更新于：2024-11-01

IL-2R x IL15R

更新于：2024-11-01

基本信息

关联

项与 IL-2R x IL15R 相关的药物

Neo-202

靶点

IL-2R x IL15R

作用机制

IL-2R激动剂 [+1]

在研机构

Neoleukin Therapeutics, Inc.

原研机构

Neoleukin Therapeutics, Inc.

在研适应症

肿瘤

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 IL-2R x IL15R 相关的临床结果

登录后查看更多信息

100 项与 IL-2R x IL15R 相关的转化医学

登录后查看更多信息

0 项与 IL-2R x IL15R 相关的专利（医药）

登录后查看更多信息

项与 IL-2R x IL15R 相关的文献（医药）

2021-04-01·Digestive Diseases and Sciences3区 · 医学

Zinc Gluconate Induces Potentially Cancer Chemopreventive Activity in Barrett’s Esophagus: A Phase 1 Pilot Study

3区 · 医学

Article

作者: Mercogliano, G ; Zitin, M ; Thornton, J ; Mayilvaganan, B ; Wong, P ; McShane, S ; McDonnell, E ; Mathew, A ; Leroy, K ; Daum, G ; Kossenkov, A ; Richardson, E ; Rybakovsky, E ; Newman, G ; Yalamanchili, S ; Raines, J ; Connor, L ; Urbas, R ; Lander, J ; Etemad, B ; Valenzano, M C ; Trembeth, S ; Huntington, W ; Chen, V ; Corcoran, A ; Mullin, J M ; Fong, L Y

BACKGROUNDChemopreventive effects of zinc for esophageal cancer have been well documented in animal models. This prospective study explores if a similar, potentially chemopreventive action can be seen in Barrett's esophagus (BE) in humans.AIMSTo determine if molecular evidence can be obtained potentially indicating zinc's chemopreventive action in Barrett's metaplasia.METHODSPatients with a prior BE diagnosis were placed on oral zinc gluconate (14 days of 26.4 mg zinc BID) or a sodium gluconate placebo, prior to their surveillance endoscopy procedure. Biopsies of Barrett's mucosa were then obtained for miRNA and mRNA microarrays, or protein analyses.RESULTSZinc-induced mRNA changes were observed for a large number of transcripts. These included downregulation of transcripts encoding proinflammatory proteins (IL32, IL1β, IL15, IL7R, IL2R, IL15R, IL3R), upregulation of anti-inflammatory mediators (IL1RA), downregulation of transcripts mediating epithelial-to-mesenchymal transition (EMT) (LIF, MYB, LYN, MTA1, SRC, SNAIL1, and TWIST1), and upregulation of transcripts that oppose EMT (BMP7, MTSS1, TRIB3, GRHL1). miRNA arrays showed significant upregulation of seven miRs with tumor suppressor activity (-125b-5P, -132-3P, -548z, -551a, -504, -518, and -34a-5P). Of proteins analyzed by Western blot, increased expression of the pro-apoptotic protein, BAX, and the tight junctional protein, CLAUDIN-7, along with decreased expression of BCL-2 and VEGF-R2 were noteworthy.CONCLUSIONSWhen these mRNA, miRNA, and protein molecular data are considered collectively, a cancer chemopreventive action by zinc in Barrett's metaplasia may be possible for this precancerous esophageal tissue. These results and the extensive prior animal model studies argue for a future prospective clinical trial for this safe, easily-administered, and inexpensive micronutrient, that could determine if a chemopreventive action truly exists.

2018-05-01·Biophysical Journal2区 · 生物学

Membrane Potential Distinctly Modulates Mobility and Signaling of IL-2 and IL-15 Receptors in T Cells

2区 · 生物学

Article

作者: Mocsár, Gábor ; Vámosi, György ; Nagy, Éva ; Papp, Ferenc ; Tóth, Katalin ; Waldmann, Thomas A ; Sebestyén, Veronika ; Panyi, György ; Damjanovich, Sándor ; Bodnár, Andrea ; Volkó, Julianna

