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.