更新于：2024-11-01

IFNLR1

更新于：2024-11-01

基本信息

别名

CRF2-12、CRF2/12、Cytokine receptor class-II member 12

+ [17]

简介

The IFNLR1/IL10RB dimer is a receptor for the cytokine ligands IFNL2 and IFNL3 and mediates their antiviral activity. The ligand/receptor complex stimulate the activation of the JAK/STAT signaling pathway leading to the expression of IFN-stimulated genes (ISG), which contribute to the antiviral state. Determines the cell type specificity of the lambda interferon action. Shows a more restricted pattern of expression in the epithelial tissues thereby limiting responses to lambda interferons primarily to epithelial cells of the respiratory, gastrointestinal, and reproductive tracts. Seems not to be essential for early virus-activated host defense in vaginal infection, but plays an important role in Toll-like receptor (TLR)-induced antiviral defense. Plays a significant role in the antiviral immune defense in the intestinal epithelium.

关联

靶点

IFNLR1

作用机制

IFNLR1激动剂

在研机构

Eiger BioPharmaceuticals, Inc.

原研机构

ZymoGenetics, Inc.

在研适应症

新型冠状病毒感染 [+1]

非在研适应症

慢性丙型肝炎基因型 1 [+7]

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

rSIFN-co

集成干扰素α(辉阳生命)

靶点

IFNLR1

作用机制

IFNLR1激动剂

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

PSP-001

靶点

IFNLR1

作用机制

IFNLR1激动剂

在研机构

德益阳光生物技术（北京）有限责任公司

原研机构-

在研适应症

诺如病毒感染

非在研适应症

乙型肝炎

最高研发阶段临床申请

首次获批国家/地区-

首次获批日期1800-01-20

项与 IFNLR1 相关的临床试验

CTRI/2024/10/074574 / Not yet recruiting临床2/3期IIT

Topical interferon as a newer treatment modality for uveitic and pseudophakic macular edema:A tertiary care centre study of northern india - NIL

开始日期2024-10-11

申办/合作机构-

ISRCTN10449048 / Recruiting临床2期IIT

Can interferon gamma prevent infection in critically ill patients at highest risk? A phase II randomised controlled trial - INFINIT (INterFeron to reduce INfection in InTensive care units)

开始日期2024-04-29

申办/合作机构

The Newcastle upon Tyne Hospitals NHS Foundation Trust

ChiCTR2400082602 / Suspended临床4期IIT

A real-world study of long-acting interferon guided by ?HBsAg levels in the treatment of HBeAg-negative patients with chronic HBV infection

开始日期2024-04-01

申办/合作机构-

100 项与 IFNLR1 相关的临床结果

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100 项与 IFNLR1 相关的转化医学

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0 项与 IFNLR1 相关的专利（医药）

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181

项与 IFNLR1 相关的文献（医药）

2024-11-01·Developmental & Comparative Immunology

Molecular characteristics of rhesus macaque interferon-lambda receptor 1 (mmuIFNLR1): Sequence identity, distribution and alteration after simian-human immunodeficiency virus infection in the skin and buccal mucosa

Article

作者: Liu, Rui-Jie ; Yang, Gui-Bo

Interferon-lambda receptor 1 (IFNLR1) is the key to interferon-lambda's biological activities. Rhesus macaques (Macaca mulatta) are supposedly more suitable for translational studies on interferon lambda-associated human diseases, yet little is known about their IFNLR1 (mmuIFNLR1). In this study, we cloned the coding sequence of mmuIFNLR1, examined its variants, and determined the distribution of mmuIFNLR1 mRNA and immunoreactivity in the buccal mucosa and arm skin of normal and immunodeficiency virus (SHIV/SIV) infected rhesus macaques. It was found that mmuIFNLR1 has 93.1% amino acid sequence identity to that of humans; all the amino acid residues of mmuIFNLR1 signal peptide, transmembrane region, PxxLxF motif and those essential for ligand binding are identical to that of humans; 6 variants of mmuIFNLR1, including the ones corresponding to that of humans were detected; IFNLR1 immunoreactivity was localized in primarily the epithelia of buccal mucosa and arm skin; SHIV/SIV infection could affect the levels of mmuIFNLR1 mRNA and immunoreactivity. These data expanded our knowledge on mmuIFNLR1 and provided a scientific basis for rational use of rhesus macaques in studies of IFN-λ associated human diseases like AIDS. Future studies testing IFNLR1-targeting therapeutics in rhesus macaques were warranted.

