更新于：2024-11-01

IL-36R

更新于：2024-11-01

基本信息

别名

IL-1Rrp2、IL-36 receptor、IL-36R

+ [6]

简介

Receptor for interleukin-36 (IL36A, IL36B and IL36G). After binding to interleukin-36 associates with the coreceptor IL1RAP to form the interleukin-36 receptor complex which mediates interleukin-36-dependent activation of NF-kappa-B, MAPK and other pathways (By similarity). The IL-36 signaling system is thought to be present in epithelial barriers and to take part in local inflammatory response; it is similar to the IL-1 system. Seems to be involved in skin inflammatory response by induction of the IL-23/IL-17/IL-22 pathway.

关联

项与 IL-36R 相关的药物

Spesolimab

佩索利单抗

靶点

IL-36R

作用机制

IL-36R抑制剂

在研机构

Boehringer Ingelheim GmbH [+8]

原研机构

Boehringer Ingelheim International GmbH

在研适应症

脓疱型银屑病 [+4]

非在研适应症

溃疡性结肠炎 [+4]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2022-09-01

Imsidolimab

靶点

IL-36R

作用机制

IL-36R抑制剂

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段临床3期

首次获批国家/地区-

首次获批日期1800-01-20

Recibokibart

靶点

IL-36R

作用机制

IL-36R抑制剂

在研机构

上海华奥泰生物药业股份有限公司

原研机构

华博生物医药技术（上海）有限公司

在研适应症

泛发性脓疱型银屑病 [+2]

非在研适应症-

最高研发阶段临床2/3期

首次获批国家/地区-

首次获批日期1800-01-20

项与 IL-36R 相关的临床试验

NCT06624670 / Not yet recruiting临床3期

A Multi-centre, Randomised, Placebo-controlled, Double-blind, Parallel-group Trial to Evaluate Safety and Efficacy of Spesolimab (BI 655130) in Adult Patients With Ulcerative Pyoderma Gangrenosum (PG) Who Require Systemic Therapy

The purpose of this study is to find out whether a medicine called spesolimab helps people with pyoderma gangrenosum (PG). The main aim is to see whether spesolimab leads to closure of PG ulcers. This study is open to adults with ulcerative PG with at least 1 ulcer that measures between 5 cm^2 to 80 cm^2 in size.
This study has 2 parts. In Part 1, participants are put into groups randomly, which means by chance. 1 group gets spesolimab and the other group gets placebo. Placebo injections look like spesolimab injections, but do not contain any medicine. Every participant has a 2 in 3 chance of getting spesolimab. For the first 8 weeks, participants also take corticosteroid medicine by mouth.
In Part 2, participants are put into groups again. Participants without open ulcers have an equal chance of getting spesolimab or placebo. Participants with open skin ulcers will get spesolimab.
In both parts, participants receive spesolimab or placebo as an infusion into a vein every 4 weeks.
Participants are in the study for about 1.5 years. During this time, they visit the study site 20 times. At study visits, doctors check the participant's skin for signs of PG. The doctors also regularly check participants' health and take note of any unwanted effects. The results of the groups are compared to see whether the treatment works.

开始日期2025-01-15

申办/合作机构

Boehringer Ingelheim GmbH

NCT06477536 / Recruiting临床2/3期

A Phase 3, Long-Term Extension Study to Evaluate the Safety and Efficacy of HB0034 in the Treatment of Adult Subjects with Generalized Pustular Psoriasis

This is a Phase IIb, long term extension study to evaluate the safety and efficacy of HB0034 in adult subjects with generalized pustular psoriasis (GPP).

开始日期2024-09-02

申办/合作机构

上海华奥泰生物药业股份有限公司

CTR20242844 / Recruiting临床2期

评价HB0034在泛发性脓疱型银屑病患者中安全性和疗效的多中心、单臂、开放标签IIb期长期安全扩展研究

评价HB0034在GPP患者中的长期安全性和耐受性

开始日期2024-09-02

申办/合作机构

上海华奥泰生物药业股份有限公司

[+1]

100 项与 IL-36R 相关的临床结果

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100 项与 IL-36R 相关的转化医学

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0 项与 IL-36R 相关的专利（医药）

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401

项与 IL-36R 相关的文献（医药）

2024-12-31·Journal of Dermatological Treatment

Successful treatment of recalcitrant generalized pustular psoriasis of pregnancy with spesolimab

