IL36G

引言 应激包括高原低氧、辐射和心理应激等，可引起免疫系统紊乱诱导抑郁。造血干细胞（HSC）可以直接感受神经内分泌信号并维持免疫系统稳态。然而HSC在应激诱发抑郁中的具体作用及其机制尚不明确。 2024年10月22日，浙江大学基础医学院陆新江团队在Cell Stem Cell杂志上在线发表题为Vasopressin drives aberrant myeloid differentiation of hematopoietic stem cells, contributing to depression in mice的研究论文。研究阐述了应激条件下精氨酸加压素（AVP）介导脑-骨髓轴的作用和机制，揭示了神经内分泌信号影响HSC髓系分化的特异性分子机制。 该研究组采用单细胞转录组测序（scRNA-seq）发现应激诱导的抑郁小鼠骨髓中髓系祖细胞CMP和GMP数量增加，并且淋巴系祖细胞CLP和ProB数量减少。scRNA-seq的数据还发现HSC的S100A9表达上调，并且介导了髓系分化。进一步深入分析scRNA-seq数据并结合ImmGen结果显示精氨酸加压素受体2（AVPR2）在中性粒祖细胞样细胞群（ProNeuL）和中性粒细胞中的表达显著高于其他细胞。采用过继性转移AVP处理后的中性粒细胞，发现其可促进骨髓的髓系细胞生成，而中性粒细胞特异性敲除AVPR2则抑制小鼠的髓系分化。进而通过小鼠体内示踪技术证明骨髓HSC来源的中性粒细胞可进入脑内。通过中性粒细胞转录组测序发现AVP处理小鼠中性粒细胞IL36G表达上调，并且造血细胞特异性敲除IL36G受体IL1RL2抑制髓系细胞产生和脑内神经炎症反应。 上述研究结果表明，造血系统在应激诱导的抑郁症发病机制中发挥了关键作用，并揭示了脑-骨髓轴在抑郁发生中的作用机制（图1）。靶向IL36G-IL1RL2的单抗已于2022年获批用于治疗银屑病，如果未来在人类中证明对抑郁症同样有效，将具有重要的临床意义。 研究团队还发现高原低氧也会引起髓系分化促进抑郁发生，但在分子机制上与心理应激诱导的抑郁症有一定差异，该工作还在进一步进行中。此外髓系分化在消化道肿瘤的发生和发展过程中也发挥了重要作用，相关研究正在深入展开。 图1 应激驱动HSC偏髓系分化促进抑郁发生（Credit: Cell Stem Cell） 参考文献 https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00358-8 责编|探索君 排版|探索君 来源|BioArt 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 Cell | 是什么决定了细胞的大小？ 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

2024年9月12日，Moderna在年度研发活动上宣布将削减研发支出，同时将实现收支平衡的目标推迟两年至2028年。Moderna制定了财务和发展计划，作为战略重新确定优先级的一部分，以助力公司应对后疫情时代的商业环境。 Moderna表示，将采用“更加具有选择性和节奏性的方法”来实施其发展战略，包括在2027年前削减11亿美元的研发支出，从2024年的48亿美元减少到2027年的36-38亿美元。同时，公司停止了5项早期资产: 一款旨在预防人类冠状病毒流行的疫苗mRNA-1287，Moderna之前表示这种病原体每年在美国导致100 万次门诊访问，不过其将在进入临床前停止研发； 用于两岁以下婴儿的呼吸道合胞病毒（RSV）候选疫苗mRNA-1345，根据最新临床数据，公司预计该研究不会超过正在进行的临床1期。 针对各种实体瘤进行评估的KRAS抗原特异性癌症疫苗mRNA-5671，没有进一步的开发计划； 三联肿瘤候选药物mRNA-2752，根据最新临床数据，公司已取消了进一步开发的优先级； 心力衰竭候选药物mRNA-0184，正在计划结束第1阶段研究。 值得注意的是，Moderna与默沙东合作开发的癌症候选药物mRNA-4157也遇到了监管障碍。据Moderna表示，“美国食品药品监督管理局（FDA）的初步反馈显示，基于当前数据，不支持加速批准，”双方仍在进行谈判，但寻求批准的计划可能会被推迟，直到合作伙伴获得“大量招募”的黑色素瘤辅助治疗三期试验数据。 除了调整研发工作外，Moderna还将更加专注于扩大其在肿瘤学、罕见病和非呼吸疾病的first-in-class疫苗和疗法方面的商业组合，力争在未来三年内获得10个产品批准。 到2026年，Moderna的目标是推出5种针对疾病负担最重的呼吸道病毒的商业疫苗。该研发管线包括下一代新冠疫苗、流感与新冠联合疫苗以及针对高风险年轻成人的呼吸道合胞病毒（RSV）疫苗，这些疫苗都将在今年内提交监管申请。 从2026年到2028年，公司将致力于通过推出针对巨细胞病毒疫苗（预计最早将于2024年底公布关键3期疫苗功效数据）、诺如病毒疫苗（计划立即启动关键的3期试验），以及丙酸血症、甲基丙二酸血症和黑色素瘤的治疗产品来加强其产品组合。 首席执行官Stéphane Bancel在一份声明中表示：“我们后期研发管线的规模加上产品上市带来的挑战，意味着我们现在必须专注于向患者提供这10种产品，放缓新研发投资的速度，并建立我们的商业业务。” Moderna还于周四提供了财务更新，指出其现在预计将在2028年实现运营层面的收支平衡，营收将达到60亿美元。这一预测不包括基于股票的薪酬、折旧和摊销费用。而此前，Moderna曾预计将在2026年实现收支平衡。公司称，其银行资金足以支持其计划，直至在现金成本基础上实现收支平衡。 然而，杰富瑞（Jefferies）分析师Michael Yee在给投资者的一份报告中表示，这“仍将是投资者激烈争论的焦点”，他们“不太可能”在“进一步证明其可信度”之前相信Moderna的说法。 周四的战略调整是在 Moderna努力在后疫情市场重新站稳脚跟之际做出的。去年，由于 新冠疫苗收入急剧下降，该公司亏损了47亿美元，而2022年公司的净收入为84亿美元。 Moderna在其第二季度财报中报告了2.41亿美元的营收，由于合同延期和新冠疫苗需求进一步下降，公司不得不下调2024年全年业绩指引。公司现在预计今年的营收将在30亿美元至35亿美元之间，低于之前40亿美元的预测。 当时，杰富瑞分析师指出了Moderna全年预测的下调，并指出这“加剧了”人们对该公司实现盈利能力的担忧。 参考资料： [1]Moderna官网 [2]Moderna Slashes R&D Budget by $1.1B, Eyes 10 Approvals Through 2027.Tristan Manalac.September 12, 2024. [3]Moderna targets $1.1B in R&D spending cuts, drops 5 programs amid profitability pressures.By Nick Paul Taylor.Sep 12, 2024 8:10am. 识别微信二维码，添加生物制品圈小编，符合条件者即可加入 生物制品微信群！ 请注明：姓名+研究方向！ 版 权 声 明 本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

