更新于：2024-11-01

IL18RAP

更新于：2024-11-01

基本信息

别名

Accessory protein-like、AcPL、CD218 antigen-like family member B

+ [17]

简介

Within the IL18 receptor complex, does not mediate IL18-binding, but involved in IL18-dependent signal transduction, leading to NF-kappa-B and JNK activation (PubMed:9792649, PubMed:14528293, PubMed:25500532). May play a role in IL18-mediated IFNG synthesis from T-helper 1 (Th1) cells (Probable).

关联

项与 IL18RAP 相关的药物

IL-1R7 antagonist (Icanomab)

IL-1R7拮抗剂(IcanoMAB)

靶点

IL18RAP

作用机制

IL18RAP 拮抗剂

在研机构

Icanomab Gmbh

原研机构

Icanomab Gmbh

在研适应症

炎症 [+6]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

WO2024174994

专利挖掘

靶点

IL18RAP

作用机制-

在研机构

瑞石生物医药有限公司初创企业

原研机构

瑞石生物医药有限公司初创企业

在研适应症

皮肤和肌肉骨骼疾病

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 IL18RAP 相关的临床结果

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100 项与 IL18RAP 相关的转化医学

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0 项与 IL18RAP 相关的专利（医药）

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235

项与 IL18RAP 相关的文献（医药）

2024-12-01·Current Computer-Aided Drug Design

The Diagnostic Features of Peripheral Blood Biomarkers in Identifying Osteoarthritis Individuals: Machine Learning Strategies and Clinical Evidence

Article

作者: Qi, Yajun ; Hu, Yuedi ; Zhou, Qiao ; Liu, Jian ; Xin, Ling

Background:People with osteoarthritis place a huge burden on society. Early diagnosis is essential to prevent disease progression and to select the best treatment strategy more effectively. In this study, the aim was to examine the diagnostic features and clinical value of peripheral blood biomarkers for osteoarthritis.Objective:The goal of this project was to investigate the diagnostic features of peripheral blood and immune cell infiltration in osteoarthritis (OA).Methods:Two eligible datasets (GSE63359 and GSE48556) were obtained from the GEO database to discern differentially expressed genes (DEGs). The machine learning strategy was employed to filtrate diagnostic biomarkers for OA. Additional verification was implemented by collecting clinical samples of OA. The CIBERSORT website estimated relative subsets of RNA transcripts to evaluate the immune-inflammatory states of OA. The link between specific DEGs and clinical immune-inflammatory markers was found by correlation analysis.Results:Overall, 67 robust DEGs were identified. The nuclear receptor subfamily 2 group C member 2 (NR2C2), transcription factor 4 (TCF4), stromal antigen 1 (STAG1), and interleukin 18 receptor accessory protein (IL18RAP) were identified as effective diagnostic markers of OA in peripheral blood. All four diagnostic markers showed significant increases in expression in OA. Analysis of immune cell infiltration revealed that macrophages are involved in the occurrence of OA. Candidate diagnostic markers were correlated with clinical immune-inflammatory indicators of OA patients.Conclusion:We highlight that DEGs associated with immune inflammation (NR2C2, TCF4, STAG1, and IL18RAP) may be potential biomarkers for peripheral blood in OA, which are also associated with clinical immune-inflammatory indicators.

2024-12-01·Molecular Biology Reports

Immunoregulatory role of AC007278.3 and HOTAIR long non-coding RNAs in lupus nephritis: potential biomarkers and therapeutic targets

Article

作者: Abdshah, Alireza ; Gadakchi, Leyla ; Rasuli, Elahe ; Shaykh-Baygloo, Nima ; Javidi-Aghdam, Kamran ; Safary, Azam ; Khabbazi, Alireza ; Akbarzadeh-Khiavi, Mostafa ; Farajnia, Safar ; Jafarpour, Mehdi