2024-10-01·Physiological Reports

Context‐specific anti‐inflammatory roles of type III interferon signaling in the lung in nonviral injuries

Article

作者: Bain, William G. ; Jie, Zhijun ; Kotenko, Sergei V. ; Robinson, Keven M. ; Wang, Victoria D. ; Feng, Jingjing ; Kim, Jooyoung ; Liu, Hongbo ; Chang, De ; Sharma, Lokesh ; Dela Cruz, Charles S.

AbstractType III interferons (λ1, λ2, and λ3) are potent antiviral cytokines in the lung. However, their roles in nonviral lung injuries are less well understood. This study investigates the activation of type III interferon signaling in three distinct models of lung injuries caused by diverse stimuli: the bacterial pathogen Pseudomonas aeruginosa, bacterial endotoxin LPS, and the chemotherapeutic agent bleomycin. Our data show that, despite inducing a potent inflammatory response, Pseudomonas and LPS did not increase IFNλ secretion. In contrast, bleomycin instillation increased secretion of IFNλ in the airways at both early and late time points. Consistent with limited secretion, type III interferon signaling had a minimal role in the host response to both Pseudomonas and LPS, as measured by pathogen burden, inflammatory response, and lung injury. Conversely, a deficiency in type III interferon signaling led to increased inflammatory signaling and elevated acute lung injury in the bleomycin model on day 3. This elevated early injury resulted in impaired recovery in IFNLR1 knockout mice, as evidenced by their recovery from bleomycin‐induced weight loss. Taken together, these data suggest a context‐specific activation of type III interferon signaling, where it plays an anti‐inflammatory role in the lung.

2024-07-17·mBio

Type III interferon drives pathogenicity to Staphylococcus aureus via the airway epithelium

Article

作者: Parker, Dane ; Kaiser, Katherine ; Pires, Silvia

ABSTRACT Type III interferon signaling contributes to the pathogenesis of the important human pathogen Staphylococcus aureus in the airway. Little is known of the cellular factors important in this response. Using Ifnl2 -green fluorescent protein reporter mice combined with flow cytometry and cellular depletion strategies, we demonstrate that the alveolar macrophage is the primary producer of interferon lambda (IFN-λ) in response to S. aureus in the airway. Bone marrow chimeras showed reduced bacterial burden in IFN-λ receptor (IFNLR1)-deficient recipient mice, indicative that non-hematopoietic cells were important for pathogenesis, in addition to significant reductions in pulmonary inflammation. These observations were confirmed through the use of an airway epithelial-specific IFNLR knockout mouse. Our data suggest that upon entry to the airway, S. aureus activates alveolar macrophages to produce type III IFN that is subsequently sensed by the airway epithelium. Future steps will determine how signaling from the epithelium then exerts its influence on bacterial clearance. These results highlight the important, yet sometimes detrimental, role of type III IFN signaling during infection and the impact the airway epithelium plays during host–pathogen interactions. IMPORTANCE The contribution of type III interferon signaling to the control of bacterial infections is largely unknown. We have previously demonstrated that it contributes to the pathogenesis of acute Staphylococcus aureus respiratory infection. In this report, we document the importance of two cell types that underpin this pathogenesis. We demonstrate that the alveolar macrophage is the cell that is responsible for the production of type III interferon and that this molecule is sensed by airway epithelial cells, which impacts both bacterial clearance and induction of inflammation. This work sheds light on the first two aspects of this important pathogenic cascade.

