更新于：2024-11-01

A3R x TNF-α

更新于：2024-11-01

基本信息

关联

项与 A3R x TNF-α 相关的药物

MDL-201449

靶点

A3R x TNF-α

作用机制

A3R激动剂 [+1]

在研机构-

原研机构

Hoechst Marion Roussel, Inc.

在研适应症-

非在研适应症

结肠炎 [+1]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 A3R x TNF-α 相关的临床结果

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100 项与 A3R x TNF-α 相关的转化医学

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0 项与 A3R x TNF-α 相关的专利（医药）

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项与 A3R x TNF-α 相关的文献（医药）

2024-10-01·Purinergic Signalling

Genetic and functional modulation by agonist MRS5698 and allosteric enhancer LUF6000 at the native A3 adenosine receptor in HL-60 cells

Article

作者: Gao, Zhan-Guo ; Jacobson, Kenneth A ; Hanover, John A ; Chen, Weiping ; Li, Jonathan ; Tosh, Dilip K ; Gao, Ray R

AbstractThe A3 adenosine receptor (AR) is an important inflammatory and immunological target. However, the underlying mechanisms are not fully understood. Here, we report the gene regulation in HL-60 cells treated acutely with highly selective A3AR agonist MRS5698, positive allosteric modulator (PAM) LUF6000, or both. Both pro- and anti-inflammatory genes, such as IL-1a, IL-1β, and NFκBIZ, are significantly upregulated. During our observations, LUF6000 alone produced a lesser effect, while the MRS5698 + LUF6000 group demonstrated generally greater effects than MRS5698 alone, consistent with allosteric enhancement. The number of genes up- and down-regulated are similar. Pathway analysis highlighted the critical involvement of signaling molecules, including IL-6 and IL-17. Important upstream regulators include IL-1a, IL-1β, TNF-α, NF-κB, etc. PPAR, which modulates eicosanoid metabolism, was highly downregulated by the A3AR agonist. Considering previous pharmacological results and mathematical modeling, LUF6000’s small enhancement of genetic upregulation suggested that MRS5698 is a nearly full agonist, which we demonstrated in both cAMP and calcium assays. The smaller effect of LUF6000 on MRS5698 in comparison to its effect on Cl-IB-MECA was shown in both HL-60 cells endogenously expressing the human (h) A3AR and in recombinant hA3AR-expressing CHO cells, consistent with its HL-60 cell genetic regulation patterns. In summary, by using both selective agonists and PAM, we identified genes that are closely relevant to immunity and inflammation to be regulated by A3AR in differentiated HL-60 cells, a cell model of neutrophil function. In addition, we demonstrated the previously uncharacterized allosteric signaling-enhancing effect of LUF6000 in cells endogenously expressing the hA3AR.

2024-05-01·International Immunopharmacology

Manual acupuncture ameliorates inflammatory pain by upregulating adenosine A3 receptor in complete Freund’s adjuvant-induced arthritis rats

Article

作者: Du, Hong ; Xu, Shang-Cheng ; Yang, Qian ; Qu, Fei ; Ke, Hong ; Cui, Yan-Ru ; Ouyang, Qian-Wen ; Xu, Jing-Ping ; Shao, Mei-Juan