BACKGROUNDLong non-coding RNAs (lncRNAs) have emerged as crucial regulators in various biological processes, including immune regulation and autoimmune pathologies. However, their specific significance in modulating the cytokine network in systemic lupus erythematosus (SLE) remains largely unexplored. This study assessed the expression patterns of immune-related lncRNAs, HOTAIR, and AC007278.3, along with their related protein-coding genes, TNF-α and IL18RAP, in nephritic SLE patients. Additionally, the potential of selected genes as diagnostic biomarkers for SLE was evaluated.METHODS AND RESULTSBlood samples were obtained from SLE patients (n = 30) and age-sex-matched healthy controls (HCs) (n = 60). Subsequently, RNA was isolated from peripheral blood mononuclear cells (PBMCs), and cDNA was synthesized to analyze the expression levels of the target genes using real-time PCR. The correlation analysis between the relative expressions of different genes was examined in both the patient and HC groups. The diagnostic potential of the lncRNAs was determined by calculating the Area Under the Curve of the Receiver Operating Characteristics (AUC of ROC), Cut-off, sensitivity, and specificity. Our results indicated a significant upregulation of lncRNAs AC007278.3 (fold change [FC] = 14.13, p-value < 0.0001) and HOTAIR (FC = 14.1, p-value < 0.0001). Correspondingly, their associated target genes, TNF-α and IL18RAP, were also overexpressed in patients (FC = 2.66 and FC = 5.18, respectively, p-value < 0.001). Notably, a strong positive correlation was observed between IL18RAP and AC007278.3 in SLE patients. Moreover, the AUC of ROC analyses underscored the diagnostic efficacy of AC007278.3 alone and combined with HOTAIR, yielding values of 0.89 and 0.86, respectively.CONCLUSIONThese findings highlight the potential immunoregulatory roles of lncRNAs AC007278.3 and HOTAIR, emphasizing their significance as promising diagnostic biomarkers and potential therapeutic targets for SLE. Additionally, they provide valuable insights into the molecular mechanisms underpinning the disease's pathogenesis.

2024-11-01·Phytomedicine

Eupafolin hinders cross-talk between gastric cancer cells and cancer-associated fibroblasts by abrogating the IL18/IL18RAP signaling axis

Article

作者: Wang, Qionglin ; Yuan, Ziqiao ; Zhou, Yang ; Zhai, Bo ; Dong, Xiangyang ; Yan, Hui ; Zhou, Qiang ; Wang, Penggao

BACKGROUNDCancer-associated fibroblasts (CAFs) are involved in the progression of gastric cancer (GC) as a critical component of the tumor microenvironment (TME), yet specific interventions remain limited. Natural products hold a promising application prospect in the field of anti-tumor in view of their high activity and ease of binding with biological macromolecules. However, the role of natural products in modulating the cross-talk between CAFs and GC cells has not been fully investigated.PURPOSEThe aim of this study was to identify a potential therapeutic target in CAFs and then screen for natural small molecule drugs with anti-tumor activity against this target.METHODSIntegrating bioinformatics analysis of public databases and experimental validation of human samples and cell lines to identify a candidate target in CAFs. Molecular docking and biolayer interferometry technique were utilized for screening potential natural small molecule drugs. The efficacy and underlying mechanisms of the candidates were explored in vitro and in vivo through techniques such as lentiviral infection, cell spheroids culture, immunoprecipitation and cells-derived xenografts.RESULTSIL18 receptor accessory protein (IL18RAP) was found to be overexpressed in CAFs derived from GC tissues and facilitated the protumor function of CAFs on GC. Based on virtual screening and experimental validation, we identified a natural product, eupafolin, that interfered with IL18 signaling. Phenotyping studies confirmed that the proliferation, spheroids formation and tumorigenesis of GC cells facilitated by CAFs were greatly attenuated by eupafolin both in vitro and in vivo. Mechanistically, eupafolin impeded the formation of IL18 receptor (IL18R) complex by directly binding to IL18RAP, thus blocking IL18-mediated nuclear factor kappa B (NF-κB) activation and reduced the synthesis and secretion of IL6 in CAFs. As a consequence, it inactivated signal transducer and activator of transcription 3 (STAT3) in GC cells.CONCLUSIONThis study provides new evidence that IL18 signaling regulates the cross-talk between GC cells and CAFs. And it highlights a novel pharmacological role of eupafolin in inhibiting IL18 signaling, thereby curbing the development of GC via modulating CAFs.

