IL-34

*仅供医学专业人士阅读参考阿尔茨海默病（AD）的病理特征包括大脑中的β-淀粉样蛋白沉积和tau蛋白纤维缠结，即当前药物研发的两个重点方向。就在本月初，仑卡奈单抗在中国获批上市，成为首款在国内上市的治疗阿尔茨海默病的抗Aβ药物。但是越来越多的研究表明，AD的发病机制复杂，具有异质性，如果仅仅集中火力攻于β-淀粉样蛋白沉淀和tau蛋白异常，不同患者的临床获益可能会有很大差异。荷兰阿姆斯特丹自由大学的Betty M. Tijms等人通过对609名参与者的脑脊液进行蛋白质组学分析，揭示5种AD分子亚型。这些亚型分别以神经元增生、先天免疫异常激活、RNA失调、脉络丛功能障碍和血脑屏障功能障碍为特点，具有不同的遗传特征、临床结局、生存时间以及脑皮质萎缩特征[1]。这项研究成果强调了AD个体化治疗的重要性，文章于近日发表在《自然·衰老》期刊上。 论文首页 脑脊液环绕在大脑和脊髓周围，充当缓冲和保护作用，同时也参与营养物质和废物的运输。位置上的接近，使得脑脊液中的成分变化能够直接反映大脑的健康状况。 2020年，Betty M. Tijms等人基于脑脊液蛋白质组学确定了3种AD分子亚型[2]。如今蛋白质组学技术日益改进，研究者们认为是时候对AD亚型的描述进行完善。 此次，他们共获取609名参与者的脑脊液样本。其中419人经生物标志物检测诊断为不同阶段的AD患者，包括认知正常、轻度认知障碍（MCI）、痴呆症；其他人具有正常认知能力且未被诊断为AD。 总体来看，有1058种脑脊液蛋白质在非AD患者与AD患者之间差异表达。 研究者们进一步采用非负矩阵分解（NMF）的方法来对AD患者进行聚类分析，从而根据脑脊液蛋白质组学特征将AD患者分为5种亚型。 5种亚型的脑脊液蛋白质组学特征 亚型1的特点为神经元增生。表达上调的蛋白质与神经元可塑性相关，如突触组装、轴突引导、神经元生成、胶质细胞生成等生理过程。与其相关的AD遗传变异是TREM2 R47H。 亚型2的特点为先天免疫异常激活。显示小胶质细胞特异性蛋白水平升高，与先天免疫激活有关。与其相关的AD遗传变异是IDUA、CLNK和SCIMP。 亚型3的特点为RNA失调（RNA dysregulation）。表达上调的蛋白质参与细胞骨架组成、轴突运输、蛋白酶体功能、蛋白质折叠，尤其是异质核核糖核蛋白（hnRNP）等RNA结合蛋白，表达明显上调。与其相关的AD遗传变异是BIN1、TREM2 R62H、SPDYE3、SNX1、KAT8。 亚型4的特点为脉络丛（产生脑脊液的地方）功能障碍。表达上调的蛋白质中有45%参与脉络丛发育，涉及细胞粘附、SMAD通路；此外还有小胶质细胞等免疫细胞特异性蛋白水平升高。与其相关的AD遗传变异是ABCA7、PICALM、IL-34、CLNK。 亚型5的特点为血脑屏障功能障碍。白蛋白、纤维蛋白原、纤溶酶原和凝血酶等本不该存在于大脑的蛋白质，在这类亚型患者的脑脊液中水平异常升高，表明来自血液的蛋白质趁血脑屏障受损渗入大脑；与血液凝固、B细胞介导的免疫反应、急性炎症反应等生理过程相关的蛋白质表达上调。与其相关的AD遗传变异是IL-34、ECHDC3、APP。 其中，亚型1、2、3患者的脑脊液tau蛋白水平显著升高，而亚型4、5患者的脑脊液tau蛋白水平大多为正常。 相比于对照组，所有AD亚型的APOE e4基因变异水平、AD多基因风险评分（PRS）均更高。亚型5的APOE e4基因变异携带者比例为最高。 不同亚型由MCI进展痴呆症的风险不同，亚型2、5的风险最高，亚型4的风险最低。 不同亚型的生存情况不同，亚型3患者的平均生存时间最短，为5.6年；亚型1患者的平均生存时间最长，为8.9年。 此外，磁共振成像（MRI）扫描结果显示，不同亚型的脑皮质萎缩程度。与亚型1、2、5相比，亚型2、4具有更严重的脑皮质萎缩现象。 5种亚型的MRI图像和临床结局 最后，研究者们利用来自欧洲、美国等多个不同国家的多组队列进行验证，通过脑脊液蛋白质组学鉴定其AD亚型。结果观察到，与上面的发现队列中的比例相近，27.9%的AD患者为亚型1，35.5%为亚型2，5.8%为亚型3，17.1%为亚型4，16.6%为亚型5，且特征相符。 多国大型队列中验证5种AD亚型 这些结果意味着，基于脑脊液确定患者AD亚型或有助于选择个体进行特定的治疗。例如，亚型1的患者可能受益于针对TREM2的治疗，亚型2需要先天免疫抑制剂，亚型3需要恢复RNA功能，亚型4可能从抑制单核细胞浸润中受益，而亚型5需要针对脑血管的治疗[3]。 同时，某些治疗产生的副作用也可能取决于亚型。例如在抗体治疗，虽然抗体可能更容易穿过亚型5患者的血脑屏障，但这些人发生脑出血的风险也会增加[3]。 总之，提到AD，我们总会下意识将其认定为单一一种疾病进行治疗。而这项研究不仅揭示了AD在分子层面的复杂性，也为AD的个性化医疗提供了新的视角。随着研究的深入，我们有望更好地理解AD的复杂机制，并为患者提供更有效的治疗方案。 参考文献：[1]Tijms, B.M., Vromen, E.M., Mjaavatten, O. et al. Cerebrospinal fluid proteomics in patients with Alzheimer’s disease reveals five molecular subtypes with distinct genetic risk profiles. Nat Aging (2024). https://doi-org.libproxy1.nus.edu.sg/10.1038/s43587-023-00550-7[2]Tijms BM, Gobom J, Reus L, Jansen I, Hong S, Dobricic V, Kilpert F, Ten Kate M, Barkhof F, Tsolaki M, Verhey FRJ, Popp J, Martinez-Lage P, Vandenberghe R, Lleó A, Molinuevo JL, Engelborghs S, Bertram L, Lovestone S, Streffer J, Vos S, Bos I; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Blennow K, Scheltens P, Teunissen CE, Zetterberg H, Visser PJ. Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics. Brain. 2020 Dec 1;143(12):3776-3792. doi: 10.1093/brain/awaa325本文作者丨张艾迪

REDWOOD CITY, Calif., Jan. 30, 2023 (GLOBE NEWSWIRE) -- AmMax Bio, Inc. (“AmMax”), a private clinical-stage biopharmaceutical company developing innovative therapeutics in oncology, including a next-generation antibody-drug conjugate (ADC) and a mAb targeting colony-stimulating factor 1 receptor (CSF1R), today announced that the first patients have been dosed in the Company’s Phase 2b study evaluating AMB-05X for the treatment of tenosynovial giant cell tumor (TGCT). The AmMax phase 2b trial is an open-label, adaptive, dose-ranging study to evaluate the safety, efficacy and pharmacokinetics of intra-articular administration of AMB-05X in patients with TGCT after 24 weeks of treatment and an additional long-term extension period. (ClinicalTrials.gov Identifier: NCT05349643) “The expansion of our TGCT