SOCS3

引言 自噬对于寿命调控通路十分关键，并且自噬也在造血干细胞（HSC）响应营养胁迫过程中起重要作用，随着衰老，HSC的再生潜力下降，而一部分HSC的自噬流增加并保持再生能力，但是激活自噬的信号以及维持这些自噬激活的衰老的HSC功能的机制仍不清楚。 近日，来自美国哥伦比亚大学的Emmanuelle Passegue研究团队在Cell Stem Cell上发表题为Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells的文章，发现在衰老的小鼠HSC中，自噬可以代偿慢性炎症诱导的代谢失调，并且对于自噬的短暂调控可以恢复衰老HSC的糖酵解状态和再生能力。 为了研究衰老的HSC（oHSC）中自噬激活和未激活之间的差异，研究人员使用24个月大的Gfp-Lc3自噬报告子小鼠进行研究，他们分离了自噬激活（AThi）的oHSC和未激活（ATlo）的oHSC，也用2个月大的小鼠分离了年轻的HSC（yHSC）作为对照，通过ATAC-seq，他们发现yHSC和oHSC的染色体可及性之间存在着很大差异，oHSC的开放位点显著增加，但是在两种oHSC亚型之间则没有显著差异，于是他们猜测这两种oHSC亚型之间的差异可能是环境介导的，并且与细胞状态和激活水平相关。接下来他们对这两种亚型进行了仔细的转录组分析，发现在AThi的oHSC中，炎症信号通路相关基因显著富集，而在ATlo的oHSC中，氧化磷酸化通路相关基因显著富集，并且AThi oHSC细胞几乎全部处于G0/G1期。 为了研究在HSC中促炎症信号是否可以直接激活自噬，他们给年轻的Gfp-Lc3报告子小鼠注射IFN-γ或TNF-α，发现在yHSC中，急性炎症可以瞬时激活自噬，而慢性炎症可以促进自噬升高保护HSC功能。为了研究慢性炎症对HSC功能的代谢影响，他们检测了cIL1刺激的yHSC和oHSC的营养感知信号通路PI3K/AKT/FoxO的状态，发现在衰老的HSC中AKT信号通路被抑制，葡萄糖代谢和摄入下降，葡萄糖转运子Glut1的细胞表面表达也降低。 在yHSC和oHSC之间差异表达最大的基因以及在炎症激活的AThi oHSC和yHSC中上调最明显的基因之一是Socs3，这是一个已知的炎症调控因子和JAK/STAT和胰岛素/IGF-1信号通路的抑制因子，他们构建了一个Socs3fl/fl:Mx1-Cre (Soc3cKO)小鼠来条件性敲除HSC中的Socs3，注射poly(IC)来诱导条件性敲除，同时注射促炎症细胞因子，发现在Soc3cKO小鼠中会诱导致死效应，并且是Socs3的上调介导了炎症导致的代谢变化。接下来他们想知道自噬的参与如何代偿oHSC中受损的糖酵解，RNA-seq结果分析发现许多与营养代谢相关的代谢酶的表达上调，包括脂肪酸氧化和谷氨酰胺摄入，其中在AThi和ATlo oHSC之间差异最大的基因之一是Ppargc1a，该基因编码线粒体生物合成和能量代谢的调控因子PGC-1α。通过对yHSC、AThi和ATlo oHSC进行代谢组分析发现，在AThi oHSC中脂肪酸代谢通路活性上调，可能可以部分替代糖酵解代谢来维持HSC功能。最后他们想知道是否可以通过操纵自噬来恢复oHSC的糖酵解代谢和再生功能，发现24小时的禁食/再进食可以恢复oHSC的再生能力。 自噬可以拮抗衰老HSC中炎症导致的糖酵解抑制（Credit: Cell Stem Cell） 总的来说，这项研究发现衰老的HSC中不同的自噬状态是环境介导的，慢性炎症诱导的糖酵解抑制可以激活自噬，Socs3介导了衰老HSC中的代谢失调和自噬适应，禁食-再进食可以恢复衰老HSC的糖酵解状态和再生能力，为将来利用调控自噬来使造血系统年轻化提供了基础。 原文链接 https://doi-org.libproxy1.nus.edu.sg/10.1016/j.stem.2024.04.020 责编|探索君 排版|探索君 文章来源|“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

▎药明康德内容团队编辑 今日，Kymera Therapeutics公布其在研蛋白降解小分子药物KT-333临床1期试验的更新数据。分析显示，KT-333完成初步临床概念验证，在多种血液恶性肿瘤中展示了抗肿瘤活性，包含在两名经典霍奇金淋巴瘤（cHL）患者中达到完全缓解。 此次所公布、进行中的1期临床试验旨在评估KT-333在复发和/或难治性淋巴瘤、白血病和实体瘤成人患者中的安全性、耐受性、药代动力学（PK）、药效学（PD）和临床活性。更新数据截至2024年6月3日，包括接受七个剂量水平（DLs）的47名患者，患者平均给药9.1次。这些患者包括cHL、B细胞非霍奇金淋巴瘤、皮肤T细胞淋巴瘤（CTCL）、外周T细胞淋巴瘤（PTCL）、大颗粒淋巴细胞白血病（LGL-L）、T细胞前淋巴细胞白血病（T-PLL）、NK细胞淋巴瘤以及实体瘤患者。主要数据包含： 抗肿瘤活性评估： cHL：在DL4水平的三名患者中，两名达到完全缓解。这两名缓解患者在之前至少接受过一种含免疫检查点抑制剂以及抗体偶联药物Adcetris（brentuximab vedotin）的治疗，并随后进行了干细胞移植。此外，在DL6水平的另一名cHL患者中观察到了疾病稳定。 NK细胞淋巴瘤：在DL7水平的STAT3突变患者中达到了完全缓解。 CTCL：在DL2和DL4-6水平的九名患者中，四名达到了部分缓解，另有一名患者在DL4水平观察到疾病稳定。 实体瘤：在DL3-4水平的14名患者中，有四名观察到了疾病稳定，包括两例头颈部肿瘤以及胆管癌和肾细胞癌患者。 ▲KT-333试验临床结果摘要（图片来源：参考资料[2]） 机制验证和药效 STAT3降解：在DL7水平，KT-333在外周血单核细胞中实现了高达95%的STAT3最大平均降解，并有证据表明STAT3通路受到抑制，和全血中炎症生物标志物的下调。特别是，在DL4水平的CTCL肿瘤活检中，KT-333显著降低了STAT3、pSTAT3和SOCS3的表达。 在外周血和肿瘤中均观察到IFN-γ刺激基因特征的诱导：此基因特征预测患者对PD-1类药物的敏感性。这表明患者在接受KT-333治疗后肿瘤微环境中存在良好的免疫调节反应，并支持在实体瘤中，KT-333与PD-1靶向药物形成新组合疗法的潜力。 剂量依赖性增加：观察到KT-333血浆暴露水平的剂量依赖性增加，达到了预测的有效水平。 ▲KT-333在外周血单核细胞中实现了高达95%的STAT3最大平均降解（图片来源：参考资料[2]） 安全性 KT-333耐受性良好，主要不良事件为1级和2级，包括口腔炎和疲劳。在LGL-L患者中，在DL5水平出现了两例剂量限制性毒性（DLTs），分别为3级口腔炎和关节痛，在DL7水平的淋巴瘤患者中观察到一例3级疲劳。 ▲靶向STAT3的抗肿瘤机制（图片来源：参考资料[2]）KT-333是一种潜在“first-in-class”、强效、高选择性的STAT3靶向小分子降解剂。根据新闻稿，KT-333是靶向未成药转录因子的首个进入临床阶段的降解剂。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放 参考资料： [1] Kymera Therapeutics Presents New Clinical Data from the Ongoing Phase 1 Trial of STAT3 Degrader KT-333 at EHA Annual Meeting. Retrieved June 14, 2024 from https://www.globenewswire.com/news-release/2024/06/14/2898896/0/en/Kymera-Therapeutics-Presents-New-Clinical-Data-from-the-Ongoing-Phase-1-Trial-of-STAT3-Degrader-KT-333-at-EHA-Annual-Meeting.html [2] Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of KT-333, a Targeted Protein Degrader of STAT3, in Patients with Relapsed or Refractory Hematologic and Solid Tumor Cancers. Retrieved June 14, 2024 from https://www.kymeratx.com/wp-content/uploads/2024/06/Kymera-Therapeutics-EHA-KT-333-Poster_June-2024.pdf 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新

