IL-33R

引言转分化代表了直接的谱系转换；然而，对这一过程的描述不足阻碍了其潜在的应用。2024年3月19日，山东大学刘峰团队（张一帆及康志鑫为论文的共同第一作者）在Developmental Cell  在线发表题为“Single-cell omics identifies inflammatory signaling as a trans-differentiation trigger in mouse embryos”的研究论文，该研究利用单细胞组学鉴定炎症信号作为小鼠胚胎的转分化触发器。为了探索转分化的潜在普遍原理，该研究在小鼠胚胎中进行了内皮到造血转化(EHT)、内皮到间充质转化和上皮到间充质转化的单细胞转录组分析。应用熵、细胞型特征转录因子表达和关键过渡信号三个评分指标来显示支持过渡状态命运可塑性的共同特征。跨模型比较确定了炎症特征的过渡状态和白细胞介素-33在促进命运转换中的共同触发作用。多模式分析(整合转录组学和染色质可及性分析)证明了造血规范的炎症调节。此外，多模态组学和命运定位分析表明，内皮特异性Spi1作为炎症效应因子，控制着适当的染色质可及性和转录程序，以保护EHT。总的来说，该研究使用单细胞组学来识别关键的过渡状态/信号以及炎症信号在发育应激诱导的命运转换中的常见触发作用。Waddington的表观遗传景观一直被认为是描述细胞从全能性状态到终末分化状态的一个隐喻该景观具有三个基本要素，即细胞类型/状态、分化路径和基因调控网络(GRN)后来，细胞重编程的成就补充了Wadding的景观。细胞重编程对再生医学至关重要。从一个成熟谱系到另一个成熟谱系的转分化是细胞重编程的主要途径通过操纵确定的因素成功的转分化表明，稳定的细胞状态在Waddington的表观遗传景观可以克服障碍，直接改变他们的命运。虽然获得具有明确功能的终末细胞是成功的转分化的标志，但对过渡状态、动态过渡路径和复杂GRN的全面理解仍然是转分化领域的重大挑战。在脊椎动物的最终造血干细胞和祖细胞(HSPC)生成过程中，内皮到造血转化(EHT)是一个被充分研究的转分化范式。在小鼠中，主动脉-性腺-中肾(AGM)中的扁平动脉内皮细胞(AECs)首先特化为具有内皮-造血双重电位的造血内皮细胞(HECs)然后，HECs萌发形成主动脉内造血集群(IAHCs)，其中包含造血祖细胞(HPCs)和造血干细胞(HSCs)的未成熟前体(1型[T1]和2型[T2]前造血干细胞)。此外，内皮-间充质转化(EndoMT)和上皮-间充质转化(EMT)也是两种典型的转分化模式，在组织发育、再生和肿瘤发生中起着至关重要的作用。与EHT类似，EndoMT和EMT也有一系列的过渡状态。尽管现有的研究为转分化提供了丰富的组学和实验数据资源，但要获得指导其广泛应用的通用原理仍然是一个巨大的挑战。模式图（Credit: Developmental Cell）体内细胞命运的转变通常由输入刺激介导，如发育线索或损伤诱导的应激炎症信号在感染或炎症期间负责防御病原体和维持机体稳态，也调节着自然或应激条件下的命运转变。在最终的HSPC出现时，toll样受体4下游的炎症信号或被干扰素、肿瘤坏死因子α和白细胞介素激活，指示EHT。内皮功能障碍时，炎症反应诱导EndoMT，进一步导致血管系统缺陷当在小鼠成纤维细胞中强制转录因子(TF) Etv2过表达以实现内皮细胞重编程时，在重编程成纤维细胞中存在激活的炎症信号通路。此外，逆转录病毒介导的多能重编程或成纤维细胞到内皮细胞(EC)的转分化导致先天免疫反应和炎症信号的激活，这有助于有效的细胞命运重编程。这些研究促使人们重新审视炎症信号在细胞命运转变中的特定作用。该研究进行了单细胞组学分析和功能分析，以揭示小鼠胚胎中EHT、EndoMT和EMT的潜在共同分子特征和机制。研究发现由炎症信号和下游效应TF介导的发育应激负责天然转分化。激活免疫/炎症信号的富集是EHT、EndoMT和EMT过渡状态的共同特征;同时，已知的EndoMT/ EMT调节剂促炎白细胞介素-33 (IL-33)通过其受体抑制致瘤性2 (ST2)触发EHT。该研究基于目前可用的单细胞转录组数据集和实验验证，提供了一个框架来表征反式分化的过渡状态和信号触发因素。将该框架应用于疾病相关数据集还可以帮助解码疾病进展过程中的关键转变，例如正常细胞向肿瘤细胞的转化。原文链接https://doi-org.libproxy1.nus.edu.sg/10.1016/j.devcel.2024.02.010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

近日，度普利尤单抗（商品名为达必妥®，由赛诺菲与再生元合作开发）用于治疗慢性阻塞性肺疾病（COPD）的补充生物制品许可申请（sBLA）获FDA受理并被予以优先审评，为COPD领域的新药研发树立了新的里程碑。作为COPD领域即将迎来的第一款生物制剂，度普利尤单抗也即将开创COPD治疗新纪元，为仅有“对症治疗”方法的患者提供全新的治疗选择。COPD“对症治疗”瓶颈已至，“对因治疗”难以突破COPD是一种常见慢性气道疾病，其临床特征为持续存在的气流受限和相应的呼吸系统症状。据统计，2019年全球约3亿COPD患者，其中有320万人死于COPD[1]，该疾病已成为全球第三大致死原因。中国是COPD大国，患病人数已达1亿[2]。目前COPD并无治愈办法，行之有效的缓解症状方案为使用支气管扩张剂（β2受体激动剂和胆碱能受体拮抗剂）和抗炎药（糖皮质激素）。然而，这些药物虽有显著效果，但仍不能满足患者的治疗需求。造成这种情况的原因，一方面是COPD具有异质性，个体差异大，因而治疗难度大；另一方面是传统吸入制剂不足以预防COPD急性加重，需要探索其它治疗策略。因此，COPD市场仍然存在一个等待被填满的大缺口。在对症治疗药物已至瓶颈的情况下，探索对因治疗便成了另一条出路。不过，COPD的发病机制较为复杂，至今尚未被完全阐明。最新的研究表明，约20%-40%的COPD患者属于嗜酸性粒细胞水平升高的2型炎症内型，因而抑制2型炎症的发生发展成为了对因治疗COPD的可行方向。已有部分靶向炎症细胞因子的生物制剂研究结果释放了积极信号，其中针对IL-4、IL-5、IL-13等2型炎症因子是目前的热门研发方向[3]。COPD的发病机制[4]不过，最终推进至临床阶段的产品仍然是少数。截至目前，全球范围内处于临床阶段的COPD生物制剂不足20款，其中靶向IL-4/IL-4Rα、IL-5/IL-5Rα、IL-13和IL-33/IL-33R的产品共10款。