BACKGROUNDAdenosine A₃ receptor (A₃R) exerts analgesic, anti-inflammatory, and anti-nociceptive effects. In this study, we determined the analgesic mechanism of manual acupuncture (MA) in rats with complete Freund's adjuvant (CFA)-induced arthritis and explored whether MA ameliorates inflammation in these rats by upregulating A₃R.METHODSSixty Sprague Dawley (SD) rats were randomly divided into the following groups: Control, CFA, CFA + MA, CFA + sham MA, CFA + MA + DMSO, CFA + MA + IB-MECA, and CFA + MA + Reversine groups. The arthritis rat model was induced by injecting CFA into the left ankle joints. Thereafter, the rats were subjected to MA (ST36 acupoint) for 3 days. The clinical indicators paw withdrawal latency (PWL), paw withdrawal threshold (PWT), and open field test (OFT) were used to determine the analgesic effect of MA. In addition, to explore the effect of A₃R on inflammation after subjecting arthritis rats to MA, IB-MECA (A₃R agonist) and Reversine (A₃R antagonist) were injected into ST36 before MA.RESULTSMA ameliorated the pathological symptoms of CFA-induced arthritis, including the pain indicators PWL and PWT, number of rearing, total ambulatory distance, and activity trajectory. Furthermore, after MA, the mRNA and protein expression of A₃R was upregulated in CFA-induced arthritis rats. In contrast, the protein levels of TNF-α, IL-1β, Rap1, and p-p65 were downregulated after MA. Interestingly, the A₃R agonist and antagonist further downregulated and upregulated inflammatory cytokine expression, respectively, after MA. Furthermore, the A₃R antagonist increased the degree of ankle swelling after MA.CONCLUSIONMA can alleviate inflammatory pain by inhibiting the NF-κB signaling pathway via upregulating A₃R expression of the superficial fascia of the ST36 acupoint site in CFA-induced arthritis rats.

2022-08-29·Evidence-Based Complementary and Alternative Medicine

FKN/NR Signaling Pathway Regulates Hippocampal Inflammatory Responses: the Survival of Hippocampal Neurons in Diabetic Rats with Chronic Unpredictable Mild Stress

Article

作者: Liu, Zhuo ; Zhao, Hongqing ; Han, Yuanshan ; Wang, Yuhong ; Liu, Jian

Aim. To investigate the mechanism via which FKN/CX3CR1 signaling abnormalities mediate N-methyl-D-aspartic acid receptor (NMDA) overexcitation-induced hippocampal neuronal injury in diabetic rats complicated with depression (DD). Methods. Sixty rats were randomly divided into 5 groups. The depression-like behaviors of the rats were evaluated by open field test and Morris water maze. The pathological changes of hippocampus in DD rats were observed by HE staining. The blood levels of inflammatory factors (IL-1β, TNF-α, and IL-6) and neurotransmitters (D-serine and glutamic acid) were determined by enzyme-linked immunosorbent assay (ELISA). The expressions of BDNF, A1 receptor (A1R), A2 receptor (A2R), A3 receptor (A3R), calmodulin dependent kinase II (CaMKII), CX3CR1, CX3CL1 (FKN), NR2A, and NR2B proteins were detected by immunohistochemistry and Western-blotting. Results. Compared with the normal control group, blood glucose level increased significantly and body weight decreased in T2DM group and T2DMC group. In addition, the number of spontaneous activities significantly decreased and the capability of learning and memory was attenuated in T2DMC group and Chronic Stress group. The blood levels of IL-1β, TNF-α, IL-6, glutamate (Glu), and D-serine significantly increased in each model group. After intervention with CX3CR1 antibody, the expressions of BDNF, CaMK II, A1R, and A3R increased and those of A2R, CX3CR1, FKN, NR2A, and NR2B decreased. Conclusion. In the diabetic state, the binding of FKN to CX3CR1 increases, which regulates a variety of adenosine receptors. When it exerts its effect on neurons, the overactivation of NR results in neuronal injury and causes depression.

