LILRB4

▎药明康德内容团队编辑  作为最常见的神经退行性疾病，阿尔茨海默病会严重损伤记忆、思考能力，最终可能导致死亡。阿尔茨海默病的一个典型症状是β淀粉样蛋白斑块，β淀粉样蛋白在大脑中堆积，导致的神经缠结与大脑萎缩以及认知能力下降密切相关。2023年，FDA完全批准的近20年来首款阿尔茨海默病新药lecanemab，正是通过抗体与β淀粉样蛋白特异性结合而起到治疗效果，成功改变阿尔茨海默病进程。现在，来自圣路易斯华盛顿大学的研究团队在一篇《科学-转化医学》论文中，展示了一种清除毒性蛋白斑块的新策略：通过抗体恢复神经系统免疫细胞的蛋白清理能力，直接动员自身的小胶质细胞来减少淀粉样蛋白沉积。在小鼠实验中，这款全新的免疫疗法能够成功减少毒性斑块，并减轻阿尔茨海默病样小鼠的行为异常，因此成为一款极具前景的潜在疗法。小胶质细胞是中枢神经系统中最重要的一类免疫细胞，正常情况下，它们会围绕着淀粉样蛋白斑块形成一道屏障，控制有害蛋白的扩散，并且还可以吞噬、破坏这些蛋白斑块。但在阿尔茨海默病中，小胶质细胞清理斑块的能力明显减弱了，而这一差异可能与ApoE蛋白有关。作为淀粉样蛋白斑块的组成部分，ApoE蛋白能够与斑块周围小胶质细胞上的白细胞免疫球蛋白样受体LILRB4结合，抑制小胶质细胞的活性。研究团队在检查阿尔茨海默病患者的脑组织切片时发现，患者的小胶质细胞表面有大量LILRB4受体；使用表达人类LILRB4受体的转基因小鼠模型，研究团队进一步证实了这一发现，并且证实LILRB4抑制了小胶质细胞清除β淀粉样蛋白斑块的能力。▲在阿尔茨海默病大脑中，β淀粉样蛋白斑块周围的ApoE蛋白（白色）与LILRB4受体（红色）结合（图片来源：参考资料[1]）上述发现也为治疗指出了潜在的路线。研究团队设计了针对人类LILRB4的单抗，并且对大脑中有β淀粉样蛋白斑块的小鼠模型进行了治疗，发现该抗体阻止了ApoE与LILRB4的结合，增强了小胶质细胞的活性。这些被激活的小胶质细胞，也有效减少了小鼠大脑中的斑块。▲与对照组相比，抗体治疗有效减少了阿尔茨海默病小鼠大脑中的淀粉样蛋白斑块（蓝色）（图片来源：参考资料[1]）全新抗体的使用也在行为测试中造成行为变化，减轻了小鼠的冒险行为。阿尔茨海默病患者往往会缺乏对过去经历的记忆，因此可能会做出冒险行为，例如更容易受骗。而用于清除蛋白斑块的抗体治疗，则显示出了改变行为的潜力。值得注意的是，直接靶向淀粉样斑块的药物可能会引起潜在的严重副作用。在阿尔茨海默病患者中，β淀粉样蛋白堆积在大脑动脉壁以及脑组织的其他部位。如果清除的是脑血管中的斑块，则可能会引起肿胀和出血，这种副作用被称为淀粉样蛋白相关影像异常（ARIA）。这项研究中使用的小鼠在血管上缺乏淀粉样斑块，因此研究人员尚无法评估这种副作用是否存在。目前，他们正在一种脑动脉上长有斑块的小鼠模型中检验这种风险。图片来源：123RF“Lecanemab作为首个能够改变疾病进程的治疗性抗体，证实了β淀粉样蛋白在阿尔茨海默病进展中的重要性，”论文作者David Holtzman教授说，“它为开发其他免疫疗法提供了新的机遇，这些疗法使用不同的方法来清除大脑中的有害蛋白。”研究团队指出，由于有毒的蛋白斑块不仅与阿尔茨海默病有关，还是帕金森病、肌萎缩侧索硬化症和亨廷顿病等多种神经退行性疾病的特征，因此这种免疫疗法可能会对更广泛的神经退行性疾病治疗产生深远影响。目前，研究团队也在探索其他潜在的免疫疗法，以清除可能促进其他疾病的有害蛋白。参考资料：[1] Jinchao Hou et al, Antibody-mediated targeting of human microglial leukocyte Ig-like receptor B4 attenuates amyloid pathology in a mouse model, Science Translational Medicine (2024). DOI: 10.1126/scitranslmed.adj9052[2] Immunotherapy for Alzheimer’s disease shows promise in mouse study. Retrieved Apr. 4, 2024 from https://www.eurekalert.org/news-releases/1039990本文来自药明康德内容微信团队，欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。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。更多推荐点个“在看”再走吧~

中国上海和香港，2024年4月6日–致力于研发，生产和销售同类首款及/或同类最优血液及实体肿瘤疗法的商业化阶段领先创新生物制药公司–德琪医药有限公司（简称“德琪医药”，香港交易所股票代码：6996.HK）今日宣布，公司于4月5日至10日在美国加利福尼亚州圣地亚哥市的圣地亚哥会展中心举行的2024年美国癌症研究协会年会（AACR 2024）上以壁报形式展示了四项临床前研究成果。这些壁报涉及了公司的四款高潜力、高差异化的产品，这些产品包括计划在2025年上半年提交临床试验申请的ATG-042、目前正在中国和澳大利亚开展II期剂量扩展阶段研究的ATG-022、德琪医药自主研发并拥有自主专利的T细胞衔接器（TCE）平台AnTenGager™，以及首款基于AnTenGager™开发的候选药物ATG-102。ATG-042是一款具有同类最佳潜力的口服型小分子MTAPnull选择性PRMT5抑制剂，它在特异性靶向作用于肿瘤细胞的同时免于损伤健康细胞并具有很好的可开发性。ATG-022是一款Claudin 18.2抗体偶联药物，其候选伴随诊断抗体的开发数据显示，由德琪医药自主开发的这款潜在伴随诊断抗体相较于其他在售试剂盒具有更高的灵敏度。AnTenGager™是德琪医药自主研发并拥有自主专利的T细胞衔接器（TCE）平台，该平台具有靶点依赖的T细胞激活特性，拥有更高的活性和更低的细胞因子释放风险。ATG-102是一款用于治疗急性髓系白血病（AML）的LILRB4 x CD3 T细胞衔接器。壁报详细信息：ATG-042（MTAPnull选择性PRMT5抑制剂）标题：新型MTAPnull选择性PRMT5抑制剂ATG-042的临床前特性摘要编号：4592会场主题：在研及分子疗法分会场主题：HDAC和甲基转移酶抑制剂日期：2024年4月9日时间：9：00 AM – 12:30 PM（美国西部时间） 2024年4月10日12：00 AM – 3：30 AM（北京时间）地点：壁报展示区24该临床前研究旨在检测ATG-042的体内/外活性以及药代动力学（PK）特性。