这条路也并非坦途，多款疗法先后遭遇临床失利，被COPD婉拒[5,6]。处于后期开发阶段的COPD生物制剂注：根据医药魔方数据库整理除此之外，患者治疗背景的复杂性也是摆在COPD生物制剂面前的一个难题。部分临床研究结果表明，因生物标志物水平、吸烟状况和哮喘病史等而异的人群对这类药物的治疗反应也有所不同[5,7,8]。这些难题如同一道道沟壑横亘在生物制剂与COPD之间，需要通过一次又一次的尝试来探索正确的解题思路。度普利尤单抗带来COPD治疗突破在2型炎症的发生过程中，IL-4扮演着关键角色。IL-4可诱导初始辅助性T细胞（Th0）分化为Th2细胞，而后者被活化后又可分泌IL-4、IL-5和IL-13，细胞因子工厂由此启动。除此之外，IL-4还可与IL-13协同刺激B细胞分泌IgE，促进下游炎症反应的发生。而且，IL-4及IL-13还可诱导巨噬细胞替代性活化，在诱导粘液产生、杯状细胞增生、平滑肌收缩等方面也有多种作用。IL-4参与的辅助性T细胞的分化过程[9]IL-4与IL-13对2型炎症反应的激活需要IL-4R的参与。IL-4R分为I型IL-4R和II型IL-4R，其中前者由IL-4Rα亚基和γc亚基组成，可特异性结合IL-4，而后者由IL-4Rα亚基和IL-13Rα1亚基组成，可结合IL-4及IL-13。IL-4/IL-13通路[9]因此，作为一款靶向IL-4Rα的单克隆抗体，度普利尤单抗可通过与其结合，阻断IL-4和IL-13与其受体复合物的结合，从而抑制IL-4和IL-13参与的2型炎症反应。此外，对IL-4/IL-13通路的抑制也可以达到抑制粘液产生、舒张气管等治疗效果。这样的机制为其突破COPD多年来构筑的防线提供了一条可行之径。在向COPD发起挑战之前，赛诺菲已在特应性皮炎、哮喘、慢性鼻窦炎伴鼻息肉（CRSwNP）、结节性痒疹、嗜酸性细胞性食管炎（EoE）、慢性自发性荨麻疹（CSU）等适应症上充分探索了度普利尤单抗的治疗潜力，并借此积累了大量临床证据。在这个过程中，赛诺菲也将度普利尤单抗打造成了抵抗2型炎症反应的利器，征战四方。从多项自免适应症上获得的经验也被赛诺菲运用到了COPD适应症的临床开发中，提高了其成功率。在BOREAS研究中，度普利尤单抗组患者的COPD急性加重发生率相比安慰剂组显著降低了30%（P=0.0005）；在NOTUS研究中，度普利尤单抗组患者的COPD急性加重发生率相比安慰剂组降低了34%（P=0.0002）。这样的结果也佐证了度普利尤单抗阻断IL-4/IL-13通路的机制在抑制2型炎症参与的COPD中的治疗作用。同时，度普利尤单抗能够在COPD领域取得突破，也是赛诺菲深耕炎症领域多年积累的经验为之所用的体现。超级重磅炸弹成就达成，将奠定赛诺菲免疫学雄主地位依靠基于2型炎症的广泛作用机制，度普利尤单抗在自免领域开疆拓土，其销售额也年年飞涨，如今已成为年销售额百亿美元药物俱乐部中的一员。若能如期攻下COPD适应症，度普利尤单抗在自免领域的影响有望进一步扩大，其130亿美元的年销售额峰值目标更是近在咫尺。度普利尤单抗销售额（来源：赛诺菲2023年财报PPT）这些年来，度普利尤单抗对赛诺菲营收的贡献占比越来越高，不仅是赛诺菲征服免疫炎症领域的中坚力量，也拉动了赛诺菲公司整体业务的增长。Dupixent历年销售额及收入贡献注：收入单位为亿欧元不过，只有一款产品在面对市场竞争时难免力量单薄，赛诺菲也布局了其它产品来辅助其坐稳“免疫巨头”宝座。在充分挖掘度普利尤单抗潜力的同时，赛诺菲正在布局“超越2型炎症”的研发管线。在去年年底的研发日会议上，赛诺菲披露了管线中多款中后期免疫产品的研发进度，每一款药物的峰值销售额均在20-50亿欧元之间，例如OX40L单抗Amlitelimab、IL-33单抗Itepekimab、IL-13/TSLP双抗Lunsekimig等药物。赛诺菲管线中的重点中后期在研免疫产品（来源：赛诺菲研发日会议PPT）在全球同步创新的大趋势之下，赛诺菲也十分重视其创新产品在中国的研发进度，力求缩短中国和全球的药物上市时间差。以Amlitelimab为例，在美欧进行特应性皮炎II期研究取得积极结果后，赛诺菲便迅速在中国启动了II期临床试验。总结透过2型炎症反应机制，度普利尤单抗为众多炎症性疾病找到了共同的突破口，也帮助赛诺菲在免疫炎症领域打下了稳固的根基。从特应性皮炎到COPD，度普利尤单抗的临床价值被充分挖掘，这既是赛诺菲打响度普利尤单抗江湖名号的晋级之路，也是其不断扩大自身在免疫炎症领域市场影响力的竞争策略。免疫和炎症疾病是仅次于肿瘤的第二大药品市场，躬身入局的赛诺菲正以度普利尤单抗为业务支柱在此领域深耕，一方面是借助挖掘度普利尤单抗的潜力创造领先身位，另一方面则是在“Play to Win”新战略下全力推进其它高潜力产品的布局开发，为免疫疾病领域的治疗突破注入新的活力。- 上下滑动查看参考资料 - [1] World Health Organization . The top 10 causes of death.[2] Prevalence and risk factors of chronic obstructive pulmonary disease in China (the China Pulmonary Health [CPH] study. Lancet. 2018. 391(10131):1706-1717.[3] GOLD 2024版 v1.1.[4] Targeting interleukin-33 and thymic stromal lymphopoietin pathways for novel pulmonary therapeutics in asthma and COPD.[5] Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease. NEJM. 2017. 377(17): 1613-1629.[6] Benralizumab for the Prevention of COPD Exacerbations. NEJM. 2019. 381(11):1023-1034.[7] Safety and efficacy of itepekimab in patients with moderate-to-severe COPD: a genetic association study and randomised, double-blind, phase 2a trial. Lancet Respiratory Medicine. 2021. 9(11):1288-1298.[8] NCT04053634.[9] Targeting key proximal drivers of type 2 inflammation in disease. Nature Reviews Drug Discovery. 2015. 15(1):35-50.Copyright © 2024 PHARMCUBE. All Rights Reserved.欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。