program into this Phase 2b study builds on the strong proof-of-concept safety and efficacy data reported in 2022 which evaluated the treatment of AMB-05X in TGCT patients over a 12-week period,” said Larry Hsu, Ph.D., Chief Executive Officer of AmMax Bio. “Since announcing those results, both FDA Fast Track designation and EMA PRIME designation have been granted to AMB-05X, reflecting its significant potential to address the unmet medical need for this patient population with few treatment options. With six months of treatment, we believe patients will receive greater benefit with AMB-05X than any other pharmacological options, and we plan to use the data from this trial to finalize our Phase 3 study design.” “Encouraged by the treatment experience with AMB-05X from the earlier POC study, our patients are excited to enroll in this Phase 2b trial,” stated the principal investigators, Hans Gelderblom, M.D., Ph.D., Chair of Medical Oncology, and Michiel van de Sande, M.D., Professor of Orthopedic Oncology at the Leiden University Medical Center in the Netherlands. “With AMB-05X already demonstrating positive safety and efficacy over a 12-week treatment period, this larger Phase 2b study, with a broader enrollment scope, will assess the treatment durability of this novel, locally administered therapy over a 24-week treatment period. If successful, AMB-05X would provide TGCT patients with a much-needed alternative to immediate surgical resection and the associated complications, long recovery times, and high rates of recurrence.” About TGCT Tenosynovial Giant Cell Tumor (TGCT), with a worldwide incidence of over 300,000, is a serious and debilitating locally aggressive tumor in which patients can experience severe pain, disability, and diminished quality of life. Surgical resection, the primary standard of care for TGCT, carries significant risk to patients, including complications from infections and prolonged postoperative care, and frequent relapse. A safe and efficacious pharmacologic therapy that can be used as an alternative to surgery remains a significant unmet need. AmMax is uniquely positioned to address this need for patients with TGCT by leveraging the target selectivity and enhanced safety profile of AMB-05X via local intra-articular administration, while creating a sizable commercial opportunity from improved patient care. About AMB-05X A potent monoclonal antibody against CSF1R granted Fast Track designation by the FDA and PRIME designation by EMA for TGCT, AMB-05X represents a therapeutic platform targeting serious macrophage-driven inflammatory, fibrotic and neovascular diseases. CSF1R, via its binding to two regulatory cytokines, CSF1 and IL-34, is critically involved in the regulation of macrophages and related cells in multiple biological processes across many organ systems, making it an attractive target with broad therapeutic applications. About AmMax Bio Inc. ​AmMax is a private biotechnology company focused on leveraging our core expertise in translational science and drug development to build a clinical portfolio of first-in-class and best-in-class oncology products in areas of significant unmet medical need. The Company’s core portfolio consists of AMB-101, a novel antibody-drug conjugate (ADC) with a proprietary next generation topoisomerase 1 inhibitor-based linker-payload that is expected to enter the clinic in 2023, and AMB-05X from the Company’s CSF1R platform as a potentially best-in-class locally administered treatment for TGCT. AmMax is currently leveraging positive clinical data and an improved safety profile to advance AMB-05X in an actively enrolling Phase 2 study.

