Voclosporin (ISAtx-247) is an orally active calcineurin inhibitor. Voclosporin blocks IL-2 expression and T cell-mediated immune responses by inhibiting calcineurin, while stabilizing renal podocytes to reduce kidney injury[1-2]. Voclosporin is used for the treatment of lupus nephritis[3-4].
In vitro, human peripheral blood CD4+ T cells were stimulated with anti-CD3/CD28 antibodies and then treated with Voclosporin (10mg/ml) for 48 hours. Voclosporin significantly inhibited the secretion of cytokines including IL-2, IL-6, IFN-γ, TNF-α, IL-4, IL-5, IL-9, IL-13, IL-17A, IL-17F, IL-22, and IL-10, and attenuated the expression of cell surface activation markers such as CD25, CD44, and CD69[5].
In vivo, in a cerebral ischemia-reperfusion model, mice were intraperitoneally administered Voclosporin (25mg/kg; 30 minutes in advance) and then subjected to middle cerebral artery occlusion (MCAO) and rtPA reperfusion. Voclosporin significantly improved neurological function scores, reduced cerebral infarction volume, alleviated blood-brain barrier damage and brain edema, and modulated the inflammatory response by promoting the polarization of microglia/macrophages toward the M2 phenotype[6]. In a desiccating stress (DS) dry eye model, mice were treated with Voclosporin (0.2% ophthalmic solution; 1 drop) topically twice daily, starting from the first day of DS induction and continuing for either 5 or 10 days. Voclosporin significantly improved corneal barrier function, increased conjunctival goblet cell density, and reduced the generation of pathogenic CD4+ T cells[7].
References:
[1] van Gelder T, Lerma E, Engelke K, et al. Voclosporin: a novel calcineurin inhibitor for the treatment of lupus nephritis. Expert Rev Clin Pharmacol. 2022 May;15(5):515-529.
[2] Heo YA. Voclosporin: First Approval. Drugs. 2021 Apr;81(5):605-610.
[3] Saxena A, Ginzler EM, Gibson K, et al. Safety and Efficacy of Long-Term Voclosporin Treatment for Lupus Nephritis in the Phase 3 AURORA 2 Clinical Trial. Arthritis Rheumatol. 2024 Jan;76(1):59-67.
[4] Menn-Josephy H, Hodge LS, Birardi V, et al. Efficacy of Voclosporin in Proliferative Lupus Nephritis with High Levels of Proteinuria. Clin J Am Soc Nephrol. 2024 Mar 1;19(3):309-318.
[5] Lindemann A, Roth D, Koop K, et al. Protective effect of the novel calcineurin inhibitor voclosporin in experimental colitis. Front Med (Lausanne). 2023 Jun 9;10:1177450.
[6] Zheng Y, Ma S, Sun W, et al. Voclosporin promotes neurological function recovery by inhibiting inflammation and maintaining blood-brain barrier integrity following rtPA reperfusion after MCAO in mice. Inflammopharmacology. 2025 Jun;33(6):3317-3328.
[7] Alam J, de Souza RG, Yu Z, et al. Calcineurin Inhibitor Voclosporin Preserves Corneal Barrier and Conjunctival Goblet Cells in Experimental Dry Eye. J Ocul Pharmacol Ther. 2020 Nov;36(9):679-685.
Voclosporin (ISAtx-247)是一种具有口服活性的钙调神经磷酸酶抑制剂，Voclosporin可通过抑制钙调神经磷酸酶来阻断IL-2的表达和T细胞介导的免疫反应，同时稳定肾脏足细胞以减少肾脏损伤[1-2]。Voclosporin可用于狼疮性肾炎的相关治疗[3-4]。
在体外，Voclosporin（10mg/ml）处理经抗CD3/CD28抗体刺激的人外周血CD4+ T细胞48小时，Voclosporin显著抑制IL-2、IL-6、IFN-γ、TNF-α、IL-4、IL-5、IL-9、IL-13、IL-17A、IL-17F、IL-22和IL-10的细胞因子分泌，减弱CD25、CD44和CD69等细胞表面活化标志物的表达[5]。
在体内，在脑缺血再灌注模型中，Voclosporin（25mg/kg；提前30min）腹腔注射小鼠，随后通过大脑中动脉阻塞（MCAO）及rtPA再灌注处理小鼠，Voclosporin显著改善神经功能评分、减少脑梗死体积、减轻血脑屏障损伤和脑水肿，并通过促进小胶质细胞/巨噬细胞向M2型极化来调节炎症反应[6]。Voclosporin（0.2%眼用溶液；1滴）每天两次局部点眼处理，用于诱导干燥应激（DS）干燥眼模型的小鼠（从干燥应激第1天开始，持续5天或10天）。Voclosporin显著改善了角膜屏障功能、增加了结膜杯状细胞密度，并减少了致病性CD4+ T细胞的产生[7]。