KT-333 demonstrated initial clinical proof of concept across multiple hematological malignancies, including complete responses in two patients with Hodgkin’s lymphoma Robust STAT3 knockdown and positive immunomodulatory effect achieved in blood and tumor KT-333 was well-tolerated with Phase 1 dose escalation ongoing and additional data expected in the second half of 2024 WATERTOWN, Mass., June 14, 2024 (GLOBE NEWSWIRE) -- Kymera Therapeutics, Inc. (NASDAQ: KYMR), a clinical-stage biopharmaceutical company advancing a new class of small molecule medicines using targeted protein degradation (TPD), today shared new clinical data from its ongoing KT-333 Phase 1 trial. KT-333, a first-in-class, potent, highly selective, heterobifunctional small molecule degrader of STAT3, demonstrated antitumor responses in hematological malignancies with high unmet need, including relapsed/refractory classic Hodgkin’s lymphoma (cHL), cutaneous T-cell lymphoma (CTCL), and NK-cell lymphoma, at doses that were well-tolerated. The data were presented at the European Hematology Association (EHA) Annual Meeting, taking place from June 13-16, 2024, in Madrid, Spain. Results released in an EHA poster today include a data cut-off of June 3, 2024. “The complete responses we’ve shown in Hodgkin’s lymphoma demonstrate the transformative therapeutic potential of STAT3 degradation, with two heavily pretreated cHL patients in the KT-333 trial moving to potentially curative stem cell transplants after treatment,” said Jared Gollob, MD, Chief Medical Officer, Kymera Therapeutics. “We continue to be encouraged by the data generated in the ongoing Phase 1 trial showing clinical translation of our degrader’s profile across multiple hematological malignancies including cHL, CTCL and NK-cell lymphoma and the potential to improve patients’ lives. With dose escalation continuing, we look forward to completing the Phase 1 study and sharing the full data set later this year.” KT-333 Clinical Update The KT-333 Phase 1 clinical trial is evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of KT-333 dosed weekly on 28-day cycles in adult patients with relapsed and/or refractory lymphomas, leukemias and solid tumors. The poster provides a clinical update as of June 3, 2024, from the ongoing KT-333 Phase 1 trial from 47 patients enrolled through seven dose levels (DLs) with a mean of 9.1 doses. This includes patients with cHL, B-cell non-Hodgkin’s lymphoma, CTCL, peripheral T-cell lymphoma (PTCL), large granular lymphocytic leukemia (LGL-L), T-cell prolymphocytic leukemia (T-PLL), NK-cell lymphoma, as well as solid tumors. Highlights from the poster include: Antitumor activity in patients with hematological malignancies evaluable for response: In cHL, complete responses were achieved in two of three patients at DL4. Both responders, who had received prior treatment with at least one regimen containing a check point inhibitor as well as brentuximab vedotin, have subsequently undergone stem cell transplantation. Additionally, stable disease was observed in a third cHL patient at DL6.In NK-cell lymphoma, one complete