项与 IL18RAP 相关的新闻（医药）

2024-09-27

·奇点网

一对促癌CP诞生了！

*仅供医学专业人士阅读参考IL-18最初以一种“正面”的形象出现在我们的视野中，这是因为它可以增强T细胞和NK细胞的免疫功能。然而近年来，不断有研究显示，IL-18似乎没有表面看起来那么正派，它也可以通过激活NF-κB通路，来促进肿瘤进展和免疫逃逸。只不过，这背后的机制，我们还不得而知。近期，中山大学附属第一医院王子洋/何伟玲团队、珠海市人民医院陆骊工团队、广州大学王雄军团队联合发表了一篇研究，他们发现，长链酰基辅酶A合成酶6（ACSL6）是IL-18介导肝癌进展和免疫逃逸的关键因子。具体来说，他们发现，IL-18会使ACSL6 S674点位磷酸化（ACSL6 pS674）和细胞膜异位。而ACSL6 pS674可通过促进IL-18受体（IL18R1-IL18RAP）异二聚体的稳定形成，激活了IL-18R1/NF-κB信号通路，进一步上调了多种促癌基因的表达，最终促进了肝癌的生长和转移。此外，研究还发现，ACSL6 pS674还可以通过招募肿瘤相关的中性粒细胞（TANs）和巨噬细胞（TAMs），来抑制肿瘤浸润性CD8阳性T细胞的活性，进而导致肿瘤免疫逃逸。而抑制ACSL6的磷酸化则可以改善这一现象，并增强抗PD-1抗体的治疗效果。这一看，IL-18就像一个敌特，需要跟ACSL6这个接头的合作，才能完成偷摸给癌细胞传递消息（NF-κB通路）的任务啊。研究发表在《科学·进展》上[1]。论文首页截图既往有研究显示，参与脂肪酸分解和合成的关键酶，ACSL，其表达上调与包括肝癌在内的多种癌症有关。而上文也提到，IL-18能介导肿瘤进展和免疫逃逸。基于此，研究人员想知道，在肝癌进展和免疫逃逸过程中，IL-18和ACSL之间是否存在某种关联。鉴于ACSL家族成员众多，研究人员先是利用基因表达数据库分析了多种ACSL在肝癌组织和相邻正常肝组织中的表达情况，结果发现，ACSL6在肝癌组织中的表达水平明显上调，且与患者的不良预后相关。ACSL6在肝癌组织中表达上调随后的体外研究显示，敲除ACSL6能明显抑制肝癌细胞的增殖和迁移，反之，过表达ACSL6则会促进肝癌细胞的增殖和迁移。更重要的是，ACSL6的促癌作用与其代谢酶活性无关（过表达酶活性丧失突变型ACSL6能恢复ACSL6敲除对肝癌细胞增殖和迁移的抑制作用）。同样，研究人员也在小鼠体内也观察到了以上现象。体外实验接下来，研究人员探究了ACSL6促进肝癌进展的机制。利用质谱分析，研究人员在5种与ACSL6相互作用的蛋白质中发现，IL-18R1与ACSL6之间的相互作用最强。随后的免疫共沉实验显示，IL-18R1与ACSL6之间的相互作用发生在细胞膜上。IL-18R1与ACSL6之间的相互作用进一步，机制上，通过磷酸化位点突变、激酶抑制剂与肝癌细胞共培养等一系列实验，研究人员发现，IL-18可激活激酶ERK2，并诱导ACSL6在S674位点发生磷酸化。ACSL6 pS674随后易位至细胞膜，在那里与IL-18R1结合，并促进IL18R1-IL18RAP异二聚体的稳定形成，实现了IL-18/IL-18R1/NF-κB信号通路的传导，进一步上调了多种促癌基因（如与肿瘤生长迁移有关基因GADD45B和MMP3）的表达，最终促进了肝癌的生长和转移。研究机制图研究还发现，ACSL6 pS674可以通过激活IL-18R1/NF-κB信号通路，上调趋化因子CXCL1和CXCL5的表达，并促进TANs和TAMs的招募，来抑制肿瘤浸润性CD8阳性T细胞的活性，进而导致肿瘤免疫逃逸。最后，通过抑制ACSL6磷酸化，研究人员发现，无论是敲除ACSL6还是对ACSL6的S674位点进行突变（rAcsl6 S674A），均可以增强抗PD-1抗体的疗效，表现为肿瘤浸润的CD8阳性T细胞数量的增加，以及TANs和TAMs数量的减少。此外，临床样本分析也发现，ACSL6 pS674水平与NF-κB信号和CXCL1表达正相关，与患者预后负相关。总之，该研究揭示了IL-18是靠与ACSL6合作，来实现NF-κB信号通路的传导，进而促进了肝癌进展和免疫逃逸。这一结果也为未来肝癌的治疗提供了新的思路。------奇点糕近期推出了《2024ASCO年会深度盘点》课程，为大家系统盘点了2024ASCO年会上实体瘤领域的重磅进展，让您在100分钟内迅速深入把握前沿。长按识别下图中的二维码即可购买，购买后您可以在「奇点网小程序」收听，或下载奇点网「医学奇点」苹果客户端收听。如果遇到任何技术问题，大家可以戳我们下图中的客服小伙伴来解决~~参考文献：[1]Di Y,Wang Z,Xiao J,Zhang X,Ye L,Wen X,Qin J,Lu L,Wang X,He W.ACSL6-activated IL-18R1-NF-κB promotes IL-18-mediated tumor immune evasion and tumor progression.Sci Adv.2024 Sep 20;10(38):eadp0719.本文作者丨张金旭

