作者: Bottelbergs, Astrid ; Rodrigues Martins, Dina ; Brepoels, Eddy ; Vandermeeren, Marc ; Van Kolen, Kristof ; Borgers, Marianne ; Theunis, Clara ; Mercken, Marc ; Delay, Charlotte ; Mirabelli, Peppino ; Wintmolders, Cindy

BACKGROUND:

Clearance of tau seeds by immunization with tau antibodies is currently evaluated as therapeutic strategy to block the spreading of tau pathology in Alzheimer's disease and other tauopathies. Preclinical evaluation of passive immunotherapy is performed in different cellular culture systems and in wild-type and human tau transgenic mouse models. Depending on the preclinical model used, tau seeds or induced aggregates can either be of mouse, human or mixed origin.

OBJECTIVE:

We aimed to develop human and mouse tau-specific antibodies to discriminate between the endogenous tau and the introduced form in preclinical models.

METHODS:

Using hybridoma technology, we developed human and mouse tau-specific antibodies that were then used to develop several assays to specifically detect mouse tau.

RESULTS:

Four antibodies, mTau3, mTau5, mTau8, and mTau9, with a high degree of specificity for mouse tau were identified. Additionally, their potential application in highly sensitive immunoassays to measure tau in mouse brain homogenate and cerebrospinal fluid is illustrated, as well as their application for specific endogenous mouse tau aggregation detection.

CONCLUSION:

The antibodies reported here can be very important tools to better interpret the results obtained from different model systems as well as to study the role of endogenous tau in tau aggregation and pathology observed in the diverse mouse models available.

2022-06-01·Seminars in cell & developmental biology2区 · 生物学

Targeting tau only extracellularly is likely to be less efficacious than targeting it both intra- and extracellularly

2区 · 生物学

Review

作者: Congdon, Erin E ; Jiang, Yixiang ; Sigurdsson, Einar M

Aggregation of the tau protein is thought to be responsible for the neurodegeneration and subsequent functional impairments in diseases that are collectively named tauopathies. Alzheimer's disease is the most common tauopathy, but the group consists of over 20 different diseases, many of which have tau pathology as their primary feature. The development of tau therapies has mainly focused on preventing the formation of and/or clearing these aggregates. Of these, immunotherapies that aim to either elicit endogenous tau antibodies or deliver exogenous ones are the most common approach in clinical trials. While their mechanism of action can involve several pathways, both extra- and intracellular, pharmaceutical companies have primarily focused on antibody-mediated clearance of extracellular tau. As we have pointed out over the years, this is rather surprising because it is well known that most of pathological tau protein is found intracellularly. It has been repeatedly shown by several groups over the past decades that antibodies can enter neurons and that their cellular uptake can be enhanced by various means, particularly by altering their charge. Here, we will briefly describe the potential extra- and intracellular mechanisms involved in antibody-mediated clearance of tau pathology, discuss these in the context of recent failures of some of the tau antibody trials, and finally provide a brief overview of how the intracellular efficacy of tau antibodies can potentially be further improved by certain modifications that aim to enhance tau clearance via specific intracellular degradation pathways.

2022-01-01·Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics2区 · 医学

The Current Landscape of Prevention Trials in Dementia

2区 · 医学

Review

作者: Lee, Jonathan ; Howard, Rebecca Sitra ; Schneider, Lon S

As the prevalence of dementia and Alzheimer's disease (AD) increases worldwide, it is imperative to reflect on the major clinical trials in the prevention of dementia and the challenges that surround them. The pharmaceutical industry has focused on developing drugs that primarily affect the Aβ cascade and tau proteinopathy, while academics have focused on repurposed therapeutics and multi-domain interventions for prevention studies. This paper highlights significant primary, secondary, and tertiary prevention trials for dementia and AD, overall design, methods, and systematic issues to better understand the current landscape of prevention trials. We included 32 pharmacologic intervention trials and 9 multi-domain trials. Fourteen could be considered primary prevention, and 18 secondary or tertiary prevention trials. Major categories were Aβ vaccines, Aβ antibodies, tau antibodies, anti-inflammatories, sex hormones, and Ginkgo biloba extract. The 9 multi-domain studies mainly focused on lifestyle modifications such as blood pressure management, socialization, and physical activity. The lack of validated drug targets, and the complexity of the diagnostic frameworks, eligibility criteria, and outcome measurements for trials, make it difficult to show efficacy for both pharmacological and multi-domain interventions. We hope that this summative analysis of trials will stimulate discussion for scientists and clinicians interested in reviewing and developing preventative interventions for AD.

