokines that support B-cell survival and differentiation. Elevated levels of these cytokines are associated with autoimmune conditions such as Systemic Lupus Erythematosus (SLE), IgA nephropathy (IgAN), and Rheumatoid Arthritis (RA). Therapeutic agents targeting these cytokines, including the anti-BAFF antibody Belimumab, anti-APRIL antibody Sibeprenlimab, and the BAFF/APRIL dual inhibitor Telitacicept, have demonstrated significant clinic efficacy, particularly in SLE and IgAN. These findings highlight the therapeutic potential of targeting BAFF and APRIL. However, the limitations associated with single-target therapies or unbalanced inhibition of these cytokines underscore the need for innovative approaches in drug development. Here，we described IBI3034, a novel chimeric fusion protein, currently at the Investigational New Drug (IND) stage, designed to address these challenges in B-cell-related autoimmune diseases.

Methods: Variants chimeric constructs combining TACI and BCMA fused with Fc were designed and generated for screening. IBI3034 was selected based on its protein developability, dual binding affinity to BAFF and APRIL and in vitro inhibitory effects on B cells. The in vitro activity comparison of IBI3034 and related benchmarks were evaluated head-to-head via reporter cell lines and BAFF and APRIL induced proliferation of human B cells derived from human peripheral blood mononuclear cells (PBMCs). Then in vivo efficacy of IBI3034 and related benchmarks were evaluated by analyzing B-cell depletion in the spleen and serum immunoglobulin levels in BAFF-induced mouse models, KLH mouse models, and cynomolgus monkeys. Additionally, the therapeutic potential of IBI3034 was assessed in mouse models of SLE and RA.

Results: IBI3034 demonstrated potent and balanced binding ability to BAFF and APRIL at nanomolar level, effectively inhibiting the proliferation of human B cells induced by a BAFF/APRIL mixture with an IC50 of 7.7 nm. In vivo studies revealed significant depletion of various B-cell subpopulations, including marginal zone B cells, germinal center B cells, and plasma cells, accompanied by reduced serum immunoglobulin levels in BAFF-induced and KLH mouse models. Notably, a single dose of IBI3034 markedly suppressed peripheral antibody-secreting cells and immunoglobulin production up to day 35 in cynomolgus monkeys. Furthermore, IBI3034 significantly reduced proteinuria levels with extended survival in a lupus mouse model and ameliorated arthritis inflammation in an RA mouse model.

Conclusion: IBI3034, a novel TACI/BCMA chimeric Fc fusion protein, exhibits potent and prolonged effects on B-cell and plasma cell depletion and immunoglobulin suppression through balanced dual inhibition of BAFF and APRIL. This innovative therapeutic approach holds promise for providing deeper clinical benefits and more convenient dosing intervals for patients with B-cell-mediated autoimmune diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/preclinical-characterization-of-ibi3034-an-taci-and-bcma-chimeric-fc-fusion-protein-that-potently-modulates-b-lymphocytes-and-serum-immunoglobulin-for-the-treatment-of-b-cell-related-autoimmune-dise/