HENDERSON, Nev.--( BUSINESS WIRE )-- Zura Bio Limited (Nasdaq: ZURA) (“Zura Bio”), a multi-asset clinical-stage biotechnology company focused on developing novel medicines for immune and inflammatory disorders, today announced two abstracts were accepted and presented at World Allergy Congress (WAC), held December 1 – 3, 2023 in Bangkok, Thailand. The abstracts highlight Zura Bio’s informative research for ZB-168, an anti-IL-7Rα monoclonal antibody with potential across a broad set of indications where the IL-7 or TSLP pathways may be involved, and ZB-880 (torudokimab), a fully human, high affinity monoclonal antibody that neutralizes IL-33 and also has potential for a broad range of indications. “ Introducing Zura Bio’s ZB-168 and ZB-880 at World Allergy Congress is an opportunity to share the unique science behind these assets. ZB-168 uniquely inhibits both IL-7 and TSLP, while ZB-880 prevents IL-33 mediated-activation of ST2-dependent and independent inflammation. The unique biology of our assets may give us access to a broad range of biology applicable in a number of autoimmune and inflammatory diseases,” said Michael Howell, Ph.D., Chief Scientific Officer and Head of Translational Science at Zura Bio. “ We believe these could have applicability in the dermatological, rheumatological, gastrointestinal and respiratory spaces, and we are very excited about taking these development programs forward.” Details are as follows: Abstract: WAC23-0180 Title: Biomarker analysis identifies subset of atopic dermatitis patients that respond to IL-33 blockade Authors: Michael Howell, Ph.D., Jackson Cabell, Brandon Walsh, Ph.D., Someit Sidhu, M.D., Christopher Cabell, M.D. Abstract: WAC23-0179 Title: ZB-168 potently inhibits thymic stromal lymphopoietin mediated Inflammation Authors: Christopher Cabell, M.D., Javier Cote-Sierra, Ph.D., Karl Deacon, Ph.D., Someit Sidhu, M.D., Michael Howell, Ph.D. Full session details can be accessed via the WAC program . ABOUT ZURA BIO Zura Bio is a multi-asset clinical-stage biotechnology company focused on developing novel medicines for immune and inflammatory disorders. Currently, Zura Bio is developing three assets which have completed Phase 1/1b studies and are Phase 2 ready. The company is developing a portfolio of therapeutic indications for ZB-106 (tibulizumab), ZB-168, and ZB-880 (torudokimab) with a goal of demonstrating their efficacy, safety, and dosing convenience in immune