Development of Therapeutic Antibody for Traumatic Brain Injury

脑外伤治疗性抗体的开发

• 批准号: 9942525
• 负责人: Mark L. Zeidel
• 金额: $ 129.27万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9942525
• 关键词: Acute; Affinity; Alzheimer' s Disease; Alzheimer' s disease brain; Animals; Antibodies; Antibody Therapy; Antigens; Axon; Biological Markers; Brain; Brain Injuries; Cause of Death; Child; Clinical Trials; Closed head injuries; Data; Development; Diffuse; Diffuse Axonal Injury; Disease; Dose; Environmental Risk Factor; Exposure to; Frequencies; Health; Hour; Human; IgG4; Immunotherapy; In Vitro; Injections; Injury; Isomerism; Kinetics; Knock-out; Lead; Life; Memory impairment; Microtubules; Mitochondria; Modeling; Molecular Conformation; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Outcome; Pathologic; Pathology; Patients; Peptidylprolyl Isomerase; Pharmaceutical Preparations; Phenotype; Physiological; Process; Property; Public Health; Reagent; Role; Safety; Severities; Specificity; Stress; TBI treatment; Tauopathies; Testing; Therapeutic; Therapeutic antibodies; Toxic effect; Toxicology; Traumatic Brain Injury; Variant; axon injury; axonopathy; brain dysfunction; cerebral atrophy; chronic traumatic encephalopathy; clinically relevant; controlled cortical impact; de-immunization; disability; efficacy evaluation; efficacy study; functional outcomes; human monoclonal antibodies; immunogenicity; in vivo; mouse model; multidisciplinary; neuron loss; neuropathology; neurotoxicity; new therapeutic target; pharmacokinetics and pharmacodynamics; prevent; safety assessment; targeted treatment; tau Proteins; tau-1; theranostics; therapeutic development; young adult

Traumatic brain injury (TBI) is a leading cause of death and disability in children and young adults and one of the best-known environmental risk factors for chronic traumatic encephalopathy (CTE) and even Alzheimer's disease (AD). Despite the immense public health burden, targeted TBI therapies remain elusive and over 30 TBI drug trials have failed to mitigate the devastating short- and long-term sequelae of TBI. One putative target after TBI is phosphorylated tau, a defining pathological signature of CTE and AD brains, however, the role of tau-related pathology (tauopathy) in short and long term outcomes of TBI was unknown until lately. We have previously identified a unique prolyl isomerase, Pin1 that inhibits tauopathy in AD by converting the phosphorylated T231-P motif in tau (P-tau) from the toxic cis isomer to the physiologic trans. By developing the antibodies capable of distinguishing these two isomers, we find that cis P-tau is a precursor of tauopathy that instigates and propagates neurodegeneration. Notably, prominent cis P-tau is localized to axons diffusely in human CTE brains. Surprisingly, hours after single severe or repetitive mild closed head injury (ssCHI or rmCHI) in mice, neurons robustly produce cis P-tau mainly at axons, which causes and spreads “cistauosis”, leading to axonopathy and eventually CTE-like phenotypes. Treating ssCHI or rmCHI mice with cis mAb not only blocks early cistauosis, but also prevents the later development of CTE-like neuropathology and clinically relevant brain dysfunction. Our preliminary data also demonstrate that robust cis P-tau is found at axons in several other CHI models that feature diffuse axon injury, as well as in human TBI brains, and that cis mAb blocked purified TBI cis P-tau or human TBI CSF from causing neuron death and/or brain dysfunction. Others have shown that tau knockout prevents axonopathy and memory deficits in rmCHI, Thus, therapies targeting cis P-tau are most effective in preventing axonal injury mechanisms and cis mAb therapy is a new targeted therapy for diffuse axon injury, a prominent feature and a therapeutic focus in TBI. We have assembled a multidisciplinary team to develop therapeutic cis mAb to treat or prevent short- and long-term sequelae after TBI. First, we will humanize our murine cis mAb and use the unique models and reagents that we have developed to identify humanized cis mAbs that have high affinity, specificity and potency against cis P-tau and cistauosis, and the physicochemical properties as a therapeutic antibody. Next, we will determine their PK/PD, efficacy, toxicology and safety profiles to select top 3 humanized mAb candidates, followed by their efficacy evaluation in ssCHI and rmCHI, two CHI mouse models of diffuse axon injury, and controlled cortical impact (CCI), one of severe focal injury, to assess TBI pathoanatomic subtypes best amenable to cis mAb therapy. Finally, we will evaluate efficacy of CSF cis P-tau as a theranostic biomarker. The outcome will be the development of unique targeted therapy against the early disease driver cis P-tau for mitigating the short- and long-term sequelae of TBI, with the potential to have major health impact.

