IL26

IL-10自1989年首次被发现，针对它的学术研究已进行了三十余年，但时至今日，它在药物研发领域仍然是个“冷门”。01靶点概述白介素10(IL-10)最初被描述为Th2细胞细胞因子。包括IL-19、IL-20、IL-22、IL-24、IL-26、IL-28A、IL-28B和IL-29等，这些与IL-10具有相似蛋白质结构和受体复合物的细胞因子也被称为IL-10家族细胞因子。IL-10是一种现在被认为是复杂的多效的细胞因子，能够影响上皮功能并参与过敏和感染等炎症疾病，具有重要的免疫调节功能。其主要由抗原呈递细胞分泌，如活化的T细胞、单核细胞、B细胞和巨噬细胞。在生物功能形式中，IL-10以同源二聚体的形式存在，与四聚体异二聚体IL-10R结合并诱导下游信号转导。功能性IL-10R复合体是由两个配体结合亚基IL-10Rα（IL-10R1）和两个辅助信号亚基IL-10Rβ（IL-10R2）组成的四聚体。[1]02信号通路IL-10与IL-10Rα胞外结构域的结合激活了受体相关的JAK1和TYK2的磷酸化，然后IL-10Rα链胞内结构域的特异性酪氨酸残基Y446和Y496被磷酸化，这些酪氨酸残基(及其侧肽序列)就会成为潜在转录因子STAT3的临时停靠点。STAT3通过其SH2结构域与这些位点结合，继而被受体相关的JAKs酪氨酸磷酸化，继而STAT3二聚化入核，激活核内基因的转录翻译，从而增加了抗凋亡和细胞周期进展基因的转录。IL-10信号通路示意图[2]此外，IL-10还可以激活PI3K及其下游底物p70S6K和Akt/PKB。尽管IL-10的抗炎作用不是通过PI3K介导的，但IL-10促进星形胶质细胞存活或诱导肥大细胞增殖的能力取决于PI3K的激活。IL-10还会干扰LPS及其受体TLR4的下游信号p38/MAPK通路，从而抑制肿瘤坏死因子的翻译通路（TNF-mRNA）。在一些研究中，IL-10促进癌细胞生长和存活，包括非霍奇金淋巴瘤、伯基特淋巴瘤和非小细胞肺癌，IL-10过表达与SLE，结核病相关，而炎症性肠病、银屑病、哮喘、类风湿性关节炎等疾病与IL-10缺乏相关。03竞争格局2018年，礼来斥资16亿美元收购ARMO Biosciences，获得其下IL-10项目pegilodecakin。2019年，其治疗胰腺癌的III期临床因未达主要终点而宣告失败，之后，其治疗肺癌的两个II期临床也终止，一番挣扎之后，这款名噪一时的候选药消失得悄无声息。同年，Biotest AG宣布其人源化IL-10单抗BT-063治疗系统性红斑狼疮的2期临床试验结果达主要终点，BT-063在自免疫疾病治疗领域大有可为。然而至今，官网管线中已不见其身影。此外，包括默沙东的MK-1966、Y-Biologics的YBL010和Cytonus Therapeutics的CA-IL10等十几条管线均已终止开发，不了了之。时至今日，IL-10赛道中多家公司或机构纷纷进入，又纷纷离开，仍然在这条赛道上奔跑的选手已所剩无几。AMT-101是一种新型的、具有消化道选择性的的口服重组生物融合蛋白——人白细胞介素10（hIL-10），主要用于治疗炎症性肠病和系统性炎症适应症。该药物采用AMT的专有平台设计，旨在利用肠道内自然生物运输机制的力量，使其能够穿过肠道上皮屏障，直接与肠道组织中丰富的免疫环境中的细胞相互作用。今年7月公布的治疗中度至重度溃疡性结肠炎（UC）的2期顶线结果显示，对于主要终点来说，AMT-101联合阿达木单抗治疗组的临床缓解率（31.8%）与对照组安慰剂联合阿达木单抗治疗组（临床缓解率33.3%）相比，并没有表现出更好的疗效优势。但是在UC病程＜5年的患者中，AMT-101联合治疗的临床缓解率为43.8%，对照组15.4%，疗效显著。Dekavil (F8IL10)由F8抗体与IL10融合组成，它对纤连蛋白的EDA结构域具有特异性，能选择性地定位在各种炎症的炎症组织中。XT-150是一种局部注射的质粒DNA基因疗法，表达IL-10v（一种IL-10的专有改良变体），以解决病理性炎症和疼痛。XT-150与目前的标准治疗相比，大大增加了其效果的持续时间。小结：IL-10自发现至今已30多年，在这条布满荆棘的道路上，有人倒下，也有人在艰难前行，致敬这些荆棘途中形单影只的孤勇者，也期待这些药物后续会有更好的进展。扫码查询现货细胞系参考：1. doi:10.1111/febs.162072.https://www.thermofisher.cn/cn/zh/home/life-science/antibodies/antibodies-learning-center/antibodies-resource-library/cell-signaling-pathways/il-10-pathway.html3. doi: 10.3389/fimmu.2022.9479834. doi: 10.1084/jem.201904185. doi: 10.1080/2162402X.2021.20035336. 各企业官网往期推荐PROTAC全球布局一览Fierce Biotech丨2022年医药企业裁员追踪盘点国产PD-1销售盘点点击下方“药研网”，关注更多精彩内容

Researchers have shown that patients with acute COVID-19 infection have increased levels of the cytokine IL-26 in their blood. Moreover, high IL-26 levels correlate with an exaggerated inflammatory response that signifies severe cases of the disease. The findings indicate that IL-26 is a potential biomarker for severe COVID-19. Researchers at Karolinska Institutet in Sweden have shown that patients with acute COVID-19 infection have increased levels of the cytokine IL-26 in their blood. Moreover, high IL-26 levels correlate with an