项与 IFNLR1 相关的新闻（医药）

2023-03-15

·生物谷

《自然》：免疫治疗认知大更新！科学家首次证实，肿瘤和血液中CD8+T细胞克隆多样性是免疫治疗的关键

基于接受PD-1抑制剂治疗的患者的肿瘤组织和血液样本，Puig-Saus等发现，无论癌症患者对免疫治疗是否有反应，他们体内都存在能识别肿瘤新抗原的效应T细胞，而且都是只识别少数新抗原；不过，不同反应 PD-1抑制剂正式被用于临床的时间，眼看就要满10年了。这近10年间，以免疫检查点抑制剂为代表的免疫治疗给癌症治疗带来了翻天覆地的变化，很多癌症的临床治疗指南因此改写，无数患者因此获得新生。以至于我们很多时候都忘记了，能从免疫治疗中获益的其实只有一小部分癌症患者，大部分患者对免疫治疗没有反应，有些患者接受治疗后甚至出现了疾病进展。因此，从免疫检查点抑制剂用于临床治疗开始，科学家就在寻找背后的原因。一些重要的发现，在一定程度上改善了免疫治疗的效果。然而，获益患者少的局面仍没有被打破。今天，顶级期刊《自然》杂志发表了加州大学洛杉机分校Antoni Ribas和Cristina Puig-Saus团队的研究成果[1]。基于接受PD-1抑制剂治疗的患者的肿瘤组织和血液样本，Puig-Saus等发现，无论癌症患者对免疫治疗是否有反应，他们体内都存在能识别肿瘤新抗原的效应T细胞，而且都是只识别少数新抗原；不过，不同反应状态患者体内的效应T细胞多样性存在巨大差异。具体来说，能从免疫治疗中获益的患者，单个新抗原对应着多样性的效应T细胞克隆（一种新抗原能被多种T细胞受体识别）；而不能从免疫治疗中获益的患者，单个新抗原仅对应着少数效应T细胞克隆，甚至是单克隆（一种新抗原只能被一种T细胞受体识别）。 Puig-Saus团队的这项突破性研究，不仅让我们对患者的不同治疗反应有了新的理解，还为设计新型T细胞疗法指出了新方向。论文首页截图 Puig-Saus团队开展的这个研究非常不易。在他们开来，要想搞清楚免疫治疗后的新抗原特异性T细胞谱，至少有两个条件。第一，需要一种极度灵敏的检测方法，能从少量血液样本的数百万个外周血单个核细胞（PBMCs）或少量活检肿瘤组织扩增的肿瘤浸润淋巴细胞（TILs）中，找到能识别数百种肿瘤新抗原的特异性效应T细胞。第二，需要一种高效的新抗原特异性TCR（neoTCRs）的重建方法，在普通T细胞中逐一插入发现的neoTCRs，逐一验证功能，并系统性评估T细胞对匹配患者自体癌细胞系的识别和抗肿瘤活性。在TCR-T细胞疗法公司PACT Pharma两项核心技术（ImPACT Isolation Technology®和PACT^NV™），分别帮助Puig-Saus团队解决了上述两个问题。有了PACT Pharma的技术加持，Puig-Saus团队招募了11名接受过PD-1抑制剂治疗的黑色素瘤患者。其中患者1到患者7从免疫治疗中获得了持久的益处，生存时间在32个月到111个月之间，而且到本研究结束时所有患者依然存活；患者8到患者11，对免疫治疗没有反应，或者治疗后病情加重，在研究结束时这些患者都已去世。研究人员还从所有患者身上采集肿瘤活检组织以及外周血，扩增了肿瘤浸润淋巴细胞，构建了癌细胞系，并给肿瘤组织和PBMCs做了全外显子组测序（WES）和RNA测序（RNA-seq）。工作量着实不小。研究流程示意图从WES数据来看，在所有患者体内发现的突变数量从31个（患者11）到3507个（患者1），中位数是380个。对免疫治疗有反应的7名患者中，非同义突变的中位数是506个；对免疫治疗没反应的4名患者这一数据为132个。虽然患者体内潜在的新抗原数量都不少，而且不同患者的变化非常大，但是被T细胞识别为新抗原的突变数量变化较小，从1到13不等。在具体到TCR来看，对免疫治疗有反应的患者1-7体内，每个突变靶点对应的neoTCRs克隆型中位数是5种，每个患者体neoTCRs克隆型的中位数是41种。相比之下，四名对治疗没有临床反应的患者（8-11）体内，每个突变靶点对应的neoTCRs克隆型中位数是2种，每个患者体neoTCRs克隆型的中位数是6.5种。不同患者的突变数量及被T细胞识别的突变数量在后续的研究中，Puig-Saus逐一研究了每个患者体内T细胞的情况。就拿患者1来说，他们从患者体内分离到571个新抗原特异性T细胞，包括针对11个突变的41种不同neoTCR克隆型。他们还从中筛选了针对9个突变的22种neoTCR克隆型，并通过CRISPR基因编辑技术将它们分别整合到健康供体的T细胞中，以研究这些neoTCR克隆型的功能。在分析患者1不同时间点的样品时，他们还发现识别NUP188、UBE2J1和WDR1三个突变新抗原的neoTCR克隆型反复出现。这说明针对癌细胞新抗原的效应T细胞在患者1体内存在普遍的扩增。他们基于患者2和6的样本也开展了类似的研究，也发现了患者特异性的neoTCR克隆型。患者1特异性T细胞的动态变化在验证患者1体内存在的neoTCR克隆型的功能时，他们发现靶向其中5个基因突变（NRP1、TRAPPC10、UBE2J1、NUP188和WDR1）的neoTCR-T细胞对患者自体癌细胞系（M495）有中等以上的细胞毒性，靶向剩余4个基因突变（IFNLR1、PLA2G4A、SLC6A3和GSDMB）的neoTCR-T细胞对M495没有细胞毒性。所有靶向9个基因突变的neoTCR-T细胞，都对非匹配的黑色素瘤细胞系（M202）没有细胞毒性。患者1的neoTCR克隆型功能验证再来看不响应免疫治疗患者的数据。在患者8的PBMC中只发现了8个neoTCR克隆型，它们分别针对NES、CTNNB1、POLR2G和SERPINH1四个基因突变。在患者9体内，发现了针对4个基因突变的5个neoTCR克隆型。在患者10体内，只发现了针对ACER3突变的两个neoTCR克隆型。在患者11体内，发现了针对5个基因突变的14个neoTCR克隆型。 Puig-Saus注意到，与对免疫治疗有反应的患者相比，这些对免疫治疗没反应的患者，不仅neoTCR克隆型少，而且在不同时间采集的血液和肿瘤样本也不经常出现。此外，这四位患者neoTCR克隆型的功能分析发现，居然都对自体癌细胞系有毒性作用，而对非匹配的黑色素瘤细胞系没有毒性作用。患者9的neoTCR克隆型在不同样本中随时间的变化基于以上研究成果，Puig-Saus等认为，别看肿瘤中的突变那么多，实际上新抗原特异性的癌症免疫反应针对的只是数量有限突变（范围为3至13）。不过，在对PD-1抑制剂有长期临床反应的患者中，新抗原特异性T细胞反应是多克隆的，即有多种新抗原特异性TCR克隆型针对同一个突变，而且在血液和肿瘤中都可以检测到这些新抗原特异性TCR克隆型。因此，Puig-Saus等认为天然T细胞反应是通过不同的T细胞克隆型，靶向非常有限的突变来清除肿瘤的。这也为基于T细胞的免疫治疗，提供了新思路。参考文献： [1].Puig-Saus, C., Sennino, B., Peng, S. et al. Neoantigen-targeted CD8+ T cell responses with PD-1 blockade therapy. Nature, 2023. https://doi.org/10.1038/s41586-023-05787-1