项与 A3R x TNF-α 相关的新闻（医药）

2023-12-30

·佰傲谷BioValley

从炎症突破：肿瘤免疫“急转弯”到减肥……？

近年来在诸多免疫疗法的开发过程中，我们往往看到，基于肿瘤和自免“一体两面”的免疫机制关系，一些免疫疗法或者管线能够依靠反向设计机制或者调整通路中的靶向方向以达到将适应症从肿瘤跨到自免、或者从自免跨到肿瘤赛道的转变。肿瘤无果，自免开花意外的反向开发，“真正”的自免CAR-T？不过有的产品则看上了更“热”的市场——减重。一家以色列生物技术公司Can-Fite近期报告了其原本靶向肿瘤的小分子候选药物Namodenoson发挥抗肥胖作用的新数据。Namodenoson是一种口服小分子药物，是A3腺苷受体(A3AR)高度特异性和选择性的激动剂。A3AR是G蛋白偶联腺苷的四种受体之一，其在炎症、肿瘤和其他病变的细胞中高表达，而在正常细胞中低表达，因此具有相当的靶向性。腺苷可以以剂量依赖的方式激活A3AR，并且以自分泌方式促进受体表达。Namodenoson的作用机制是通过PI3K/NF-κB和Wnt/β-catenin通路失调介导对细胞凋亡(apoptosis)的，在肿瘤治疗中旨在诱导肿瘤细胞凋亡。此次宣布新适应症的机制是Namodenoson可以影响脂肪细胞中蛋白质的调节，从而增加脂联素水平。Namodenoson已经进入临床阶段的适应症包括肝癌、胰腺癌、非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)。最快的是肝癌，已经获得FDA批准展开3期临床。针对自身免疫性肝炎也展开了临床前动物模型实验。该产品的中国区商业化权益已经授权给康哲药业(CMC)。在NASH中，Namodenoson的抗炎保护作用是通过下调NF-kB信号转导途径和防止细胞凋亡介导的。在STAM模型中，Namodenoson显著降低NAFLD活动评分。它还改善了丙氨酸氨基转移酶(ALT)、脂联素和瘦素水平，改善肝脏炎症/纤维化表现。该公司管线中的另一款A3AR同靶点同结构类型产品Piclidenoson则是直接作为抗炎药物开发，已进行临床前试验的适应症包括胶原诱导的关节炎和炎症性肠病。其机制包括通过下调NF-κB/TNF-α信号通路，调节关键信号蛋白，导致Wnt/β-catenin通路失调，抑制IL-17和IL-23等炎症细胞因子产生，促进炎症细胞凋亡。数据上，其2021年完成的靶向NASH的2期临床(NCT02927314)数据可以反映其在减重方向上的一定效果：实际参与的56人中，安全性方面无SAE，主要为手臂肌痛、肌肉无力和头痛。抗炎效果由血清AST水平体现。25mg高剂量组患者的AST水平降低降低36.8%，最后达到统计学差异，但在第16周才表现出来。12.5mg低剂量组则持续无统计学差异。Aliment Pharmacol Ther.体重下降：在研究期间，在两组患者中都观察到了体重的下降，其中25mg组的体重下降更为明显。在第12周，12.5mg组的患者平均减重1.6公斤，25mg组的患者平均减重2.1公斤，而服用安慰剂组的患者平均减重0.5公斤。