项与 APN-1808 相关的新闻（医药）

2023-10-25

·NS Medical Devices

Lucent rolls out p-Tau 217 blood-based biomarker test for Alzheimer’s disease

The LucentAD p-Tau 217 test leverages a combination of Quanterix’ Simoa technology and J&J Innovative Medicine’s p-Tau 217 antibodies to provide high accuracy with a simplified workflow and expands Lucent’s LucentAD portfolio of products The new blood-based test expands Lucent’s LucentAD portfolio. (Credit: Annett_Klingner from Pixabay) Lucent Diagnostics, a brand of Quanterix, has introduced LucentAD p-Tau 217, its new high-accuracy p-Tau 217 blood test to detect Alzheimer’s disease (AD). The test expands Lucent’s LucentAD portfolio and advances the scalable immunoassay-based blood biomarker tests for evaluating amyloid pathology in people with memory complaints. Recently, Quanterix signed a licence agreement with Johnson & Johnson (J&J)’s subsidiary Janssen Sciences Ireland UC, to advance the blood-based testing of AD. Quanterix has obtained non-exclusive rights to J&J’s p-Tau 217 antibodies and assay designs for potential use in clinical research and diagnostic products. The LucentAD p-Tau 217 test leverages a combination of Quanterix’ Simoa technology and J&J Innovative Medicine’s p-Tau 217 antibodies to provide high accuracy with a simplified workflow. Quanterix CEO Masoud Toloue said: “The launch of LucentAD p-Tau 217 is an important milestone in our efforts to build broad-based non-invasive testing for amyloid pathology. “We believe that Simoa technology offers the world’s only full-range scalable clinical solution, overcoming the complexities and limitations of less sensitive single-plexed analog immunoassay platforms that struggle to measure this important biomarker. “We will make this test available worldwide to all, in our pursuit of improving access to life-changing diagnostics and treatments for the millions of individuals and their families living with Alzheimer’s disease.” According to the company, p-Tau 217 has emerged as a top biomarker for assessing Alzheimer’s pathology, with clinical sensitivity and specificity. Traditional methods such as positron emission tomography (PET) or lumbar puncture for cerebrospinal fluid (CSF) biomarkers are expensive, invasive, and not widely available. Its LucentAD p-Tau 217 blood test can speed up the diagnosis and expand access to treatments for individuals with early Alzheimer’s disease, said Lucent. The company said that the test has been validated in a clinical trial cohort comprising more than 500 subjects with subjective cognitive decline, mild cognitive impairment, and early AD. When compared to the amyloid status determined by CSF biomarker testing, the LucentAD p-Tau 217 test achieved an overall accuracy of more than 90%, said the diagnostics company.

临床结果引进/卖出诊断试剂

2023-10-23

·BioSpace

Quanterix Announces New Agreement to Advance Blood Based Alzheimer's Disease Detection

Agreement provides Quanterix a license to extensively studied p-Tau 217 antibodies to enable global access to plasma-based testing for Alzheimer’s Disease research and diagnostics BILLERICA, Mass.--(BUSINESS WIRE)-- Quanterix Corporation (NASDAQ: QTRX), a leading provider of ultra-sensitive research products and high-definition diagnostics, today announced the signing of a license agreement with Janssen Sciences Ireland UC (Janssen), a Johnson & Johnson (J&J) Company. Under this agreement, Quanterix will receive worldwide, non-exclusive rights to J&J’s extensively studied p-Tau 217 antibodies and assay designs for potential use in clinical research and diagnostic products, further strengthening Quanterix’s position at the forefront of the Alzheimer's Disease (AD) biomarker field. Under the terms of the license agreement, Janssen will grant Quanterix a worldwide non-exclusive license for J&J-developed technology to produce Simoa p-Tau 217 research-use only (RUO) assay kits for global distribution. Furthermore, under the agreement Quanterix will launch a Laboratory Developed Test (LDT) based on the J&J p-Tau 217 antibodies and assay, offered through Accelerator under the Lucent Diagnostics brand. These advances mark a significant milestone for Quanterix's continued leadership in advancing Alzheimer's Disease diagnosis and treatment, providing a path for the first scalable immunoassay-based p-Tau 217 test to potentially become widely available to researchers and clinicians. p-Tau 217 has emerged as a top performing biomarker for AD, enabling clinical sensitivity and specificity in blood1. Highly sensitive and specific blood-based biomarker tests may improve diagnosis by expanding access to treatments for millions of individuals with early Alzheimer’s Disease, which is currently detected using positron emission tomography (PET) or lumbar puncture for CSF biomarkers. These methods are expensive, lack wide availability, and are invasive. There is growing consensus that high performing blood-based biomarker tests may be an appropriate alternative for patient care. "This collaboration demonstrates the scientific advances that are possible when Simoa’s ultra-sensitive detection is combined with clinically validated antibodies and critical reagents,” said Masoud Toloue, CEO of Quanterix. “Providing access to high-performing blood-based p-Tau 217 assays are an important step as we work with several partners to build the global infrastructure for non-invasive testing of Alzheimer’s Disease.” For more information about Quanterix’s work in neurology, visit: . About Quanterix From discovery to diagnostics, Quanterix’s ultrasensitive biomarker detection is fueling breakthroughs only made possible through its unparalleled sensitivity and flexibility. The Company’s Simoa® technology has delivered the gold standard for earlier biomarker detection in blood, serum or plasma, with the ability to quantify proteins that are far lower than the Limit of Quantification (LoQ) of conventional analog methods. Its industry-leading precision instruments, digital immunoassay technology and CLIA-certified Accelerator laboratory have supported research that advances disease understanding and management in neurology, oncology, immunology, cardiology and infectious disease. Quanterix has been a trusted partner of the scientific community for nearly two decades, powering research published in more than 2,000 peer-reviewed journals. Find additional information about the Billerica, Massachusetts-based company at or follow us on Twitter and LinkedIn. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as “may,” “will,” “expect,” “plan,” “anticipate,” “estimate,” “intend” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. Forward-looking statements in this news release are based on Quanterix’s expectations and assumptions as of the date of this press release. Each of these forward-looking statements involves risks and uncertainties. Factors that may cause Quanterix’s actual results to differ from those expressed or implied in the forward-looking statements in this press release are discussed in Quanterix’s filings with the U.S. Securities and Exchange Commission, including the “Risk Factors” sections contained therein. Except as required by law, Quanterix assumes no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available. 1Brum WS, Cullen NC, Janelidze S, et al. A two-step workflow based on plasma p-tau217 to screen for amyloid β positivity with further confirmatory testing only in uncertain cases. Nat Aging. 2023;3(9):1079-1090