response was achieved at DL7 in a patient with STAT3 mutation.Among nine patients with CTCL, partial responses were achieved in four patients at DL2 and DL4-6, and stable disease was observed in one patient at DL4.In solid tumors, stable disease was observed in four of fourteen patients, including two head and neck tumor types as well as patients with cholangiocarcinoma and renal cell cancer, at DL3-4. Strong proof of mechanism with KT-333 achieving up to 95% mean maximum STAT3 degradation in peripheral blood mononuclear cells at DL7 with evidence of STAT3 pathway inhibition and downregulation of inflammatory biomarkers in whole blood. Notably, KT-333 resulted in robust reduction of STAT3, pSTAT3, and SOCS3 expression in a CTCL tumor biopsy in DL4.Induction of an IFN-γ stimulated gene signature predictive of sensitivity to anti-PD1 was seen in both peripheral blood and tumor as previously shown, suggestive of favorable immunomodulatory response in the tumor microenvironment following KT-333 treatment and supporting a potential novel combination partner with anti-PD-1 drugs in solid tumors.Dose dependent increases in KT-333 plasma exposure were observed, achieving levels predicted to be efficacious.KT-333 was well tolerated with primarily Grade 1 and 2 adverse events, including stomatitis and fatigue. Two dose-limiting toxicities (DLTs), Grade 3 stomatitis and arthralgia, occurred in LGL-L patients at DL5 and one DLT, Grade 3 fatigue, was observed in a lymphoma patient treated at DL7. The Phase 1a trial for KT-333 is currently ongoing. The Company expects to complete the study and share additional clinical data to inform the program’s next development steps in 2024 at an upcoming medical meeting. A copy of the EHA poster presentation is available in the Resource Library section of Kymera's website. About KT-333 STAT3 Degrader KT-333 is a potent, highly selective degrader of STAT3 in development for the treatment of multiple STAT3-dependent pathologies, including hematological malignancies and solid tumors. STAT3 is an undrugged transcription factor activated through a variety of different cytokine and growth factor receptors via Janus kinases (JAKs), as well as through oncogenic fusion proteins and mutations in STAT3 itself. In certain malignant cells, STAT3 activation is set into overdrive, leading to a dampened immune response, tumor progression, and metastasis. STAT3’s role as a cancer driver and tumor microenvironment modulator has been validated in a multitude of studies, making it a strong candidate to target in the treatment of cancer. KT-333 was the first degrader against an undrugged transcription factor to enter the clinic and the Phase 1 clinical trial is designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of KT-333 dosed weekly in adult patients with relapsed and/or refractory lymphomas, leukemias, and solid tumors. Clinical data from the KT-333 Phase 1 trial has shown evidence of STAT3 targeted protein degradation in humans with associated STAT3 pathway inhibition, along with early signs of antitumor activity, highlighting the potential of heterobifunctional degraders for targeting this previously undruggable transcription factor. The Phase 1a trial for KT-333 is currently ongoing. More information on the Phase 1 study can be found at www.clinicaltrials.gov, identifier NCT05225584. About Kymera TherapeuticsKymera is a clinical-stage biotechnology company pioneering the field of