两组之间的循环血流量差异无统计学意义。Aliment Pharmacol Ther.小结①如果要说领域交叉的程度，肥胖作为一种慢性疾病，确实和肿瘤、自身免疫病具有相似的特征——慢性炎症。肥胖本身就会导致全身性的、多样性的几类慢性炎症。Can-Fite先是从肝癌出发，拓展到同样涉及免疫影响肝实质性病变的NAFLD和NASH。而NAFLD这个疾病本身与肥胖、内脏肥胖、2型糖尿病和代谢综合征谱系也有显著的关系。相关的细胞因子包括：(炎症细胞因子调节代谢)IL-6作为炎症性疾病中关键的细胞因子，在代谢调节中也有非常重要的作用。IL-6浓度增加促进脂肪分解、脂肪动员、肝葡萄糖输出。TNF在脂肪细胞中起到保护细胞“脂质过载”的作用，引起胰岛素抵抗和促进脂肪分解来减少细胞中能量储存的上限，但有可能导致高脂血症。此外，TNF还可诱导脂质向肝脏运输，促进肝脏脂肪生成和脂质摄取。巨噬细胞分泌的IL-1β则通过IL1β-迷走神经-胰岛β细胞促进胰岛素分泌。②免疫系统和代谢存在着非常密切的联系，不仅因为免疫细胞的代谢状态影响着效应功能，而且免疫细胞还主动调控代谢。Can-Fite的这款小分子药物本身就选择了一个在免疫代谢中极为基础但也极为广泛的靶向信号通路。NF-κB通路在各种人类恶性肿瘤以及炎症相关疾病中普遍被激活，影响炎症细胞的活化。在免疫稳态中，NF-κB调节CCL19、CCL21、CCR7等趋化因子及其受体，影响免疫细胞发育和分化。NF-κB：维持免疫稳态的核心炎症到肿瘤的替代NF-κB信号通路虽然说，A3AR似乎只在病变的细胞中表达，调节的也是和慢性炎症高度相关的NF-κB通路，但是作为一个经典、庞大的信号通路，NF-κB信号传导的上下游调节因素和来源都非常复杂。就比方说免疫细胞在受到代谢影响的同时，也会反过来主动调控代谢以扭转异常代谢状态；脂肪相关巨噬细胞还会通过补偿脂肪细胞的受抑代谢功能，等等。这种不确定性的具体表现或许就是可见体重下降，但不一定能达到明显的差异性结果。当然，从出发点上说，还是期待这款药物能成功拓展减重的适应症，其他的肿瘤免疫、自身免疫病疗法或许也有机会复制这种转型，带来的前景是广阔的。参考来源：1.https://www.biospace.com/article/releases/the-anti-obesity-effect-of-can-fite-s-namodenoson-molecular-mechanism-of-action-in-pre-clinical-and-human-studies/?s=862.Safadi R, Braun M,et al.Randomised clinical trial: A phase 2 double-blind study of namodenoson in non-alcoholic fatty liver disease and steatohepatitis. Aliment Pharmacol Ther. 2021 Dec;54(11-12):1405-1415. doi: 10.1111/apt.16664. Epub 2021 Oct 20.