Article

作者: Li, Ruoyu ; Tu, Ping ; Wang, Ruojun ; Wang, Yang ; Yang, Chenxin

Generalized pustular psoriasis (GPP) in pregnancy can lead to severe complications for both mother and fetus. The treatment of this disease is challenging, especially in recalcitrant and severe cases. Until present, there are no evidence-based guidelines for the treatment of GPP in pregnancy. Spesolimab, a human monoclonal antibody against the IL-36 receptor, has recently attracted attention as a new therapy for GPP flare. This biologic provides rapid and sustained control of symptoms of GPP flare, although its use in pregnant women has not been reported to date. Here, we report a pregnant woman with refractory GPP who did not respond well to systemic steroids. Administration of spesolimab resulted in complete control of the disease and the birth of a healthy baby. Our case demonstrates that IL-36RN inhibitors are a potentially effective and safe treatment option for GPP in pregnancy.

2024-12-01·International Immunopharmacology

Casting NETs on Psoriasis: The modulation of inflammatory feedback targeting IL-36/IL-36R axis

Article

作者: Zhan, Zi-Ying ; Nan, Ji-Xing ; Quan, Shu-Lin ; Zhang, Zhi-Hong ; Jiang, Min ; Lian, Li-Hua ; Wu, Yan-Ling ; Wang, Xiang-Yuan

NETosis happens when neutrophils are activated and neutrophil extracellular traps (NETs) are formed synchronously, which is a hallmark of psoriasis. However, the specific trigger that drives NET formation and the distinct contents and interaction with interleukin-36 receptor (IL-36R) of NETs remain to be further elucidated. This work identified NET formation driven by toll-like receptor (TLR) 3 ligand (especially polyinosinic-polycytidylic acid (Poly(I:C)) were enhanced by purinergic receptor P2X ligand-gated ion channel 7 receptor (P2X7R) ligands (especially adenosine 5'-triphosphate (ATP)). NET formation was accompanied by the secretion of inflammatory cytokines and characterized by IL-1β decoration. NET formation blockade decreased expressions of inflammatory cytokines and chemokines, which consequently improved inflammatory responses. Additionally, imiquimod (IMQ)-induced psoriasiform symptoms including neutrophilic infiltration tended to be time-sensitive. Mouse primary keratinocytes and mice deficient in Il1rl2, which encodes IL-36R, mitigated inflammatory responses and NET formation, thereby delaying the pathophysiology of psoriasis. Together, the findings provided the therapeutic potential for IL-36 targeting NET inhibitors in psoriasis treatment.

2024-10-01·Journal of the European Academy of Dermatology and Venereology

The role of interleukin‐36 in health and disease states

Review

作者: Fujita, Hideki ; Yamanaka, Keiichi ; Komine, Mayumi ; Akiyama, Masashi ; Sugiura, Kazumitsu

AbstractThe interleukin (IL)‐1 superfamily upregulates immune responses and maintains homeostasis between the innate and adaptive immune systems. Within the IL‐1 superfamily, IL‐36 plays a pivotal role in both innate and adaptive immune responses. Of the four IL‐36 isoforms, three have agonist activity (IL‐36α, IL‐36β, IL‐36γ) and the fourth has antagonist activity (IL‐36 receptor antagonist [IL‐36Ra]). All IL‐36 isoforms bind to the IL‐36 receptor (IL‐36R). Binding of IL‐36α/β/γ to the IL‐36R recruits the IL‐1 receptor accessory protein (IL‐1RAcP) and activates downstream signalling pathways mediated by nuclear transcription factor kappa B and mitogen‐activated protein kinase signalling pathways. Antagonist binding of IL‐36Ra to IL‐36R inhibits recruitment of IL‐1RAcP, blocking downstream signalling pathways. Changes in the balance within the IL‐36 cytokine family can lead to uncontrolled inflammatory responses throughout the body. As such, IL‐36 has been implicated in numerous inflammatory diseases, notably a type of pustular psoriasis called generalized pustular psoriasis (GPP), a chronic, rare, potentially life‐threatening, multisystemic skin disease characterised by recurrent fever and extensive sterile pustules. In GPP, IL‐36 is central to disease pathogenesis, and the prevention of IL‐36‐mediated signalling can improve clinical outcomes. In this review, we summarize the literature describing the biological functions of the IL‐36 pathway. We also consider the evidence for uncontrolled activation of the IL‐36 pathway in a wide range of skin (e.g., plaque psoriasis, pustular psoriasis, hidradenitis suppurativa, acne, Netherton syndrome, atopic dermatitis and pyoderma gangrenosum), lung (e.g., idiopathic pulmonary fibrosis), gut (e.g., intestinal fibrosis, inflammatory bowel disease and Hirschsprung's disease), kidney (e.g., renal tubulointerstitial lesions) and infectious diseases caused by a variety of pathogens (e.g., COVID‐19; Mycobacterium tuberculosis, Pseudomonas aeruginosa, Streptococcus pneumoniae infections), as well as in cancer. We also consider how targeting the IL‐36 signalling pathway could be used in treating inflammatory disease states.