ATR-04 is in development for epidermal growth factor receptor inhibitor (EGFRi)-induced dermal toxicity, which affects approximately 150,000 patients in the US Reduces methicillin-resistant S. aureus by 99% on ex vivo pig skin Reduces IL-36g, a pro-inflammatory cytokine that drives inflammation in EGFRi-induced toxicity, in human skin model by 75% compared to erlotinib-treated skin Increases human beta defensin 18-fold vs. vehicle on human skin model BRANFORD, Conn.--(BUSINESS WIRE)-- Azitra, Inc. (NYSE American: AZTR), a clinical-stage biopharmaceutical company focused on developing innovative therapies for precision dermatology, today announced preclinical data from the Company’s platform and pipeline. The data are being presented on Friday, May 17, 2024, in two oral sessions entitled “Staphylococcus epidermidis for the topical treatment of epidermal growth factor receptor (EGFR) inhibitor-induced dermal toxicity” and “Cutaneous delivery of LEKTI via an engineered strain of Staphylococcus epidermidis for the treatment of Netherton syndrome” at the Society of Investigative Dermatology (SID) 2024 Annual Meeting in Dallas, TX. “We are pleased to announce the first publication of preclinical data around ATR-04 in EGFR inhibitor (EGFRi)-associated dermal toxicity,” said Travis Whitfill, Azitra’s co-founder and COO. “These data show robust preclinical activity of ATR-04 in models of EGFRi-induced dermal toxicities that support an upcoming Investigational New Drug (IND) application to the FDA for a Phase 1b in patients undergoing EGFR inhibitors with dermal toxicity. We anticipate the expansion of our clinical-stage pipeline this year with ATR-04.” ATR-04 is a live biotherapeutic product candidate consisting of an S. epidermidis strain that was isolated from a healthy volunteer and engineered to be safer by deleting an antibiotic resistance gene and engineering auxotrophy to control the growth of ATR-04. ATR-04 is in development for EGFRi-associated skin toxicity, which is caused by the suppression of skin immunity by EGFRis and subsequent inflammation and often elevated levels of IL-36γ and S. aureus. There are approximately 150,000 patients suffering from EGFRi-induced skin toxicity in the United States. The data in the oral presentations today showcase the preclinical development of ATR-04. ATR-04 led to a decrease in S. aureus across multiple models. In in vitro skin models, ATR-04 treatment led to a 96% reduction in methicillin-resistant S. aureus (MRSA) compared to untreated skin (p<0.0001). In ex vivo pig skin treated with ATR-04, there was a ~99% reduction in MRSA compared to untreated skin (p=0.012). Additionally, in human skin models treated with erlotinib, an EGFRi, ATR-04 reduced IL-36γ by 