免疫疗法细胞疗法临床2期ASH会议快速通道

2023-01-06

·生物制药小编

免疫代谢与ICI治疗耐药

免疫抑制剂（ICI）治疗为多种肿瘤带来的非常有希望的治疗效果，但是对ICI的原发和继发性耐药仍然是我们正在面临的主要问题。肿瘤微环境（TME）和宿主生理过程的代谢改变是肿瘤发生时的一个重要标志，这不但能够为肿瘤创造生存条件，同时还会促进免疫抑制环境的形成，是ICI耐药性产生的重要原因。ICI耐药的产生涉及多种代谢通路，通路的的异常改变能够通过改变肿瘤部位免疫细胞的状态和功能而使ICI治疗效果变差。腺苷通路腺苷是外周组织免疫反应的主要抗炎调节剂，它2核外核苷酸酶CD39+和CD73+催化ATP产生。在发生肿瘤的情况下，胞外腺苷浓度可升高100多倍，并不断积聚，会抑制多种免疫细胞的功能而导致肿瘤免疫降低。腺苷受体（AR）包含4种（A1R、A2AR、A2BR、A3R），被激活后会：诱导单核细胞分化为巨噬细胞，促进巨噬细胞产生IL-12和TNFα导致免疫耐受。影响嗜中性粒细胞的活性，减少其粘附、迁移、脱颗粒作用，最终导致Fc受体介导的吞噬作用被抑制，并减少超氧化物的生成。已有研究证明CD73+肿瘤细胞对于抗PD-1阻断剂具有治疗抗性，因此同时阻断CD73和PD-1能够增强瘤内CD8+T细胞的浸润和肿瘤治疗效果。Clin Cancer Res. 2013 Oct 15;19(20):5626-35. 同时，靶向CD39和CD73以及抗AR药物在临床前模型中已被证明有效。并且针对该途径的新型抗体和小分子药物正在进行联合ICI治疗的临床前研究。【36,37】Int J Mol Sci. 2020 Jun 21;21(12):4414. 血管生成脉管系统由血管和淋巴管组成，其中充斥着大量的免疫细胞和间质细胞（如癌症成纤维细胞CAF），异常的脉管系统有利于形成低pH和高度缺氧环境，对多种免疫细胞产生影响：抑制DC成熟。抑制CD8+T细胞增殖、迁移和免疫功能，并导致其发生耗竭。促进TAM由抗癌M1表型向免疫抑制M2表型极化。诱导髓源性抑制细胞（MDSC）的生长和免疫抑制活性。因此使用抗血管生成药物能够减轻免疫抑制，增加CD8+T细胞的浸润来增强ICI药物效果。VEGF联合抗PD-L1、抗PD-1、抗CTLA-1疗法已在多类肿瘤中进行了试验。Nat Rev Clin Oncol. 2018 May;15(5):310-324. 色氨酸分解代谢通路色氨酸-犬尿氨酸-芳基烃受体（Trp-Kyn-AhR）通路参与生理性免疫抑制的形成，该通路包括三种酶，分别是IDO1、TDO、IDO2，其中IDO1对免疫治疗耐药的形成起主要作用。IDO1的生理作用是诱导获得性免疫耐受，它能够促进色氨酸的消耗以及犬尿氨酸积累，对免疫细胞产生影响：促进Treg活化抑制T细胞活化诱导T细胞无能状态黑色素瘤患者前哨淋巴结中IOD1高表达降低了抗CTLA1-4和抗PD1/PDL1治疗效果，并且导致肿瘤部位淋巴细胞浸润程度降低以及预后较差，在多种肿瘤中均观察到了相同的现象。Br J Dermatol. 2014 Nov;171(5):987-95. 无论是敲除IDO基因或者使用IDO抑制剂，与ICI联用均能使肿瘤小鼠存活时间延长。PI3K/AKT/mTOR通路该通路参与细胞生长、存活、代谢、运动，是生理活动的重要通路。除正常功能外，约30%的癌症中发现了该通路功能失调，通过多种机制介导肿瘤发生、进展、耐药。PTEN是PI3K/AKT通路的主要负调控因子，其突变导致免疫抑制细胞因子表达水平升高、CD8+T细胞浸润程度降低、毒性降低。并且PTEN突变型三阴性乳腺癌（TNBC）和CRC中观察到了高水平的PD-L1。参与调节MDSC分化。PI3Kδ高表达与FOXP3+Treg细胞数量增加相关。使效应CD8+T细胞转化为记忆T细胞，并调节肿瘤相关巨噬细胞（TAM）的免疫刺激和免疫抑制开关。该通路已常威多种肿瘤的的治疗靶点，相关药物如PI3K抑制剂、mTOR抑制剂、PI3K-mTOR双重抑制剂已被批准用于治疗不同肿瘤。PI3K/AKT/mTOR抑制剂与ICI药物联用的多项临床试验正在进行中。Int J Mol Sci. 2020 Jun 21;21(12):4414. 小结代谢途径对ICI原发和获得性耐药至关重要，从根本上了解耐药的产生原因可能发现用于预测ICI疗效的标志物，并同时可以为“冷”肿瘤和耐药患者提供治疗帮助以提高ICI治疗效果。参考资料Allard B et al. Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin Cancer Res. 2013 Oct 15;19(20):5626-35. Giannone G et al. Immuno-Metabolism and Microenvironment in Cancer: Key Players for Immunotherapy. Int J Mol Sci. 2020 Jun 21;21(12):4414. Khan KA et al. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol. 2018 May;15(5):310-324. Chevolet I et al. Peritumoral indoleamine 2,3-dioxygenase expression in melanoma: an early marker of resistance to immune control? Br J Dermatol. 2014 Nov;171(5):987-95.

免疫疗法