Current therapies for systemic lupus erythematosus that target a particular factor or cell type exhibit limited effectiveness. To address this limitation, our focus was on CD132, a subunit common to six inflammatory factor receptors implicated in SLE. Our study revealed heightened CD132 expression in SLE patients’ lymphocytes, contributing to the production of pro-inflammatory cytokines and immunoglobulins. We developed a novel humanized anti-CD132 monoclonal antibody, named as 2D4. 2D4 efficiently blocked IL-21 and IL-15, with limited effectiveness against IL-2, thereby suppressing T and B cells without disrupting immune tolerance. In the mouse immunization model, 2D4 virtually inhibited T cell-dependent, antigen-specific B-cell response. In lupus murine models, 2D4 mitigated inflammation by suppressing multiple pro-inflammatory cytokines and anti-dsDNA antibody titers, also diminishing proteinuria and glomerulonephritis. Compared to Belimumab, 2D4 exhibited superior efficacy in ameliorating the inflammatory state and preserving renal function. Moreover, 2D4 exhibited the ability to inhibit the production of pro-inflammatory factors and autoantibodies in PBMCs from individuals with SLE, highlighting its therapeutic potential for SLE individuals. Potent, 2D4 has the potential to significantly improve clinical outcomes in SLE and other complex autoimmune disorders.

目前针对特定因子或细胞类型的系统性红斑狼疮疗法效果有限。为了解决这一限制，我们的重点是 CD132，这是与 SLE 相关的 6 种炎症因子受体共有的亚基。我们的研究揭示了 SLE 患者淋巴细胞中 CD132 表达的增加，有助于促炎细胞因子和免疫球蛋白的产生。我们开发了一种新型人源化抗 CD132 单克隆抗体，命名为 2D4。2D4 有效阻断 IL-21 和 IL-15，对 IL-2 的有效性有限，从而抑制 T 细胞和 B 细胞而不破坏免疫耐受。在小鼠免疫模型中，2D4 几乎抑制了 T 细胞依赖性抗原特异性 B 细胞反应。在狼疮鼠模型中，2D4 通过抑制多种促炎细胞因子和抗 dsDNA 抗体滴度来减轻炎症，还减少了蛋白尿和肾小球肾炎。与 Belimumab 相比，2D4 在改善炎症状态和保持肾功能方面表现出卓越的疗效。此外，2D4 表现出抑制 SLE 个体在 PBMC 中产生促炎因子和自身抗体的能力，突出了其对 SLE 个体的治疗潜力。有效的 2D4 有可能显著改善 SLE 和其他复杂自身免疫性疾病的临床结果。