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）是儿童和年轻人死亡和残疾的主要原因， 慢性创伤性脑病（CTE）甚至阿尔茨海默氏症最著名的环境风险因素 疾病（AD）。尽管有巨大的公共卫生负担，但靶向TBI治疗仍然难以捉摸，超过30 TBI药物试验未能减轻TBI的破坏性短期和长期后遗症。一个假定目标 TBI后，tau蛋白磷酸化，这是CTE和AD脑的病理特征，然而， TBI的短期和长期结果中的tau相关病理学（tau病变）直到最近才被发现。 我们之前已经鉴定了一种独特的脯氨酰异构酶Pin1，其通过以下方式抑制AD中的tau蛋白病： 将tau（P-tau）中的磷酸化T231-P基序从毒性顺式异构体转化为生理性反式。 通过开发能够区分这两种异构体的抗体，我们发现顺式P-tau是 引发和传播神经变性的tau蛋白病。值得注意的是，突出的顺式P-tau定位于 弥漫性轴突在人类CTE大脑。令人惊讶的是，在单次严重或重复轻度闭头后数小时 损伤（ssCHI或rmCHI）时，神经元主要在轴突处稳健地产生顺式P-tau，这引起并 传播“cistauosis”，导致轴突病并最终导致CTE样表型。治疗ssCHI或rmCHI cis mAb小鼠不仅阻断了早期cistauosis，而且还阻止了CTE样的后期发展。 神经病理学和临床相关的脑功能障碍。我们的初步数据还表明， 在其他几种以弥漫性轴突损伤为特征的CHI模型以及人TBI中，在轴突处发现P-tau 顺式mAb阻断纯化的TBI顺式P-tau或人TBI CSF引起神经元死亡和/或 脑功能障碍其他人已经表明，tau敲除可预防rmCHl中的轴突病和记忆缺陷， 因此，靶向顺式P-tau的疗法在预防轴突损伤机制和顺式mAb中是最有效的。 弥漫性轴索损伤是脑外伤的突出特点，也是治疗的重点。 我们已经组建了一个多学科团队来开发治疗性顺式mAb，以治疗或预防 TBI后的短期和长期后遗症。首先，我们将人源化我们的鼠顺式mAb，并使用独特的 我们已经开发了用于鉴定具有高亲和力、特异性和特异性的人源化顺式mAb的模型和试剂， 和抗顺式P-tau和cistauosis的效力，以及作为治疗性抗体的物理化学性质。 接下来，我们将确定其PK/PD、疗效、毒理学和安全性特征，以选择前3种人源化mAb 候选物，然后在ssCHI和rmCHI中进行其功效评价，这两种CHI小鼠模型的弥漫性轴突损伤 损伤和控制性皮质撞击（CCI），严重局灶性损伤之一，以评估TBI病理解剖亚型 最适合顺式mAb治疗。最后，我们将评估CSF cis P-tau作为治疗诊断剂的有效性。 生物标记物。其结果将是针对早期疾病驱动因素的独特靶向治疗的发展 cis P-tau用于减轻TBI的短期和长期后遗症，具有重大健康影响的潜力。

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