189

项与 IL-36R 相关的新闻（医药）

2024-10-27

·微信

Cell Stem Cell | 陆新江团队发现精氨酸加压素驱动造血干细胞偏髓系分化参与小鼠抑郁

引言应激包括高原低氧、辐射和心理应激等，可引起免疫系统紊乱诱导抑郁。造血干细胞（HSC）可以直接感受神经内分泌信号并维持免疫系统稳态。然而HSC在应激诱发抑郁中的具体作用及其机制尚不明确。 2024年10月22日，浙江大学基础医学院陆新江团队在Cell Stem Cell杂志上在线发表题为Vasopressin drives aberrant myeloid differentiation of hematopoietic stem cells, contributing to depression in mice的研究论文。研究阐述了应激条件下精氨酸加压素（AVP）介导脑-骨髓轴的作用和机制，揭示了神经内分泌信号影响HSC髓系分化的特异性分子机制。该研究组采用单细胞转录组测序（scRNA-seq）发现应激诱导的抑郁小鼠骨髓中髓系祖细胞CMP和GMP数量增加，并且淋巴系祖细胞CLP和ProB数量减少。scRNA-seq的数据还发现HSC的S100A9表达上调，并且介导了髓系分化。进一步深入分析scRNA-seq数据并结合ImmGen结果显示精氨酸加压素受体2（AVPR2）在中性粒祖细胞样细胞群（ProNeuL）和中性粒细胞中的表达显著高于其他细胞。采用过继性转移AVP处理后的中性粒细胞，发现其可促进骨髓的髓系细胞生成，而中性粒细胞特异性敲除AVPR2则抑制小鼠的髓系分化。进而通过小鼠体内示踪技术证明骨髓HSC来源的中性粒细胞可进入脑内。通过中性粒细胞转录组测序发现AVP处理小鼠中性粒细胞IL36G表达上调，并且造血细胞特异性敲除IL36G受体IL1RL2抑制髓系细胞产生和脑内神经炎症反应。上述研究结果表明，造血系统在应激诱导的抑郁症发病机制中发挥了关键作用，并揭示了脑-骨髓轴在抑郁发生中的作用机制（图1）。靶向IL36G-IL1RL2的单抗已于2022年获批用于治疗银屑病，如果未来在人类中证明对抑郁症同样有效，将具有重要的临床意义。研究团队还发现高原低氧也会引起髓系分化促进抑郁发生，但在分子机制上与心理应激诱导的抑郁症有一定差异，该工作还在进一步进行中。此外髓系分化在消化道肿瘤的发生和发展过程中也发挥了重要作用，相关研究正在深入展开。图1 应激驱动HSC偏髓系分化促进抑郁发生（Credit: Cell Stem Cell）参考文献 https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00358-8 责编|探索君排版|探索君来源|BioArt End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