数据显示，ATG-042对于MTAP敲除的细胞存在明显的选择性抑制效应、较高的渗透性、良好的代谢稳定性、较低的药物相互作用（DDI）风险以及较高的口服生物利用度。更重要的是，ATG-042显示了良好的脑部穿透。在CDX模型中，ATG-042也强效和选择性地抑制了肿瘤生长，且未造成体重下降。这些数据说明，ATG-042是一款针对MTAPnull肿瘤具有较强活性和良好耐受性及临床前PK特性的口服型MTAPnull选择性PRMT5抑制剂。ATG-022（Claudin 18.2 抗体偶联药物）的伴随诊断抗体标题：用于Claudin 18.2靶向疗法的新型伴随诊断免疫组织化学抗体的开发摘要编号：1032会场主题：临床研究分会场主题：诊断用生物标志物1日期：2024年4月7日时间：1：30 PM – 5:00 PM（美国西部时间） 2024年4月8日4：30 AM – 8：00 AM（北京时间）地点：壁报展示区42尽管CLDN18.2表达水平与靶向作用于CLDN18.2的药物的疗效高度相关，但目前尚无用于检测CLDN18.2表达水平的特异性伴随诊断（CDx）抗体获批。摘要介绍了一款可选择性识别CLDN18.2的新型高敏感免疫组化（IHC）抗体的发现及验证过程。数据显示，单克隆抗体（mAb）克隆43F11在经固定的存在CLDN18.2表达的细胞上显示了阳性细胞表面IHC染色，但在表达CLDN18.1的细胞上没有染色。此外，抗体43F11在基于具有不同的已知CLDN18.2表达水平的肿瘤组织和人源肿瘤异体移植（PDX）样本的IHC试验中准确识别了CLDN18.2表达水平。较在售的IHC抗体EPR19202，抗体43F11显示了更高的敏感度，这使其能够对CLDN18.2表达水平极低的肿瘤组织实现染色。这些数据说明，抗体43F11较对照抗体具有更高的敏感度并有望成为一款用于患者分类的有效工具。AnTenGager™技术平台标题：新型“2+1”T细胞衔接器平台AnTenGager™可诱导T细胞条件性激活并降低CRS风险摘要编号：6343会场主题：临床研究分会场主题：抗体药物2日期：2024年4月9日时间：1：30 PM – 5:00 PM（美国西部时间） 2024年4月10日4：30 AM – 8：00 AM（北京时间）地点：壁报展示区41该壁报深入介绍了自研T细胞衔接器（TCE）平台AnTenGager™的设计和作用机制。这些TCE经过特别设计，可在较低系统性CD3激活和细胞因子释放综合征（CRS）风险水平下产生抗肿瘤效应，有望被用于实体瘤的治疗。AnTenGager™ TCE的设计使其可通过形成 T 细胞受体 (TCR) 非依赖性免疫突触诱导细胞毒性。AnTenGager™通过同时结合肿瘤细胞表面的肿瘤相关抗原 (TAA) 和 CD3+ T 细胞上的特定构象表位实现这一功能。AnTenGager™可高效地与特定CD3构象表位结合并显示了较对照药物更强的细胞毒性。AnTenGager™可匹配多种TAA，并在细胞试验和骨髓瘤小鼠模型中显示了较对照药物更强的细胞毒性。从小鼠模型中获得的数据显示，AnTenGagerTM诱导的促炎细胞因子水平明显更低，这意味着更低的CRS风险。AnTenGager™在多种实验条件下稳定性良好，所以具有较高的可开发性。总体而言，该壁报展示的数据显示AnTenGager™对于实体瘤具有治疗潜力并有望成为一个新的肿瘤药物类型，因为它具有同时与TAA和特定CD3+构象表位结合的能力，这就为其带来了较对照药物更高的TAA依赖的细胞毒性和更低的CRS风险。ATG-102（LILRB4 x CD3 T细胞衔接器）标题：ATG-102，一款靶向LILRB4的两个非重叠抗原表位用于治疗单核细胞AML的新型LRLRB4 x CD3 T细胞衔接器摘要编号：2372会场主题：临床研究分会场主题：抗体药物1日期：2024年4月8日时间：9：00 AM – 12：30 PM（美国西部时间） 2024年4月9日12：00 AM – 3：30 AM（北京时间）地点：壁报展示区38识别表达于AML和白血病干细胞表面但在正常造血干细胞上不表达的特异抗原比较困难，这限制了TCE在AML治疗中的应用。LILRB4在M4/M5亚型AML细胞上的表达使其成为了一个高潜力的治疗靶点。数据显示，基于AnTenGager™平台开发的TCE由于可通过与LILRB4受体的两个特殊表位结合，诱导强效的T细胞依赖的细胞毒性（TDCC），进而产生明显的体内和体外抗肿瘤活性。该壁报介绍了ATG-102的设计和结构特征。ATG-102的结构包含两个LILBR4表位和一个插入至一个LILBR4重链的铰链区的抗CD3单链抗体（scFv）。ATG-102的特征数据包括：结合表位及亲和力研究显示，ATG-102可与靶点TAA表位及CD3构象表位结合。T细胞结合及T细胞依赖性细胞毒性试验显示，ATG-102可实现较对照药物更低的非特异性T细胞结合或激活，同时可诱导针对LILRB4+细胞的强效TDCC和更强的体内抗AML活性。该壁报着重介绍了ATG-102的结构特点和较强的体内和体外抗肿瘤活性。这些数据将支持开展对于ATG-102的临床评估。关于德琪医药        德琪医药有限公司（简称“德琪医药”，香港交易所股票代码：6996.HK）是一家以研发为驱动，并已进入商业化阶段的生物制药领先企业，以“医者无疆，创新永续”为愿景，德琪医药专注于血液及实体肿瘤领域的同类首款和同类最优疗法的早期研发、临床研究、药物生产及商业化，致力于通过提供突破性疗法，改善全球患者生活质量。自2017年以来，德琪医药现已建立起一条拥有9款从临床延展至商业化阶段的肿瘤药物资产研发管线，其中，6款产品具有全球权益，3款产品具有亚太权益。公司已在美国及多个亚太市场获得29个临床批件（IND），并递交了11个新药上市申请（NDA）。目前，希维奥®（塞利尼索片）已获得中国大陆、中国台湾、中国香港、中国澳门、韩国、新加坡和澳大利亚的新药上市批准。