创伤性脑损伤（TBI）是儿童和年轻人的死亡和残疾的主要原因，其中之一 慢性创伤性脑病（CTE）甚至阿尔茨海默氏病的最著名的环境风险因素 疾病（AD）。尽管伯恩（Burnen）拥有巨大的公共卫生，但有针对性的TBI疗法仍然难以捉摸，超过30种 TBI药物试验未能减轻TBI的毁灭性短期和长期后遗症。一个推定的目标 TBI被磷酸化tau后，CTE和AD大脑的定义病理学特征，但是， TBI的短期和长期结局与TAU相关的病理学（Taupathy）直到最近才知道。 我们以前已经确定了独特的丙酸异构酶，PIN1，该异构酶抑制AD中的tauopathy 将tau（p-tau）中的磷酸化的T231-P基序从有毒的顺式异构体转换为生理trans。经过 开发能够区分这两个异构体的抗体，我们发现顺式p-tau是 刺激和传播神经退行性的陶氏病。值得注意的是，突出的顺式p-tau本地化为 轴突在人体CTE大脑中扩散。令人惊讶的是，在一次严重或重复的轻度闭合头几小时后 在小鼠中损伤（sschi或rmchi），神经元可鲁棒地产生顺式p-tau，主要是在轴突处，这会引起和 传播“ Cistauisis”，导致轴突病，最终导致CTE样表型。治疗sschi或rmchi 带有顺式mAb的小鼠不仅阻止早期的cistauisis，而且还阻止了CTE样的后期发展 神经病理学和临床相关的大脑功能障碍。我们的初步数据还表明了鲁棒的顺式 在其他几种具有分散轴突损伤以及人类TBI中的CHI模型中发现了P-TAU 大脑，顺式mab阻塞了纯化的TBI tbi cis p-tau或人类TBI CSF导致神经元死亡和/或 脑功能障碍。其他人则表明，tau敲除可以防止轴突病，并且记忆在rmchi中定义， 靶向顺式P-TAU的疗法在防止轴突损伤机制和顺式mAB方面最有效 治疗是一种针对弥漫性轴突损伤的新靶向疗法，在TBI中是突出特征和治疗焦点。 我们已经组建了一个多学科团队，以开发治疗性的顺式mAB来治疗或预防 TBI后短期和长期后遗症。首先，我们将人性化我们的鼠顺式mab并使用独特 我们开发的模型和试剂旨在识别具有高亲和力的人性化顺式mAB 以及针对顺式p-tau和cistauisis的效力，以及作为治疗抗体的物理特性。 下一 候选人，然后在SSCHI和RMCHI中进行效率评估，这是两个弥漫性轴突的CHI鼠标模型 损伤和受控皮质冲击（CCI）是严重局灶性损伤之一，以评估TBI病原体亚型 最好适合顺式mAb疗法。最后，我们将评估CSF顺式P-TAU作为Theranotic的有效性 生物标志物。结果将是开发针对早期疾病驱动因素的独特靶向疗法 顺式p-tau用于减轻TBI的短期和长期后遗症，并有可能产生重大健康影响。

项目成果

Decompressive Hemicraniectomy for Stroke in Older Adults: A Review.

• DOI: 10.29245/2572.942x/2017/2.942x/2017/1.1103
• 发表时间: 2017-01-01
• 期刊: Journal of neurology & neuromedicine
• 作者: Robertson, Faith C;Dasenbrock, Hormuzdiyar H;Gormley, William B
• 通讯作者: Gormley, William B

Short-Term Neurologic Manifestations of Repetitive Head Impacts Among Athletes: A Scoping Review.

运动员重复头部撞击的短期神经表现：范围界定审查。

• DOI: 10.1097/htr.0000000000000767
• 发表时间: 2022
• 期刊: The Journal of head trauma rehabilitation
• 作者: Stephen,SteveJ;Hasman,Linda;Goldenberg,May;Merchant-Borna,Kian;Kawata,Keisuke;Mannix,Rebekah;Bazarian,JeffreyJ
• 通讯作者: Bazarian,JeffreyJ