Itacitinib is a JAK1 inhibitor (IC₅₀=2nM). Itacitinib selectively inhibits JAK1 tyrosine kinase to modulate the JAK-STAT signaling pathway while regulating immune responses by reducing the production of pro-inflammatory cytokines[1-2]. Itacitinib can be used in research related to myelofibrosis, graft-versus-host disease (GVHD), and cytokine release syndrome (CRS)[3-4].
In vitro, human CAR-T cells (including GD2, EGFR, and CD19 constructs) were pretreated with Itacitinib (100–250nM) and cultured under anti-CD3/CD28 antibody activation conditions. Itacitinib did not inhibit T cell proliferation and maintained the specific killing activity of CAR-T cells against target tumor cells (SY5Y neuroblastoma cells)[5]. Mouse colon cancer cells CT26.WT were pretreated with Itacitinib (0.5μM) for 2 hours and then co-cultured with IFN-γ (100ng/mL). Itacitinib significantly inhibited IFN-γ-induced phosphorylation of JAK1/STAT1 and cleavage of caspase-3, while reducing the apoptosis rate. Itacitinib blocked the JAK-STAT signaling pathway, thereby inhibiting IFN-γ-mediated pro-apoptotic effects[6].
In vivo, Itacitinib (120mg/kg) was administered twice daily via oral gavage to xenograft graft-versus-host disease (xGVHD) model mice induced by intravenous injection of 2×10⁷ human peripheral blood mononuclear cells (hPBMCs) from day 3 to day 28 post-transplantation. Itacitinib significantly prolonged the median survival of the model mice, reduced the absolute numbers of human CD4⁺ T cells and human CD8⁺ T cells in peripheral blood, and increased the frequency of human regulatory T cells (Tregs) among CD4⁺ T cells[7]. In a secondary hemophagocytic lymphohistiocytosis (HLH) model induced by CpG/αIL-10R, Itacitinib (120mg/kg; twice daily) was administered from days 4 to 8 post-induction. Itacitinib significantly improved mouse survival rates, enhanced clinical scores, and reduced serum levels of cytokines such as CXCL10, IL-12, IL-6, and GM-CSF, as well as the number of neutrophils in the spleen[8].
References:
[1] Mascarenhas JO, Talpaz M, Gupta V, et al. Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis. Haematologica. 2017 Feb;102(2):327-335.
[2] Lescoat A, Lelong M, Jeljeli M, et al. Combined anti-fibrotic and anti-inflammatory properties of JAK-inhibitors on macrophages in vitro and in vivo: Perspectives for scleroderma-associated interstitial lung disease. Biochem Pharmacol. 2020 Aug;178:114103.
[3] Chen X, Xun Z, Yuska B, et al. Itacitinib Population Pharmacokinetics and Exposure-Response in Patients With Acute Graft-Versus-Host Disease. J Clin Pharmacol. 2023 May;63(5):622-632.
[4] Etra A, Capellini A, Alousi A, et al. Effective treatment of low-risk acute GVHD with itacitinib monotherapy. Blood. 2023 Feb 2;141(5):481-489.
[5] Huarte E, O'Connor RS, Peel MT, et al. Itacitinib (INCB039110), a JAK1 Inhibitor, Reduces Cytokines Associated with Cytokine Release Syndrome Induced by CAR T-cell Therapy. Clin Cancer Res. 2020 Dec 1;26(23):6299-6309.
[6] Yang X, Gao DD, Zhang H, et al. Combining Radiation and anti-PD-L1 Enhances the Antitumor Activity in Colorectal Cancer via IFN-γ-Dependent Activation of STAT1. Technol Cancer Res Treat. 2025 Jan-Dec;24:15330338251406931.
[7] Courtois J, Ritacco C, Dubois S, et al. Itacitinib prevents xenogeneic GVHD in humanized mice. Bone Marrow Transplant. 2021 Nov;56(11):2672-2681.
[8] Keenan C, Albeituni S, Oak N, et al. Differential effects of itacitinib, fedratinib, and ruxolitinib in mouse models of hemophagocytic lymphohistiocytosis. Blood. 2024 Jun 6;143(23):2386-2400.
Itacitinib是一种JAK1抑制剂（IC50=2nM），Itacitinib可通过选择性抑制JAK1酪氨酸激酶以调节JAK-STAT信号通路，同时通过减少促炎细胞因子的产生以调控免疫反应[1-2]。Itacitinib可用于骨髓纤维化、移植物抗宿主病（GVHD）及细胞因子释放综合征（CRS）的相关研究[3-4]。
在体外，Itacitinib（100–250nM）预处理人源CAR T细胞（包括GD2、EGFR和CD19构建体）在抗CD3/CD28抗体激活条件下培养，Itacitinib不会抑制T细胞增殖，且维持CAR T细胞对靶肿瘤细胞（SY5Y神经母细胞瘤细胞）的特异性杀伤活性[5]。Itacitinib（0.5μM）预处理小鼠结肠癌细胞CT26.WT 2小时，随后与IFN-γ（100ng/mL）共培养，Itacitinib显著抑制IFN-γ诱导的JAK1/STAT1磷酸化及caspase-3切割，并降低细胞凋亡率，Itacitinib阻断JAK-STAT信号通路抑制IFN-γ介导的促凋亡效应[6]。
在体内，Itacitinib（120mg/kg）每日两次灌胃给药，用于处理经2×107人外周血单核细胞（hPBMC）静脉注射诱导的异种移植物抗宿主病小鼠（从移植后第3天开始至第28天）。Itacitinib显著延长了模型小鼠的中位生存期，降低了外周血中人CD4+ T细胞和人CD8+ T细胞的绝对数量，并提高了人调节性T细胞（Treg）在CD4+ T细胞中的频率[7]。Itacitinib（120mg/kg；每日两次）于CpG/αIL-10R诱导的继发性噬血细胞性淋巴组织细胞增生症小鼠发病后第4至8天给药，Itacitinib显著提高小鼠生存率、改善临床评分，降低血清CXCL10、IL-12、IL-6、GM-CSF等细胞因子水平及脾脏中性粒细胞数量[8]。