CRTC1

人口老龄化是21世纪全球重大挑战之一1。随着年龄增长，老年群体因新冠感染住院和死亡的比例远高于年轻群体，且老年性疾病如心脑血管疾病、阿尔兹海默症和癌症等的发病率与严重程度与日俱增，生活质量逐渐下降1,2。值得庆幸的是，科学研究显示，恰当的药物介入或能有效地进行抗衰老干预，提升老年人生活质量并降低疾病风险3。雷帕霉素（Rapamycin），一种过去普遍用于治疗癌症和对抗器官移植排斥的药物，因其可以在多种模式动物中稳定的延长寿命且提高老年动物的健康水平而被科学家们公认为目前最有前途的抗衰老候选药之一3。目前已知雷帕霉素通过作用于TORC1（Target of Rapamycin Complex 1）下游的自噬（Autophagy）和S6蛋白激酶（S6K）从而调控衰老进程4。尽管早在2009年已有研究证明了S6K的缺失能延长小鼠寿命5，但其具体作用机制至今依然不明确。2024年2月27日，来自德国马克斯普朗克衰老生物学研究所和英国伦敦大学学院健康衰老研究所的Linda Partridge教授课题组（张平仄博士为论文的第一作者）在Nature Aging杂志在线发表了题为Inhibition of S6K lowers age-related inflammation and increases lifespan through the endolysosomal system的研究论文。这项研究借助果蝇和小鼠为模型，揭示了S6K调控寿命和免疫系统衰老的机制，确立了内吞溶酶体系统在衰老过程中的重要作用，并指出了衰老过程中的性别差异。 研究团队首先借助果蝇模型探索了S6K延寿机制的保守性和组织特异性。研究表明，尽管在成年果蝇的神经组织、肌肉、肠道和心脏管中降低S6K水平并不能延长寿命，但在脂肪体（功能类似于哺乳动物肝脏和白色脂肪组织）中，降低S6K水平不仅延长了果蝇的寿命，且在脂肪体中过表达高活性S6K也可阻断雷帕霉素的延寿效果。这证明了成年果蝇的脂肪体是TORC1-S6K通路调控衰老的关键组织。进一步的蛋白组学研究发现，在年轻果蝇的脂肪体中S6K的活性可以影响溶酶体和自噬相关的通路。尽管共聚焦显微镜结果显示雷帕霉素能上调脂肪体内的溶酶体信号，但过表达S6K并未阻止此变化，反而导致了异常的巨型溶酶体形成。研究人员通过电子显微镜观察，发现这些巨型溶酶体是由多层溶酶体结构聚集形成的。这些多层结构溶酶体的形成机制是什么呢？在排除了自噬和溶酶体生成（Lysosome biogenesis）的可能性后，研究人员注意到蛋白组学分析中出现了内体融合（Endosomal vesical fusion）相关蛋白的富集，推测这些结构可能是由于晚期内体（Late endosome）和溶酶体的膜融合障碍造成的。随后的实验证明了与细胞膜融合相关的SNARE蛋白Syx13（Syntaxin 13）是决定S6K引起的内吞溶酶体（Endolysosome）形态改变的关键。然而，这些内吞溶酶体的改变均发生在年轻果蝇的脂肪体中，S6K是如何调控衰老的？在老年果蝇的脂肪体中，雷帕霉素和S6K敲减都影响了免疫反应（antibacterial humoral response及defense response）相关蛋白的富集，并降低了IMD通路（Immune deficiency pathway，其功能和机制类似于哺乳动物的NF-kB通路）下游分子的表达水平。研究人员发现通过抑制S6K活性，可以降低老年果蝇脂肪体中IMD通路介导的衰老相关性炎症（又名为炎症性衰老，Inflammaging）并改善因衰老引起的免疫功能降低（又名为免疫衰老，Immunosenescence）。有趣的是，通过抑制脂肪体内的炎症性衰老，可以提升老年果蝇的免疫功能并延长寿命，说明炎症性衰老是导致衰老和老年个体免疫功能下降的关键因素之一。鉴于先前的发现，即S6K能够通过影响Syx13来改变年轻果蝇脂肪体中的内吞溶酶体形态，研究人员推测雷帕霉素和S6K可能通过调控内吞溶酶体来影响免疫系统衰老和寿命。实验结果确实表明，无论是抑制初级内体（Early endosome）还是次级内体（Late endosome）的功能，都能有效阻断雷帕霉素对炎症性衰老的改善效果。研究者进一步探讨了这些内体如何调控炎症性衰老，并重点关注了与内体运输相关的免疫调控因子。IMD通路的受体PGRP-LC具有一个调控性亚型rPGRP-LC（Regulatory PGRP-LC），其在感染后可以通过初级内体的运输来抑制过度炎症反应6。由于发现rPGRP-LC和S6K诱导的巨型内吞溶酶体高度共定位，研究人员据此探索了其在炎症性衰老的作用。结果显示，在中年果蝇中，rPGRP-LC的过表达能够激活IMD通路，并在老年果蝇中抵消雷帕霉素对炎症性衰老的改善效果。此外，作为S6K的下游靶点，Syx13也对炎症性衰老、免疫衰老和寿命调控起到了关键作用，说明TORC1-S6K-Syx13信号通路通过内吞溶酶体系统调控免疫系统衰老和寿命。研究还揭示了性别在炎症性衰老中的差异，发现在雌性果蝇中，炎症性衰老比雄性更加严重，而且雷帕霉素喂养或S6K敲减并未在雄性中显著降低炎症水平，提示未来的衰老研究中需要重视性别因素。此外，研究人员发现雷帕霉素喂养不仅在果蝇中显示出延长寿命的效果，也在小鼠肝脏中提高了Stx12/13（Syntaxin 12/13）的水平，并且抑制了与衰老相关的非典型NF-κB信号通路（Noncanonical NF-κB signaling）的激活，表明TORC1-S6K通路对内吞溶酶体和炎症性衰老的调控效应在进化上具有保守性。 总的来说，这项研究揭露了TORC1-S6K-Syx13信号通路在炎症性衰老、免疫衰老和寿命调控中的核心作用，这一作用在从无脊椎动物到哺乳动物的演变过程中高度保守。研究结果为雷帕霉素和S6K调控在模型生物中的寿命增益和免疫益处提供了机制性的阐释。此外，这项研究确立了内吞溶酶体系统作为一个全新的细胞机制，它介导了雷帕霉素和S6K对免疫系统衰老和寿命的调控作用，从而为我们理解衰老过程打开了新的视角，并为未来衰老相关的研究与治疗提供了新的方向。本文的第一作者为张平仄博士，原为马克斯普朗克衰老生物学研究所博士生，现为耶鲁大学博士后。本文通讯作者为马克斯普朗克衰老生物学研究所创始所长、英国皇家学会副会长、伦敦大学学院健康衰老研究所Linda Partridge教授和马克斯普朗克衰老生物学研究所资深博士后Sebastian Grönke博士。  参考文献：1 Partridge, L., Deelen, J. & Slagboom, P. E. Facing up to the global challenges of ageing. Nature 561, 45-56 (2018). https://doi.org/10.1038/s41586-018-0457-82 Chen, Y. et al. Aging in COVID-19: Vulnerability, immunity and intervention. Ageing Res Rev 65, 101205 (2021). https://doi.org/10.1016/j.arr.2020.1012053 Partridge, L., Fuentealba, M. & Kennedy, B. K. The quest to slow ageing through drug discovery. Nat Rev Drug Discov 19, 513-532 (2020). https://doi.org/10.1038/s41573-020-0067-74 Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab 11, 35-46 (2010). https://doi.org/10.1016/j.cmet.2009.11.0105 Selman, C. et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140-144 (2009). https://doi.org/10.1126/science.11772216 Neyen, C., Runchel, C., Schupfer, F., Meier, P. & Lemaitre, B. The regulatory isoform rPGRP-LC induces immune resolution via endosomal degradation of receptors. Nat Immunol 17, 1150-1158 (2016). https://doi.org/10.1038/ni.3536本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