The high electric field across the plasma membrane might influence the conformation and behavior of transmembrane proteins that have uneven charge distributions in or near their transmembrane regions. Membrane depolarization of T cells occurs in the tumor microenvironment and in inflamed tissues because of K⁺ release from necrotic cells and hypoxia affecting the expression of K⁺ channels. However, little attention has been given to the effect of membrane potential (MP) changes on membrane receptor function. Therefore, we studied the influence of membrane de- and hyperpolarization on the biophysical properties and signaling of interleukin-2 (IL-2) and interleukin-15 (IL-15) receptors, which play important roles in T cell function. We investigated the mobility, clustering, and signaling of these receptors and major histocompatibility complex (MHC) I/II glycoproteins forming coclusters in lipid rafts of T cells. Depolarization by high K⁺ buffer or K⁺ channel blockers resulted in a decrease in the mobility of IL-2Rα and MHC glycoproteins, as shown by fluorescence correlation spectroscopy, whereas hyperpolarization by the K⁺ ionophore valinomycin increased their mobility. Contrary to this, the mobility of IL-15Rα decreased upon both de- and hyperpolarization. These changes in protein mobility are not due to an alteration of membrane fluidity, as evidenced by fluorescence anisotropy measurements. Förster resonance energy transfer measurements showed that most homo- or heteroassociations of IL-2R, IL-15R, and MHC I did not change considerably, either. MP changes modulated signaling by the two cytokines in distinct ways: depolarization caused a significant increase in the IL-2-induced phosphorylation of signal transducer and activator of transcription 5, whereas hyperpolarization evoked a decrease only in the IL-15-induced signal. Our data imply that the MP may be an important modulator of interleukin receptor signaling and dynamics. Enhanced IL-2 signaling in depolarized T_reg cells highly expressing IL-2R may contribute to suppression of antitumor immune surveillance.

2016-01-02·Journal of Immunotoxicology4区 · 医学

Vanadium pentoxide prevents NK-92MI cell proliferation and IFNγsecretion through sustained JAK3 phosphorylation

4区 · 医学

ArticleOA

作者: Fortoul van der Goes, Teresa ; Montaño, Luis F ; Masso, Felipe ; Diaz, Daniel ; Tapia-Rodriguez, Miguel ; Rendon-Huerta, Erika ; Gallardo-Vera, Francisco

Vanadium is a major air pollutant with toxic and carcinogenic effects; it also exercises immunosuppressive effects on the adaptive immune response. Its effect on the innate immune response is poorly explored. The aim of this study was to identify if vanadium pentoxide (V2O5) impairs the function of immunoregulatory NK cells and to determine possible mechanisms associated with this effect. Interleukin-2-independent NK-92MI cells were exposed to different V2O5 concentrations for 6, 12, or 24 h periods. Cell proliferation was then evaluated using CFSE staining, apoptosis by Annexin V binding, and necrosis by 7-AAD staining. The release of IL-2, -4, -6, -10, -17A, IFNγ, and TNFα by the cells were assessed using a human CBA kit. Expression of CD45, SOCS1, JAK3, pJAK3, STAT5, pSTAT5, IL-2R, IL-15R, Fas, and FasL in/on the cells was determined by flow cytometry; JAK3 and pJAK3 expression were also evaluated via confocal microscopy. The results indicated that V2O5 could inhibit NK-92MI cell proliferation and induce cell apoptosis in a dose- and time-related manner. V2O5 also inhibited IL-2, IL-10, and IFNγ secretion but mostly only after 24 h of exposure and with primarily the higher doses tested. V2O5 had no effect on expression of JAK3 and STAT5, but did cause an increase in pJAK3 and appeared to lead (trend) to reductions in levels of phosphorylated STAT5. V2O5 increased the expression of IL-2R, IL-15R, Fas, and FasL at concentrations above the 50-100 µM range. V2O5 had no effect on expression of the CD45 membrane phosphatase, but it did cause an increase in the expression of SOCS1. These results indicate that a key toxic effect of V2O5 on NK cells is a dysregulation of signaling pathways mediated by IL-2. These effects could help to explain the previously-reported deleterious effects on innate immune responses of hosts exposed to inhaled V2O5.