SHANGHAI and HONG KONG, April 5, 2024 /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 the presentation of four preclinical posters at the 2024 American Association for Cancer Research Annual Meeting (AACR 2024), taking place from April 5th to April 10th at the San Diego Convention Center in San Diego, California, the United States. The posters showcased four of Antengene's high-potential emerging programs, including ATG-042, tracking to a H1 2025 IND filing; ATG-022, in Phase II dose expansion studies in China and Australia; AnTenGagerTM platform, Antengene's proprietary T-cell engager (TCE) platform; and ATG-102, which could be the first IND candidate from AnTenGagerTM platform. ATG-042, an oral small molecule MTAPnull-selective PRMT5 inhibitor holding the promise as a best-in-class drug. Study results showed that ATG-042 has the potential to elegantly target tumor cells while sparing healthy cells, with an attractive developability profile. ATG-022 is an Claudin 18.2 antibody-drug conjugate. The detailed updated data of the Claudin 18.2 (CLDN18.2) companion diagnostic antibody candidate for ATG-022 showed that the antibody has higher sensitivity compared to commercially available kits. AnTenGagerTM, Antengene's proprietary TCE platform with the ability to induce target-dependent T-cell activation, has potent anti-tumor effects and lower risk of cytokine release syndrome (CRS). ATG-102, a LILRB4 x CD3 TCE, is being developed for the treatment of acute myeloid leukemia (AML). Details of the posters: ATG-042 (MTAPnull-selective PRMT5 Inhibitor) Title: Preclinical characterization of ATG-042, a novel MTAPnull-selective PRMT5 inhibitor Abstract: 4592 Session Category: Experimental and Molecular Therapeutics Session Title: HDAC and Methyltransferase Inhibitors Date: April 9, 2024 Time: 9:00 AM - 12:30 PM (Pacific Time) 12:00 AM - 3:30 AM, April 10, 2024 (Beijing Time) Location: Poster Section 24 This preclinical study was designed to test the in vitro/in vivo efficacy, and preclinical pharmacokinetic (PK) properties of ATG-042. According to the results, ATG-042 demonstrated a potent and selective inhibitory effect on the proliferation of MTAP knockout cells, showed high permeability, good metabolic stability, a low risk of drug-drug interaction (DDI), and high oral bioavailability. Importantly, ATG-042 demonstrated good brain penetrability. In CDX models, ATG-042 also potently and selectively inhibited tumor growth without inducing weight loss. These data suggest that ATG-042 is an orally administered, MTAPnull-selective PRMT5 inhibitor with potent efficacy against MTAP-null tumors, as well as demonstrating good tolerability and favorable preclinical PK profiles. Companion Diagnostic Antibody for ATG-022 (Claudin 18.2 ADC) Title: Development of a novel companion diagnostic immunohistochemistry antibody for Claudin 18.2-targeted therapies Abstract: 1032 Session Category: Clinical Research Session Title: Diagnostic Biomarkers 1 Date: April 7, 2024 Time: 1:30 PM - 