The TORCH-2 study is a Phase I/II trial of the mTORC1/2 inhibitor ATG-008 plus the Anti-PD-1 monoclonal antibody toripalimab for the treatment of patients with advanced solid tumors The combination treatment produced an objective response rate (ORR ) of 52.4% in the advanced cervical cancer cohort (including 75% in PD-L1 positive and 41.7% in PD-L1 negative patients), a disease control rate (DCR) of 90.5% and a median progression-free survival (mPFS) of 7.2 months. SHANGHAI and HONG KONG, May 25, 2023 /PRNewswire/ -- Antengene Corporation Limited ( "Antengene" SEHK: 6996.HK), a leading innovative, commercial-stage global biopharmaceutical company dedicated to discovering, developing and commercializing first-in-class and/or best-in-class medicines for cancer, today announced that the latest results from the Phase I/II TORCH-2 study will be presented as a poster at the 2023 American Society for Clinical Oncology Annual Meeting (ASCO 2023) taking place from June 2nd to 6th, 2023 at the McCormick Place Convention Center in Chicago, IL. Being among the 22 China studies selected for Poster Discussions this year, the abstract will also be presented in a Poster Discussion session on June 3rd. "It is our pleasure to have the latest results from the TORCH-2 study selected for Poster Discussion at ASCO 2023," said Dr. Amily Zhang, Antengene's Chief Medical Officer. "Going forward, we will maintain close collaboration with the investigator team of the TORCH-2 study and liaise with regulatory authorities in China and other APAC markets to align on a registration path in cervical cancer and to continue evaluating the combination in additional ongoing studies in other solid tumors." The TORCH-2 study is a Phase I/II trial of the mTORC1/2 inhibitor ATG-008 plus the Anti-PD-1 monoclonal antibody toripalimab for the treatment of patients with advanced solid tumors . The study enrolled 46 patients, including 21 patients with cervical cancer, to evaluate ATG-008 at three doses (15, 20 and 30 mg) in combination with the standard dose of toripalimab. Study patients had advanced solid tumors with a baseline Eastern Cooperative Oncology Group (ECOG) score of 0-1 (the majority scored 1 on the ECOG scale) and a median of 2 lines of therapy (range:0-7). Median patient age was 53 years. Patients with prior PI3K/AKT/mTOR therapy were excluded. Pharmacokinetics and exploratory biomarkers of drug activity were also evaluated. The data are presented as of the cut-off date of October 21st, 2022. Poster Details Title: A phase I/II study of the TORC1/2 inhibitor onatasertib combined with toripalimab in patients with advanced solid tumors Abstract: 2526 Session: Developmental Therapeutics – Immunotherapy Poster : 368 Poster Discussion Session Date and Time: 3:00 PM - 4:30 PM, June 3, 2023 (Central Time) / 4:00 AM – 5:30 AM, June 4, 2023 (Beijing Time) 52.4% ORR in the Cervical Cancer Cohort: Among the 21 patients in the cervical cancer cohort, 1 patient with negative PD-L1 expression experienced a CR and 9 patients experienced a partial response (PR). Note that the patient who achieved a CR in this cohort remained on treatment for more than 883 days and is on treatment with single agent ATG-008 as of the cut-off date. The mPFS for the cohort was 7.2 months. Additional Responses in Patients with Nasopharyngeal Carcinoma ( NPC): The study reported one additional PR in a patient with NPC; this patient remained on study for over two years. Recommended Phase II Dose (RP2D) was Defined: The RP2D for ATG-008 was determined to be 15 mg in combination with toripalimab. Safety Evaluation Did Not Identify any Dose-Limiting