and inflammatory disorders, including systemic sclerosis, hidradenitis suppurativa, and other novel indications with unmet needs. ABOUT ZB-106 (tibulizumab) ZB-106 (tibulizumab) is a potential first-in-class, anti-IL-17 and anti-BAFF dual antagonist that Zura Bio plans to develop for the treatment of systemic sclerosis and hidradenitis suppurativa. ZB-106 is an IgG-scFv bispecific dual-antagonist antibody engineered by the fusion of Taltz® (ixekizumab) and tabalumab that neutralizes IL-17A and BAFF. ZB-106 has been assessed in two Phase 1b studies completed in rheumatoid arthritis and Sjögren's syndrome. The safety profile to date appears to be acceptable, with no new findings relative to known IL-17 and BAFF inhibitors. Chronic toxicology studies have been completed with no adverse drug-related findings. Phase 2 clinical trials of ZB-106 in systemic sclerosis and hidradenitis suppurativa are planned to initiate 2H-2024. ABOUT ZB-168 ZB-168 is a fully human, high affinity monoclonal antibody that binds and neutralizes the IL-7 receptor chain (“IL-7R”) alpha. IL-7Rα sits at the nexus of two key immune pathways (IL-7 and TSLP), thus inhibiting IL-7Rα has the potential to block activation through both of these pathways. As a result, we believe ZB-168 could be therapeutically beneficial in a broad set of indications where the IL-7 or TSLP pathways may be involved. ZB-168 has been assessed in Phase 1/1b clinical studies in Type 1 diabetes and multiple sclerosis. Safety and pharmacokinetics were evaluated and the safety profiles from these studies support further development. A Phase 2 clinical trial of ZB-168 in alopecia areata is planned to initiate in 2024. FORWARD-LOOKING STATEMENTS This communication includes “forward-looking statements” within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. Words such as “expect,” “estimate,” “project,” “budget,” “forecast,” “anticipate,” “intend,” “plan,” “may,” “will,” “could,” “should,” “believe,” “predict,” “potential,” “continue,” “strategy,” “future,” “opportunity,” “would,” “seem,” “seek,” “outlook” and similar expressions are intended to identify such forward-looking statements. Forward-looking statements are predictions, projections and other statements about future events that are based on current expectations and assumptions and, as a result, are subject to risks and uncertainties that could cause the actual results to differ materially from the expected results. These statements are based on various assumptions, whether or not identified in this communication. These forward-looking statements are provided for illustrative purposes only and are not intended to serve as, and must not be relied on by an investor as, a guarantee, an assurance, a prediction or a