targeted protein degradation (TPD) to develop medicines that address critical health problems and have the potential to dramatically improve patients’ lives. Kymera is deploying TPD to address disease targets and pathways inaccessible with conventional therapeutics. Having advanced the first degrader into the clinic for immunological diseases, Kymera is focused on delivering oral small molecule degraders to provide a new generation of convenient, highly effective therapies for patients with these conditions. Kymera is also progressing degrader oncology programs that target undrugged or poorly drugged proteins to create new ways to fight cancer. Founded in 2016, Kymera has been recognized as one of Boston’s top workplaces for the past several years. For more information about our science, pipeline and people, please visit www.kymeratx.com or follow us on X (previously Twitter) or LinkedIn. Cautionary Note Regarding Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements by Kymera Therapeutics regarding its: strategy, business plans and objectives for its clinical programs; plans and timelines for the preclinical and clinical development of its product candidates, including the therapeutic potential, clinical benefits and safety thereof; expectations regarding timing, success and data announcements of current ongoing preclinical and clinical trials; the ability to initiate new clinical programs; and Kymera's financial condition and expected cash runway into the first half of 2027. The words "may," "might," "will," "could," "would," "should," "expect," "plan," "anticipate," "intend," "believe," "expect," "estimate," "seek," "predict," "future," "project," "potential," "continue," "target" and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks associated with: the timing and anticipated results of our current and future preclinical studies and clinical trials, supply chain, strategy and future operations; the delay of any current and future preclinical studies or clinical trials or the development of Kymera Therapeutics' drug candidates; the risk that the results of current preclinical studies and clinical trials may not be predictive of future results in connection with current or future preclinical and clinical trials, including for KT-333; Kymera Therapeutics' ability to successfully demonstrate the safety and efficacy of its drug candidates; the timing and outcome of the Kymera Therapeutics' planned interactions with regulatory authorities; obtaining, maintaining and protecting its intellectual property; the risks associated with pandemics or epidemics; and Kymera Therapeutics' relationships with its existing and future collaboration partners. These and other risks and uncertainties are described in greater detail in the section entitled "Risk Factors" in the Annual Report on Form 10-K for the period ended December 31, 2023, as well as discussions of potential risks, uncertainties, and other important factors in Kymera Therapeutics' subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Kymera Therapeutics' views only as of today and should not be relied upon as representing its views as of any subsequent date. Kymera Therapeutics explicitly disclaims any obligation to update any forward-looking statements. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. Investor and Media Contact: Justine KoenigsbergVice President, Investor Relationsinvestors@kymeratx.commedia@kymeratx.com 857-285-5300