5:00 PM (Pacific Time) 4:30 AM - 8:00 AM, April 8, 2024 (Beijing Time) Location: Poster Section 42 Despite the substantial correlation between the expression of CLDN18.2 and the efficacy of therapies targeting CLDN18.2, no companion diagnostic (CDx) antibodies specific to CLDN18.2 have been approved to date. This poster presents the discovery and validation of a novel, highly sensitive immunohistochemistry (IHC) antibody that selectively identifies CLDN18.2. According these data, the monoclonal antibody (mAb) clone 43F11 showed positive cell surface IHC staining on CLDN18.2-expressing cells following fixation but demonstrated no staining on CLDN18.1-expressing cells. Moreover, the 43F11 antibody accurately identified the expression level of CLDN18.2 in an IHC assay, utilizing tumor tissues and patient-derived xenograft (PDX) samples with predetermined expression levels of CLDN18.2. When compared to the commercially available IHC antibody EPR19202, the 43F11 antibody demonstrated greater sensitivity, enabling positive staining on cancer tissues with significantly lower expression levels of CLDN18.2. These data suggest that the 43F11 antibody possesses superior sensitivity compared to the benchmark antibody and has the potential to serve as an effective patient stratification tool. AnTenGager TM Platform Title: AnTenGagerTM, a novel "2+1" T cell engager platform, enables conditional T cell activation with reduced risk of CRS Abstract: 6343 Session Category: Clinical Research Session Title: Antibodies 2 Date: April 9, 2024 Time: 1:30 PM - 5:00 PM (Pacific Time) 4:30 AM - 8:00 AM, April 10, 2024 (Beijing Time) Location: Poster Section 41 This poster presents an in-depth overview of the design and mechanism of action for the proprietary AnTenGagerTM T cell engager (TCE) platform. These TCEs are specifically designed to produce an anti-cancer effect with a lower risk of systemic CD3 activation and cytokine release syndrome (CRS), potentially paving the way for use in solid tumors. AnTenGagers TCE constructs are designed to induce cytotoxicity by forming a T cell receptor (TCR)-independent immune synapse. AnTenGagers do this by simultaneously binding tumor associated antigens (TAAs) on cancer cells and specific conformational epitopes on CD3+ T-cells. Presented data show that AnTenGagers are able to effectively bind to specific CD3 confirmational epitopes and demonstrate higher cytotoxicity compared to benchmark compounds. AnTenGagers are compatible with a range of TAAs, and that AnTenGagers have improved cytotoxicity compared to benchmark compounds, as demonstrated in cellular assays and a murine myeloma model. Data from the murine models also showed that AnTenGagers resulted in significantly lower concentrations of pro-inflammatory cytokines, further supporting