免疫疗法细胞疗法

2022-03-16

·BioSpace

Eiger BioPharmaceuticals to Host Conference Call to Discuss Phase 3 TOGETHER Study Results of Peginterferon Lambda for COVID-19 on Thursday, March 17, 2022

Eiger BioPharmaceuticals, Inc (Nasdaq:EIGR), a commercial-stage biopharmaceutical company focused on the development of innovative therapies to treat and cure Hepatitis Delta Virus (HDV) and other serious diseases, today announced that it will host a conference call on Thursday, March 17, 2022, at 5:30 AM Pacific / 8:30 AM Eastern, to discuss the results from the Phase 3 TOGETHER study of Peginterferon Lambda for COVID-19. The live and replayed webcast of the call will be available through the company's website at . To participate in the live call by phone, dial (844) 743-2495 (U.S.) or (661) 378-9529 (International) and enter conference ID 8990285. The webcast will be archived and available for replay for at least 90 days after the event.

新型冠状病毒感染Peginterferon lambda-1a(ZymoGenetics, Inc.)

2021-05-26

·BioSpace

Prosit Sole Biotechnology Initiates First-In-Human Clinical Trial of Novel Interferon Lambda Chimera in US

BALTIMORE, May 26, 2021 /PRNewswire/ -- Prosit Sole Biotechnology, a clinical-stage biotech company developing novel protein therapeutics, today announces that it has initiated the first-in-human ("FIH") Phase I clinical trial of PSP001 in US. PSP001 is a novel, long acting and potent interferon lambda chimera injection. The first dose was administered on May 25, 2021. Type III interferons (IFN's), also termed interferon lambda's (IFNλ's) constitute a new addition to the IFN family. Their unique receptor IFNλR1 is particularly abundant at the barrier surfaces, such as the respiratory tracts, the gastrointestinal tracts, and the liver. Non-redundant to type I interferons (IFNα and IFNβ), IFNλ's exhibit unique antiviral and immune modulatory activities. Prosit Sole Biotechnology is developing PSP001 for the treatment of chronic norovirus enteritis in hematopoietic and solid organ transplant recipients. "Chronic norovirus enteritis in immunocompromised patients is an urgent unmet medical need. There are no approved therapies for this debilitating disease." said Hongyu Liu, PhD, CEO of Prosit Sole Biotechnology. "We are also actively developing PSP001 for additional indications such as chronic hepatitis B." Investor Contact: Email: liuhongyu@prositsole.com Cindy Yu Email: cindy.yu@prositsole.com 010-62975234 Source: Prosit Sole Biotechnology To learn more, please visit View original content: SOURCE Prosit Sole Biotechnology (Beijing) Co., Ltd.