Toxicity ( DLT) or Maximum Tolerated Dose (MTD) from the Dose Escalation Phase : The study did not identify any DLT or reach the MTD; 97.8% of patients had more than one treatment emergent adverse event (TEAE) and 69.6% of patients had TEAEs > grade 3, most common of which were decreased lymphocytes (23.9%), rash (10.6%) and hyperglycemia (10.9%). Pharmacokinetic profiles of ATG-008 in combination with toripalimab were similar to ATG-008 monotherapy across APAC and US patients. No new safety signals were reported. About ATG-008 ATG-008 (onatasertib) is an orally available mTORC 1/2 inhibitor. ATG-008 inhibits the activity of mTOR, which may result in the induction of tumor cell apoptosis and a decrease in tumor cell proliferation. mTOR, a serine/threonine kinase that is upregulated in a variety of tumors, has an important role in the PI3K/AKT/mTOR signaling pathway, which is frequently dysregulated in human cancers. ATG-008 has been studied in clinical trials to treat a broad range of tumor types including multiple myeloma (MM), glioblastoma (GBM), hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), diffuse large B-cell lymphoma (DLBCL), etc. About Antengene Antengene Corporation Limited ( "Antengene", SEHK: 6996.HK) is a leading commercial-stage R&D-driven global biopharmaceutical company focused on the discovery, development, manufacturing and commercialization of innovative first-in-class/best-in-class therapeutics for the treatment of hematologic malignancies and solid tumors, in realizing its vision of "Treating Patients Beyond Borders". Since 2017, Antengene has built a pipeline of 9 oncology assets at various stages going from clinical to commercial, including 6 with global rights, and 3 with rights for the APAC region. To date, Antengene has obtained 29 investigational new drug (IND) approvals in the U.S. and Asia, and submitted 10 new drug applications (NDAs) in multiple Asia Pacific markets, with the NDA for XPOVIO® (selinexor) already approved in Mainland China, Taiwan China, South Korea, Singapore and Australia. Forward-looking statements The forward-looking statements made in this article relate only to the events or information as of the date on which the statements are made in this article. Except as required by law, we undertake no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise, after the date on which the statements are made or to reflect the occurrence of unanticipated events. You should read this article completely and with the understanding that our actual future results or performance may be materially different from what we expect. In this article, statements of, or references to, our intentions or those of any of our Directors or our Company are made as of the date of this article. Any of these intentions may alter in light of future development. For a further discussion of these and other factors that could cause future results to differ materially from any forward-looking statement, please see the other risks and uncertainties described in the Company's Annual Report for the year ended December 31, 2022, and the documents subsequently submitted to the Hong Kong Stock Exchange. For more information, please contact: Investor Contacts: Donald Lung E-mail: [email protected] Mobile: +86 18420672158 PR Contacts: Peter Qian E-mail: [email protected] Mobile: +86 13062747000 SOURCE Antengene Corporation Limited

