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.

创伤性脑损伤是导致儿童和年轻人死亡和残疾的主要原因之一。 慢性创伤性脑病(CTE)甚至阿尔茨海默氏症最常见的环境危险因素 疾病(AD)。尽管公共卫生负担巨大，但有针对性的脑损伤疗法仍然难以捉摸，超过30 脑损伤药物试验未能减轻脑损伤的破坏性短期和长期后遗症。一个假定的目标 在脑损伤后，tau被磷酸化，这是CTE和AD脑的一个决定性的病理特征，然而， 颅脑损伤的短期和长期结局中与tau相关的病理(tau病)直到最近才为人所知。 我们之前已经确定了一种独特的Pro异构酶Pin1，它通过以下方式抑制AD的转位性病变 将tau(P-tau)中的磷酸化T231-P基序从有毒的顺式异构体转化为生理反式。通过 发展能够区分这两种异构体的抗体，我们发现顺式P-tau是 引发和传播神经退化的变态反应。值得注意的是，突出的顺P-tau被本地化到 轴突广泛分布于人的CTE脑内。令人惊讶的是，在单次重度或重复轻度封闭性头部数小时后 在小鼠的损伤(ssCHI或rmCHI)中，神经元主要在轴突强烈地产生顺式P-tau，这导致和 传播“脊椎病”，导致轴索病变，并最终表现为CTE样表型。治疗ssCHI或rmCHI 使用顺式单抗的小鼠不仅可以阻止早期的囊虫病，还可以阻止后期的CTE样病变的发展。 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，稳健的顺位 在其他几个以弥漫性轴突损伤为特征的CHI模型中，以及在人类脑外伤中，P-tau在轴突中被发现。 并且该顺式单抗可阻断纯化的脑损伤顺式P-tau或人脑损伤后脑脊液引起神经元死亡和/或 大脑功能障碍。其他研究表明，tau基因敲除可以预防rmCHI中的轴突病变和记忆缺陷， 因此，针对cis P-tau的治疗在预防轴突损伤机制和cis mAb方面是最有效的。 治疗是弥漫性轴索损伤的一种新的靶向治疗方法，是颅脑损伤的一个显著特点和治疗重点。 我们已经组建了一个多学科的团队来开发治疗性的顺式单抗来治疗或预防 颅脑损伤后的短期和长期后遗症。首先，我们将人源化我们的小鼠顺式单抗，并使用唯一的 我们开发的用于鉴定具有高亲和力、特异性的人源化顺式单抗的模型和试剂 以及对顺式P-tau和囊虫病的效力，以及作为治疗性抗体的理化性质。 接下来，我们将对它们的PK/PD、疗效、毒理学和安全性进行测定，以选出排名前3位的人源化mAb 候选，然后评估他们在ssCHI和rmCHI，两个弥漫性轴突模型CHI小鼠中的疗效 损伤和受控皮质撞击(CCI)是一种严重的局灶性损伤，用于评估颅脑损伤的病理解剖亚型 顺式单抗治疗效果最好。最后，我们将评估脑脊液顺式P-tau作为治疗药物的疗效。 生物标志物。其结果将是针对早期疾病驱动因素开发独特的靶向治疗 顺铂用于减轻脑损伤的短期和长期后遗症，有可能对健康产生重大影响。

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