definitive statement of fact or probability. Actual events and circumstances are difficult or impossible to predict and will differ from assumptions. You should carefully consider the risks and uncertainties described in the “Risk Factors” sections of Zura Bio’s recent filings with the SEC. These filings would identify and address other important risks and uncertainties that could cause actual events and results to differ materially from those contained in the forward-looking statements. Many of these factors are outside Zura Bio’s control and are difficult to predict. Many factors could cause actual future events to differ from the forward-looking statements in this communication, including but not limited to: (1) the outcome of any legal proceedings that may be instituted against Zura Bio; (2) volatility in the price of Zura Bio’s securities; (3) the ability of Zura Bio to successfully conduct research and development activities, grow and manage growth profitably, maintain relationships with customers and suppliers, and retain key employees; (4) the ongoing costs relating to operating as a public company; (5) changes in the applicable laws or regulations; (6) the possibility that Zura Bio may be adversely affected by other economic, business, and/or competitive factors; (7) the risk of downturns and a changing regulatory landscape in the highly competitive industry in which Zura Bio operates; (8) the potential inability of Zura Bio to raise additional capital needed to pursue its business objectives or to achieve efficiencies regarding other costs; (9) the enforceability of Zura Bio’s intellectual property, including its patents, and the potential infringement on the intellectual property rights of others, cyber security risks or potential breaches of data security; and (10) other risks and uncertainties described in the registration statement on Form S-1 filed with the SEC on June 14, 2023, and such other documents filed by Zura Bio from time to time with the SEC. These risks and uncertainties may be amplified by the COVID-19 pandemic or other unanticipated global disruption events, which may continue to cause economic uncertainty. Zura Bio cautions that the foregoing list of factors is not exclusive or exhaustive and not to place undue reliance upon any forward-looking statements, including projections, which speak only as of the date made. Zura Bio gives no assurance that it will achieve its expectations. Zura Bio does not undertake or accept any obligation to publicly provide revisions or updates to any forward-looking statements, whether as a result of new information, future developments or otherwise, or should circumstances change, except as otherwise required by securities and other applicable laws.