SHANGHAI and HONG KONG, April 26, 2023 /PRNewswire/ -- Antengene Corporation Limited ( "Antengene" SEHK: 6996.HK), a leading innovative, global biopharmaceutical company dedicated to discovering, developing and commercializing first-in-class and/or best-in-class medicines for cancer, today announced that the results of the Phase I/II TORCH-2 study will be presented as a poster discussion during the American Society for Clinical Oncology Annual Meeting (ASCO 2023), taking place from June 2nd to 6th at the McCormick Place Convention Center in Chicago, IL. The TORCH-2 study is an open-label dose escalation and expansion study to evaluate ATG-008, an mTORC1/2 inhibitor, in combination with the anti-PD-L1 antibody, toripalimab, in patients with advanced solid tumors. "We believe that combining ATG-008 with an immune checkpoint inhibitor could lead to more effective and durable control of tumors, because the mTOR signaling pathway plays multiple roles in immune cell biology. We look forward to sharing the results of the TORCH-2 study with the oncology community at ASCO 2023." said Dr. Amily Zhang, Antengene's Chief Medical Officer. Details of the poster to be presented: Title: A phase I/II study of the TORC1/2 inhibitor onatasertib combined with toripalimab in patients with advanced solid tumors Abstract: 2526 Session: Developmental Therapeutics – Immunotherapy Poster Session Display Date and Time: 8:00 AM - 11:00 AM, June 3, 2023 (Central Time) / 9:00 PM, June 3 – 12:00 AM, June 4, 2023 (Beijing Time) Poster Board Number: 368 Poster Discussion Session Date and Time: 3:00 PM - 4:30 PM, June 3, 2023 (Central Time) / 4:00 AM – 5:30 AM, June 4, 2023 (Beijing Time) About Antengene Antengene Corporation Limited ( "Antengene", SEHK: 6996.HK) is a leading commercial-stage R&D-driven global biopharmaceutical company focused on the discovery, development, manufacturing and commercialization of innovative first-in-class/best-in-class therapeutics for the treatment of hematologic malignancies and solid tumors, in realizing its vision of "Treating Patients Beyond Borders". Since 2017, Antengene has built a pipeline of 9 oncology assets at various stages going from clinical to commercial, including 6 with global rights, and 3 with rights for the APAC region. To date, Antengene has obtained 28 investigational new drug (IND) approvals in the U.S. and Asia, and submitted 9 new drug applications (NDAs) in multiple Asia Pacific markets, with the NDA for XPOVIO® (selinexor) already approved in Mainland of China, Taiwan,China, South Korea, Singapore and Australia. Forward-looking statements The forward-looking statements made in this article relate only to the events or information as of the date on which the statements are made in this article. Except as required by law, we undertake no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise, after the date on which the statements are made or to reflect the occurrence of unanticipated events. You should read this article completely and with the understanding that our actual future results or performance may be materially different from what we expect. In this article, statements of, or references to, our intentions or those of any of our Directors or our Company are made as of the date of this article. Any of these intentions may alter in light of future development. For a further discussion of these and other factors that could cause future results to differ materially from any forward-looking statement, see the section titled "Risk Factors" in our periodic reports filed with the Hong Kong Stock Exchange and the other risks and uncertainties described in the Company's Annual Report for year-end December 31, 2021, and subsequent filings with the Hong Kong Stock Exchange. For more information, please contact: Investor Contacts: Donald Lung E-mail: [email protected] Mobile: +86 18420672158 PR Contacts: Peter Qian E-mail: [email protected] Mobile: +86 13062747000 SOURCE Antengene Corporation Limited