临床研究

2024-08-08

·正大天晴药业集团

评价TQH2929注射液在泛发性脓疱型银屑病受试者中的安全性、耐受性、药代动力学特征和药效的Ⅰ期临床试验

招募受试者正大天晴药业集团南京顺欣制药有限公司正在全国开展一项“评价TQH2929注射液在健康成人受试者及银屑病受试者中的安全性、耐受性、药代动力学特征和药效的Ⅰ期临床试验”。这项研究已得到国家药品监督管理总局的批准（批件号：2023LP01086）并通过中心伦理，现在全国招募拓展阶段的泛发性脓疱型银屑病受试者。试验药物简介 TQH2929注射液是正大天晴自主研发的一款治疗泛发性脓疱型银屑病等疾病的人源化单克隆抗体药物，注册分类为治疗用生物制品1类新药。主要入选标准（1）18-75岁；（2）诊断为泛发性脓疱型银屑病（GPP）；（3）符合GPP急性发作，需满足以下条件： ① GPPGA评分≥3（中重度）； ② 存在新发脓疱或原有脓疱加重，GPPGA脓疱亚项评分≥2； ③ 脓疱和红斑累及至少10%全身体表面积（BSA）。主要排除标准（1）之前使用过任何IL-36R抑制剂（包括但不限于佩索利单抗）；（2）脓疱仅局限于银屑病斑块上的寻常型银屑病；（3）近期感染史：前2个月内有带状疱疹感染史；前4周内有需要全身抗生素或全身抗病毒治疗的任何活动性感染；前3个月内有导致住院或静脉输注抗生素或抗病毒治疗的严重感染史；（4）药物洗脱期（参加研究给药需要停用相关药物的时间）：治疗银屑病的外用药需至少停用1周；全身性治疗如环孢素、甲氨蝶呤（MTX）、阿维A、糖皮质激素等需停用4周（使用稳定剂量的维A酸类口服药或甲氨蝶呤超过4周者，也可入组）；4周内定期接受光疗；前3个月内接受过生物制剂治疗。研究中心信息如果您符合以上条件或有意向参加该项研究，请扫描下方二维码报名。正大天晴药业集团是集药品的科研、生产和销售为一体的创新型医药集团企业，员工14000多人，是国内抗肿瘤、肝病、呼吸领域的知名企业，位列中国医药工业百强榜第13位，为中国医药研发产品线最佳工业企业。正大天晴始终将科技创新作为企业可持续发展的重要战略，为积极研制创新和高品质药品不懈努力，重点打造肿瘤、肝病、呼吸等产品集群。公司年研发投入占销售收入的17%，在研项目148个，其中创新药80个，先后承担国家重大专项课题33项，累计有效申请及专利3080项，拥有有效授权专利1137项，形成了“上市一代、储备一代、研发一代”的良性格局。健康科技，温暖更多生命。为社会提供优质产品是我们不变的初心，正大天晴希望为患者提供更佳的健康解决方案，为提高公众健康水平与药品可及性不懈努力。注：以上数据来自正大天晴内部报表，统计时间截至2023年底

临床1期临床申请

2024-07-31

·PMLiVE

Boehringer Ingelheim’s Spevigo recommended by CHMP for generalised pustular psoriasis

Boehringer Ingelheim’s Spevigo (spesolimab) injection has been recommended by the European Medicines Agency’s committee for human medicines as a new indication for the prevention of generalised pustular psoriasis (GPP). The injection has been recommended to prevent GPP flares in adults and adolescents from 12 years of age, as well as the extension approval of Spevigo infusion to treat GPP flares in adults and adolescents from 12 years of age as a monotherapy. Recognised as a separate clinical entity from other forms of psoriasis, GPP is a chronic, heterogeneous, neutrophilic inflammatory disease that is associated with skin and systemic symptoms distinct from plaque psoriasis and can sometimes lead to multiple complications, including multisystem organ failure and sepsis. Already approved in 51 countries, including the EU , US and China, Spevigo is a novel, humanised selective IgG1 antibody that binds to the interleukin-36 receptor, a key part of a signalling pathway within the immune system shown to be associated with GPP. The Committee for Medicinal Products for Human Use’s decision was based on positive results from the 48-week phase 2b EFFISAYIL 2 clinical trial, as part of the EFFISAYIL clinical programme combining EFFISAYIL 1, a phase 2 study, EFFISAYIL ON, an open-label extension study and the ongoing EFFISAYIL REP open-label, phase 3b/4 trial. Results from the phase 2b trial showed that Spevigo significantly reduced the risk of GPP flares by 84% in 123 patients compared with placebo and no flare-ups were observed in patients from the high-dose group with Spevigo subcutaneous treatment after week four. In addition, the trial showed a consistent incidence of patients with adverse events across the Spevigo and placebo treatment arms. Commenting on the recommendation, Carinne Brouillon, head of human pharma at Boehringer, said: “The CHMP’s positive opinion on Spevigo… signals a strong shift in treatment, offering people living with [GPP] the potential for significant improvement of their condition and a better quality of life.” The company recently announced its acquisition of Nerio Therapeutics for up to $1.3bn, expanding its immune-oncology pipeline by gaining access to its small molecules designed to inhibit the protein tyrosine phosphatases N1 and N2.