75% (p=0.009) to levels comparable to untreated skin models. Finally, ATR-04 increased human beta defensin, a key protein involved in host defenses, by 18-fold compared to vehicle. Together, the data show that ATR-04 can address multiple drivers of EGFRi-induced skin toxicity. The presentations are now available on Azitra’s website at . About Azitra, Inc. Azitra, Inc. is an early-stage clinical biopharmaceutical company focused on developing innovative therapies for precision dermatology using engineered proteins and topical live biotherapeutic products. The Company has built a proprietary platform that includes a microbial library comprised of approximately 1,500 unique bacterial strains that can be screened for unique therapeutic characteristics. The platform is augmented by artificial intelligence and machine learning technology that analyzes, predicts, and helps screen the Company's library of strains for drug like molecules. The Company's initial focus is on the development of genetically engineered strains of Staphylococcus epidermidis, or S. epidermidis, which the Company considers to be an optimal therapeutic candidate species for engineering of dermatologic therapies. For more information, please visit . Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. These statements may be identified by words such as “aims,” “anticipates,” “believes,” “could,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “will,” and variations of these words or similar expressions that are intended to identify forward-looking statements. Any such statements in this press release that are not statements of historical fact may be deemed to be forward-looking statements. These forward-looking statements include, without limitation, statements regarding the advancement of ATR-04 into a Phase 1b clinical trial; expectation that the initial pre-clinical data for ATR-04 will be consistent with the further pre-clinical data; and the benefits of the Company’s proprietary platform and microbial library. Any forward-looking statements in this press release are based on current expectations, estimates and projections only as of the date of this release and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to (i) the risk that the further data from the ongoing pre-clinical trial for ATR-04 will not be favorably consistent with the initial pre-clinical data to date, (ii) the risk that the Company’s IND application for ATR-04 may not receive a safe to proceed letter from the FDA, (iii) success in early phases of pre-clinical trials do not ensure later clinical trials will be successful; we may fail to timely raise additional required funding; and those additional risks concerning Azitra's programs and operations are described in its annual report on Form 10-K filed with the SEC on March 15, 2024. Azitra explicitly disclaims any obligation to update any forward-looking statements except to the extent required by law.