细胞疗法免疫疗法引进/卖出

2024-06-24

·BioSpace

Evommune Secures Exclusive Rights to Develop and Commercialize a Phase 2-ready IL-18 targeted fusion protein from AprilBio

IL-18 modulation has potential for broad applicability in multiple inflammatory diseases Phase 2-ready program complementary to Evommune's immunology pipeline Phase 1 trial demonstrated good safety and tolerability, favorable pharmacokinetics and target engagement PALO ALTO, Calf., June 24, 2024 /PRNewswire/ -- Evommune, Inc., a clinical stage biotechnology company discovering and developing new ways to treat immune-mediated inflammatory diseases, today announced it has entered into a definitive, worldwide license agreement with AprilBio Co., Ltd. (Kosdaq: 397030), a biopharmaceutical company based in South Korea dedicated to developing specialized biologics and antibody drugs, for an IL-18 targeted fusion protein. Under the terms of the agreement, Evommune receives exclusive, worldwide rights to research, develop and commercialize APB-R3, to now be known as EVO301, a long-acting injectable fusion protein that is designed to neutralize the signal pathway of IL-18 for the regulation of inflammation. Evommune plans to initiate a Phase 2 clinical trial in early 2025. "We are committed to making a difference for patients suffering from chronic inflammation. Adding this exciting new targeted molecule is another important growth step for Evommune. EVO301 is a product candidate leveraging a novel approach in a mechanism that has demonstrated activity in prior clinical trials. While we continue to execute on our pipeline, including EVO756, our MRGPRX2 antagonist, EVO301 provides the potential to offer a best-in-class therapeutic for patients being underserved by existing treatment options in multiple diseases. We believe the proprietary serum albumin binding motif fused to an IL-18 binding protein may facilitate deep tissue penetration with an extended half-life," said Luis Pena, Evommune President & CEO. "As we evaluate partners of our pipeline products, we are thrilled to license the IL-18 fusion protein to Evommune, a company with significant drug development expertise in the areas of chronic inflammatory diseases. Evommune's ability to broadly develop this product candidate throughout its potentially broad life cycle process was a key driver of our desire to collaborate with them," commented Dr. Sang-hoon Cha, CEO at AprilBio. About EVO301 A long-acting injectable therapeutic, EVO-301 is a fusion-protein that is designed to neutralize the signal pathway of IL-18 for the regulation of inflammation. IL-18, a proinflammatory cytokine of the IL-1 family, plays an important role in the T-cell-helper type 1 inflammatory response, primarily by its ability to induce IFN-gamma production in T-cells and natural killer cells. About AprilBio AprilBio Co., Ltd. is a biopharmaceutical company in South Korea founded in 2013. The company is specialized in development of specialized biologics and antibody drugs. The company's platform technologies include a human phage-display Ab library and Anti-Serum Albumin Fab-Associated (SAFA) technology (versatile building block for half-life extension and generation of novel biological therapeutics). AprilBio is focused on rare diseases, oncology, autoimmune and inflammatory diseases. About Evommune, Inc. Evommune, Inc., a Palo Alto based biotech company, is creating game-changing science to treat immune-mediated inflammatory diseases by discovering, developing, and delivering therapies that address symptoms and halt progressive disease. For more information, please visit Evommune.com.