项与 IL-2R x IL15R 相关的新闻（医药）

2023-07-19

·佰傲谷BioValley

聊聊“ENFJ人格型”免疫调节因子——IL-15

主人公型人格（ENFJ）是16型人格中的一种人格类型。他们浑身散发着天然的自信，潜移默化地影响着周围的人，能够指导他人团结协作，帮助别人提升自己并促进集体的共同进步。ENFJ的精神世界永远散发着利他主义者的光芒。在免疫系统中就存在着这样一种人格类型的角色，它积极帮助其他细胞的成长和功能发挥，进而促进整个免疫系统的高效运行。本期我们就一起去认识这个免疫系统中的多面手——IL-15。背景介绍白细胞介素是由多种细胞产生并作用于多种细胞的一类细胞因子。由于最初是由白细胞产生又在白细胞间发挥作用，所以由此得名，现仍一直沿用。现是指一类分子结构和生物学功能已基本明确，具有重要调节作用而统一命名的细胞因子。白细胞介素在传递信息，激活与调节免疫细胞，介导T、B细胞活化、增殖与分化及在炎症反应中起重要作用。1994 年，Grabstein 等首先在猴肾表皮细胞系上清中发现一种能维持T细胞增殖的细胞因子，随后基因克隆获得成功并命名IL-15(interleukin-15，白介素-15)，其具有与IL-2类似的结构和功能。虽然基因工程使IL-2应用于肝炎以及某些癌症的治疗已经取得了令人瞩目的成果，但是大剂量长时间的用药对患者仍然存在一定的不良反应( 如发热、头晕、水盐代谢紊乱) ，导致肾、肝、心、肺等功能异常，其中最常见、最严重的是毛细血管渗漏综合征。IL-15具备一些IL-2所不具备的优势而受到广泛重视。近些年， IL-15在抗肿瘤免疫治疗方面的应用也得到了研究者的关注。图1、2：IL-15在细胞间的传递与结合靶点结构IL-15是分子量为14～15 kDa 的糖蛋白，由169 个氨基酸构成。人IL-15 基因位于染色体4q31，跨度约34 kb，有7 个内含子和9 个外显子，其mRNA 长1.5～1.8kb。IL-15 的等电点约为4.35，在pH 值为2～10时较为稳定。IL-15由不同细胞产生，如单核细胞、巨噬细胞、树突状细胞、基质细胞、上皮细胞等，属于四个α- 螺旋束细胞因子家族。IL-15受体(IL-15R) 与IL-2 受体(IL-2R) 一样，包含3条链，分别命名为IL-15Rα、IL-15Rβ( 也称为CD122) 、RIL-15Rγ(也称CD132) 。其中β 和γ亚单位相同，但IL-15R本身有特异的IL-15Rα，是IL-15 的高亲和力受体。当IL-2Rα亚基( 也称为CD25) 与其β、γ 亚基结合后， IL-2Rαβγ成为IL-2的高亲和力受体，但IL-15Rαβγ对IL-15的亲和力没有改变，这有可能是两者具有不同生物学效应的基础之一。图3：IL-2和IL-15与细胞表面受体结合的比较信号通路IL-15 的生物学作用范围非常广泛，是机体免疫调节网络中的重要物质，与其他细胞因子有协同或拮抗作用，共同完成机体免疫功能的平衡调节作用。IL-15在NK细胞、T细胞及某些内皮细胞的发育中起重要作用，并且是记忆性CD8+T细胞的生长因子和调节因子，而其能诱导细胞毒性T细胞和淋巴因子激活的杀伤细胞的活化和增殖。图4：IL-15的多功能作用下面介绍IL-15的两种信号通路：1️⃣ IL-15与其在抗原呈递细胞上表达的高亲和力IL-15Rα结合，并反向呈递给IL-2 /15Rβγ异二聚体，随后，效应细胞的激活可以通过三种不同的途径进行：涉及JAK / STAT激活，磷酸化的STAT蛋白形成异二聚体，然后转运至细胞核进行转录激活；将Shc募集到IL-2 /15Rβ链上的磷酸化位点，然后激活Grb2；Grb2可以沿着PI3K途径继续磷酸化Akt，或者可以结合鸟嘌呤核苷酸交换因子SOS激活RAS–RAF，最终激活MAPK。2️⃣在肥大细胞中，IL-15通过独特的受体链IL-15RX发出信号，从而激活JAK2/STAT5途径。IL-15还可以与常见的γ链结合，以通过Tyk2/STAT6传递其信号，从而启动生存（Bcl-XL）和Th2免疫应答。图5：IL-15的信号通路但是硬币总是有两面，过多的IL-15可能会引发强烈的免疫应答，引发炎症。在排斥反应和多种自身免疫性疾病中IL-15 表达增加的现象很明显。所以对于炎症性疾病，需要阻断IL-15的活性，抑制免疫反应，以改善临床症状。使用抗IL-15R抗体，可防止IL-15通过其受体结合和发出信号。靶向JAK/STAT途径的抑制剂可防止STAT异二聚体活化和转运至细胞核。蛋白酶体抑制剂如硼替佐米可防止NF-κB和Myc的活化。值得注意的是，这些疗法都靶向恶性细胞中的IL-15信号传导，但这可能对依赖IL-15的正常细胞产生影响。研究现状临床前的动物试验研究中，IL-15在研究中的疗效已得到证实，包括前列腺癌、黑色素瘤、结肠癌模型等，表明IL-15可能比IL-2在癌症治疗中的作用更为有效。IL-15的具体给药方案可分为单药治疗和联合用药治疗。IL-15的首次人体临床研究是通过静脉推注，在转移性肾细胞癌和黑色素瘤患者中开展的，研究者在患者的外周血中观察到NK细胞和CD8＋记忆性T细胞显著增加，但同时伴有剂量限制毒性。