exaggerated inflammatory response that signifies severe cases of the disease. The findings, which are presented in Frontiers in Immunology, indicate that IL-26 is a potential biomarker for severe COVID-19. Vaccines for SARS-CoV-2 have proved effective at reducing the number of cases of severe COVID-19. However, the emergence of new viral variants, limited distribution of the vaccine and declining immunity are problems that drive scientists to find more efficacious treatments for the disease. "We need to understand more about underlying immunological mechanisms in order to find better treatments. There is also a need for improved diagnostics in COVID 19-patients," says Eduardo Cardenas, postdoc researcher at the Institute of Environmental Medicine, Karolinska Institutet, and principal author of the new pilot study. The researchers have tried, for the first time, to ascertain whether immune signalling via the cytokine interleukin-26 (IL-26) is involved in severe COVID-19. "We already know that IL-26 is engaged in mobilising immune cells that combat bacterial infections in the lungs and also in chronic respiratory disease in humans," says the study's last author Anders Lindén, consultant and professor at the Institute of Environmental Medicine, Karolinska Institutet. "What's more, IL-26 has antiviral and antibacterial effects." To study how the molecule is involved in COVID-19, the scientists recruited 49 patients who had been hospitalised with SARS-CoV-2-infection, 44 of whom had severe symptoms and needed oxygen therapy. The patients were recruited at a hospital in Stockholm from June 2020 to January 2021. A control group of 27 healthy individuals was also recruited during the same period. The researchers then measured levels of IL-26 protein and other inflammatory compounds in the blood. "We can show for the first time that blood levels of the cytokine IL-26 are much higher in patients with COVID-19 than in healthy controls," says Dr Cardenas. The researchers could also see that the increase was associated with the so-called cytokine storm -- an excessive and dangerous inflammatory response that signifies severe cases of COVID-19. "Our discovery gives us a potential biomarker for severe COVID-19, but given the antiviral effects of IL-26, we may also have identified a new therapeutic target," says Professor Lindén. According to Dr Cardenas, the results are promising but are preliminary and warrant further study with a larger patient cohort. "Such a study is on the way and can give more information on the clinical value of measuring IL-26 in COVID-patients, such as whether the levels reflect the severity of the disease. The study was financed by the Swedish Research Council and the Swedish Heart-Lung Foundation.