a lower risk of CRS. AnTenGagers also have good "developability" properties based on good stability under stress conditions. Together, these data support the potential for AnTenGagers to be used in solid tumors, based on their ability to simultaneously bind TAAs and specific CD3+ confirmational epitopes, resulting in higher TAA-dependent cytotoxicity compared to benchmarks and the reduced risk of CRS, opening the door to a broad new class of cancer therapies. ATG-102 (LILRB4 x CD3 T Cell Engager) Title: ATG-102, a novel LILRB4 x CD3 T cell engager, targeting two non-overlapping epitopes of LILRB4, for the treatment of monocytic AML Abstract: 2372 Session Category: Clinical Research Session Title: Antibodies 1 Date: April 8, 2024 Time: 9:00 AM - 12:30 PM (Pacific Time) 12:00 AM - 3:30 AM, April 9, 2024 (Beijing Time) Location: Poster Section 38 The use of TCEs to treat AML (acute myeloid leukemia) has been limited the difficulty in identifying specific antigens that are expressed on AML and leukemic stem cells but not normal hematopoietic stem cells. The preferential expression of LILRB4 on M4/M5 subtype acute myeloid leukemia (AML) cells renders it a highly attractive target for the treatment of AML. These data show that an AnTenGagerTM based TCE, which binds to two distinct epitopes of the LILRB4 receptor, can induce potent T-cell dependent cellular cytotoxicity (TDCC) to produce potent anti-tumor efficacy in vitro and in vivo. The poster outlines the design and structural characteristics of ATG-102 comprised of two LILRB4 epitopes and an anti-CD3 single chain fragment variable (scFv) inserted in the hinge region on one of the LILRB4 heavy chains. Characterization data include: -Binding epitope and affinity studies showing that ATG-102 binds to the target TAA epitopes as well as conformational CD3 epitopes. -T cell binding and T-cell dependent cytotoxicity assays show that compared to the benchmark, ATG-102 demonstrated less non-specific T cell binding or activation, whilst inducing more potent TDCC against LILRB4+cells and enhanced in vivo anti-AML efficacy. These data highlight the structural characteristics of ATG-102 and demonstrate potent in vitro and in vivo anti-tumor efficacy which support further clinical evaluation of ATG-102. 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 11 new drug applications (NDAs) in multiple Asia Pacific markets, with the NDA for XPOVIO® (selinexor) already approved in Mainland of China, Taiwan China, Hong Kong China, Macau China, South Korea, Singapore and Australia. 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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, 2023, and the documents subsequently submitted to the Hong Kong Stock Exchange. 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