相关研究表明，静脉推注IL-15 对CD8＋T细胞和NK细胞有显著作用。上述研究提示IL-15单药治疗方案疗效有限，需考虑其单药治疗疗效受限机制及进一步的改进方案。IL-15的单药治疗效果可能受到体内IL-15Rα表达的限制，而后者是IL-15发挥生物活性所必需的。其次，由于IL-15分子量小，给药后半衰期相对较短。为解决上述问题，相关研究者研发出由IL-15蛋白N72D突变后结合IL-15Rα及IgG1Fc共同表达的融合蛋白，该融合蛋白是一种独特的新型IL-15超级激动剂。相关研究显示，此IL-15衍生物具有良好的分布和持久性，其治疗潜力优于天然IL-15。图6：突变体IL-15与IL-15Rα受体融合蛋白 (IL-15Rα-Fc) 非共价相互结合，可增强更久的半衰期和生物活性IL-15 还可与ICIs（免疫检查点抑制剂）联合应用，实验证明IL-15 与PD-1/PD-L1单抗联合应用比单独用药更有效。此外IL-15还可与治疗性单克隆抗体、单倍体相合NK细胞、卡介苗等联合应用，在癌症治疗领域表现出不俗的实力。活性检测细胞株甲贝医药构建的Jurkat-IL15-Luc的细胞表面高表达IL-15受体，下游具有报告基因Luciferase。当IL-15蛋白与细胞表面IL-15受体结合后，会诱导下游Luciferase信号的表达，该信号值高低和IL-15蛋白活性或浓度成正比，形成剂量依赖型曲线。图7：报告基因法检测IL15的作用机制图构建的报告基因法优势如下：方法稳定、变动小；实验窗口大、响应值高；利用转基因构建的细胞可稳定传代；该细胞株可以作为以IL-15为靶点的药物活性检测细胞株；适合放行、长期稳定性检测，方便方法验证；报告基因法Jurkat-IL15-Luc测试活性数据展示：图8：Jurkat-IL15-Luc的活性结果图报告基因法Jurkat-IL15-Luc的专属性数据展示：图9：Jurkat-IL15-Luc的专属性结果图细胞增殖法与报告基因法检测对比：图10：细胞增殖法检测IL-15生物学活性图11：报告基因法检测IL-15生物学活性表1:报告基因法与细胞增殖法检测IL-15生物学活性的比较报告基因法（Jurkat-IL15-Luc）与细胞增殖法检测同一IL-15蛋白样品的EC50趋于相似。但相比细胞增殖法，报告基因法的优势在于：该方法窗口更高，重复率佳，方法变异低，更容易操作，同时检测时间较短，所以该方法更加适合方法验证，QC放行，稳定性检测等需求。而细胞增殖法因为药物因子干扰多,如:GM-CSF、IFN-α、IFN-β、IFN-γ、IL-2、IL-3、IL-4、IL-6、IL-15、NGF、SCF、TNF-α、TPO等都可促进细胞增殖，所以导致专属性较差。另外细胞增殖法所需检测时间更长,和报告基因法相比，该方法中IL-15和细胞作用时间长可达24，48，72小时，甚至更长。文献引用：【1】Anjali Mishra, Laura Sullivan and Michael A. Caligiuri. Molecular Pathways: Interleukin-15 Signaling in Health and in Cancer, Clinical Cancer Research, 2014, 20(8). 【2】Marek Jakobisiak, Jakub Golab, Witold Lasek, Interleukin 15 as a promising candidate for tumor immunotherapy, Cytokine & Growth Factor Reviews, 22(2), 2011. 【3】Jason C. Steel, Thomas A. Waldmann, John C. Morris, Interleukin-15 biology and its therapeutic implications in cancer, Trends in Pharmacological Sciences, 33(1), 2012. 【4】Jakobisiak M, Golab J, Lasek W. Interleukin 15 as a promising candidate for tumor immunotherapy. Cytokine Growth Factor Rev. 2011 Apr;22(2):99-108. 【5】Patidar M, Yadav N, Dalai SK. Interleukin 15: A key cytokine for immunotherapy. Cytokine Growth Factor Rev. 2016 Oct;31:49-59.【6】丁子文,汪璐,任燕,郑岩,李渊,张婧妍,倪娜.白介素15在肿瘤免疫治疗中的临床研究进展[J].世界临床药物,2022,43(01):87-90+104.【7】赵煜,张涛,谭勇.白细胞介素15的研究进展[J].医述,2013,19(03):414-416.【近期活动】

临床结果免疫疗法信使RNA