AMB-05X is the First and Only Investigational Drug Candidate to Receive PRIME Designation for the Treatment of TGCT PRIME Designation Validates Unique Therapeutic Potential of AMB-05X as Demonstrated in Prior Phase 2 Study of TGCT Initial Results from Phase 2b Trial Remains on Track for Second Half of 2023 REDWOOD CITY, Calif., Jan. 19, 2023 (GLOBE NEWSWIRE) -- AmMax Bio, Inc. (“AmMax”), a private clinical-stage biopharmaceutical company developing innovative therapeutics in oncology, including a next-generation antibody-drug conjugate (ADC) and a mAb targeting colony-stimulating factor 1 receptor (CSF1R), today announced that the European Medicine Agency (EMA) has granted AMB-05X Priority Medicines (PRIME) designation for the treatment of tenosynovial giant cell tumor (TGCT). “The positive proof-of-concept data from our prior 12-week Phase 2 study of AMB-05X in TGCT provided the basis for our PRIME application,” said Larry Hsu, Ph.D., Chief Executive Officer of AmMax Bio. “We appreciate EMA’s decision to award AMB-05X its PRIME designation, which validates the high potential therapeutic value of the program and the significant unmet medical need for patients impacted by TGCT.” In November 2022, AmMax presented positive Phase 2 data for the novel local administration of AMB-05X in patients with TGCT at the Connective Tissue Oncology Society (CTOS) meeting. The significant efficacy data across multiple clinical endpoints and a favorable safety pro the potential of AMB-05X as a best-in-class therapy for the treatment of TGCT, regardless of surgical resectability. PRIME designation was launched by the EMA to enhance support for the development of medicines that target an unmet medical need. PRIME fosters the efficient development of medicines by enhancing interaction and early dialogue with developers of promising medicines, to optimize development plans and speed up evaluation so these medicines can reach patients earlier. Through PRIME, the EMA offers early and proactive support to medicine developers to optimize the generation of robust data on a medicine's benefits and risks and enable accelerated assessment of medicines applications. This will help patients to benefit as early as possible from therapies that may significantly improve their quality of life.1 In September 2022, AMB-05X was also granted Fast Track designation by the U.S. Food and Drug Administration (FDA). 1 About TGCT Tenosynovial Giant Cell Tumor (TGCT), with a worldwide incidence of over 300,000, is a serious and debilitating locally aggressive tumor in which patients can experience severe pain, disability, and diminished quality of life. Surgical resection, the primary standard of care for TGCT, carries significant risk to patients, including complications from infections and prolonged postoperative care, and frequent relapse. A safe and efficacious pharmacological therapy that can be used alongside surgery remains a significant unmet need. AmMax is uniquely positioned to address this need for patients with TGCT by leveraging the target selectivity and enhanced safety pro AMB-05X via local intra-articular administration, while creating a sizable commercial opportunity from improved patient care. About AMB-05X A potent monoclonal antibody against CSF1R granted Fast Track designation by the FDA and PRIME designation by EMA for TGCT, AMB-05X represents a therapeutic platform targeting serious macrophage-driven inflammatory, fibrotic and neovascular diseases. CSF1R, via its binding to two regulatory cytokines, CSF1 and IL-34, is critically involved in the regulation of macrophages and related cells in multiple biological processes across many organ systems, making it an attractive target with broad therapeutic applications. About AmMax Bio Inc. ​AmMax is a private biotechnology company focused on leveraging our core expertise in translational science and drug development to build a clinical portfolio of first-in-class and best-in-class oncology products in areas of significant unmet medical need. The Company’s core portfolio is a novel antibody-drug conjugate (ADC) with a proprietary next generation topoisomerase 1 inhibitor-based linker-payload (the TMALIN platform) that is expected to enter the clinic in 2023. Additionally, the Company’s CSF1R platform includes AMB-05X, a potentially best-in-class locally administered treatment for TGCT. AmMax is currently leveraging positive clinical data and an improved safety pro advance AMB-05X in an actively enrolling Phase 2 study. For more information, please visit the company’s website at . Contact AmMax Bio, Inc. Andrew Sauter, CFO Email: andrewsauter@ammaxbio.com Tel: 650-787-3777