引进/卖出临床1期

2024-05-26

·生物探索

Cell Rep Med | 老药新用！中国科学技术大学倪芳/郑昌成/魏海明发现增强过继NK细胞对白血病免疫治疗的潜在新策略

引言基于自然杀伤(NK)细胞的免疫疗法有望治疗癌症；然而，它的效力仍然有限，因此有必要制定替代战略。2024年5月21日，中国科学技术大学倪芳、郑昌成及魏海明共同通讯在Cell Reports Medicine在线发表题为“Venetoclax acts as an immunometabolic modulator to potentiate adoptive NK cell immunotherapy against leukemia”的研究论文，该研究表明，venetoclax，一种FDA批准的BCL-2抑制剂，在体外和体内直接激活NK细胞，增强其对急性髓性白血病(AML)的细胞毒性，可能独立于BCL-2抑制。该研究通过大量和单细胞RNA测序、亲和度测量和功能分析等综合方法，证明venetoclax增加NK细胞对AML细胞的亲和度，并在免疫突触(IS)形成过程中促进溶解颗粒极化。值得注意的是，研究发现了一个独特的CD161lowCD218b+ NK细胞亚群，对venetoclax治疗表现出显著的敏感性。此外，venetoclax通过NF-κB途径促进线粒体呼吸和ATP合成，从而促进NK细胞中IS的形成。基于细胞的抗癌免疫疗法已经彻底改变了癌症治疗。不同类型的免疫细胞，特别是那些通过直接接触或释放细胞毒性分子破坏靶细胞的免疫细胞，已被用于这一目的。自然杀伤(NK)细胞是细胞毒性先天淋巴样细胞，保护宿主免受病毒感染和癌症。与T细胞不同，NK细胞可以自发地检测和消除感染和恶性细胞，而无需事先特异性激活。同种异体NK细胞特别适合用于过继性转移，因为它们可以减轻细胞因子释放综合征发生的风险。NK细胞的这些特性使得它们在基于细胞的癌症免疫治疗中具有很高的吸引力。NK免疫疗法作为一种可行有效的治疗方法，在临床前和早期临床研究中显示出巨大的前景。然而，基于NK细胞的癌症免疫治疗面临着重大挑战，主要集中在优化NK细胞来源，增强其功能能力和体内长期持久性。正在作出广泛的努力来克服这些障碍，并最大限度地发挥NK细胞的治疗潜力。治疗性NK细胞的多种来源已被探索，包括单倍体、脐带血、干细胞衍生、适应性、细胞因子诱导的记忆样、嵌合抗原受体和NK细胞系。基于细胞因子的药物、接合分子和免疫检查点抑制剂已被用于增强NK细胞的功能。尽管研究NK细胞免疫疗法的临床前和临床试验取得了相当大的进展，但其在癌症治疗中的疗效仍然有限。因此，迫切需要探索能够增强NK细胞免疫治疗并提高其治疗癌症疗效的策略。模式图（Credit: Cell Reports Medicine）Venetoclax是FDA批准的BCL-2小分子抑制剂，BCL-2是一种关键的抗凋亡蛋白，在肿瘤发生、肿瘤存活、淋巴细胞发育和免疫系统调节中起着至关重要的作用。它适用于患有慢性淋巴细胞白血病/小淋巴细胞白血病的成人患者，也可用于75岁以上的急性髓系淋巴瘤（AML）成人患者或患有阻止强化诱导化疗的疾病的患者，也可与低甲基化剂或低剂量阿糖胞苷联合使用。尽管venetoclax具有公认的凋亡作用，但其对抗肿瘤免疫反应的广泛影响在很大程度上仍未被探索。该研究提出了一种潜在可行的方法来增强NK细胞免疫疗法。通过确定venetoclax增强NK细胞功能的潜力，包括促进线粒体代谢、IS形成和细胞毒性，发现了一种改善癌症治疗结果的有希望的策略。总的来说，该研究结果表明venetoclax是NK细胞功能的多方面免疫代谢调节剂，并为增强NK细胞为基础的癌症免疫治疗提供了一个有希望的策略。原文链接https://doi-org.libproxy1.nus.edu.sg/10.1016/j.xcrm.2024.101580责编|探索君排版|探索君文章来源|“iNature”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Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文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

免疫疗法细胞疗法临床研究