引进/卖出诊断试剂

2023-09-07

·生物谷

《自然·衰老》：两步法搞定AD筛查！以血检为基础，大幅度简化流程

瑞典哥德堡大学的Wagner S.Brum和隆德大学的Oskar Hansson等人成功开发一种血液检测方法，瑞典哥德堡大学的Wagner S.Brum和隆德大学的Oskar Hansson等人成功开发一种血液检测方法，通过p-tau217血液水平来评估轻度认知障碍（MCI）患者大脑中的Aβ状态，划分为低、中、高风险人群，其中只有中风险组的Aβ阳性结果需要接受进一步的CSF检测。这种基于p-tau217血液水平的检测方法，准确度可高达92.0%，并帮助61.2%-85.9%的MCI患者避免不必要的CSF检测。文章于近日发表在《自然·衰老》期刊上。论文首页截图近年来，抗β淀粉样蛋白（Aβ）单抗aducanumab、lecanemab获得FDA批准，为阿尔茨海默病（AD）治疗领域带来万众瞩目的突破。这些药物通过清除脑内的Aβ斑块，能够减缓早期AD的疾病进展。与此同时，如何诊断AD患者、识别Aβ病理阳性的AD前驱期患者，成为迫切需要解决的难题，以帮助患者尽早采取治疗手段缓解AD病程。在这项研究中，研究者们开发的血液检测方式，共分为两步来进行。首先，利用构建的数学模型对p-tau217血液水平和已知的两项Aβ阳性预测因子（年龄、APOE e4基因表达情况）进行分析，从而预测轻度认知障碍（MCI）患者的Aβ阳性风险。根据预测结果，该模型将MCI患者进行分层，分为低、中、高风险组。其中，中风险组患者的Aβ状态需要接受第二步来确认，即基于CSF中的Aβ42/Aβ40比值进行评估。其余两组患者则可直接根据第一步中的Aβ状态采取相应的临床决策。高风险MCI患者接受进一步的AD临床诊断或抗Aβ抗体治疗，低风险MCI患者继续排查其它类型的神经退行性疾病或接受心理学评估。基于p-tau217的血液检测来筛查AD高危人群的设计流程在设计和验证用于分析p-tau217血液水平的数学模型时，研究者们利用了两组独立的MCI患者队列研究数据（N=348）。另外，他们在该数学模型中设置了低（90%）、中（95%）、高（97.5%）三种阈值的灵敏度/特异性来评估患者的风险分层，以避免漏检Aβ阳性患者或将Aβ阴性患者分类为“高风险”。验证结果显示，该数学模型性能较高，AUC为94.3%（95%CI，91.2-97.4%）。从总体流程来看，按照第一步中数学模型所设置的灵敏度/特异性阈值由低到高，这种基于p-tau217血液检测的AD检测方法，准确度达到88.2%、90.5%、92.0%，并将需要接受CSF检测的MCI患者数量降低85.9%、72.7%、61.2%；假阴性率为18.0%、11.0%、6.6%，假阳性值为7.8%、4.8%、2.3%。研究者们还在第三组患者队列中进行评估（N=84），结果与之相似。 p-tau217血液检测方法的性能总而言之，这项研究结果表明，p-tau217血液检测用于AD筛查，经济且有效。在保证高准确度的情况下，能够帮助患者避免复杂的CSF或PET检查，极大地降低医疗负担。

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适应症	最高研发状态	国家/地区	公司	日期
阿尔茨海默症	临床前	中国台湾	新旭生技股份有限公司初创企业	-
额颞痴呆	临床前	中国台湾	新旭生技股份有限公司初创企业	-
进行性核上性麻痹	临床前	中国台湾	新旭生技股份有限公司初创企业	-