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Brain-cell penetrating antibodies for treatment of progressive multiple sclerosis

用于治疗进行性多发性硬化症的脑细胞穿透抗体

基本信息

批准号：
10322911
负责人：
Hiep T Tran
金额：
$ 39.91万
依托单位：
ABZYME THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322911
关键词：
Acute Adult Age Agonist Agreement Amino Acids Animal Model Animals Antibodies Antibody Therapy Bacterial Infections Binding Biological Biological Assay Bispecific Antibodies Blood Blood - brain barrier anatomy Brain Brain Injuries Brain-Derived Neurotrophic Factor C-terminal Catalytic Antibodies Cell Culture Techniques Cells Central Nervous System Diseases Chronic Clinical Collaborations Complement Complement 1q Complement Activation Complement Inactivators Data Demyelinating Diseases Development Disease Disease Outcome Disease model Dose Drug Delivery Systems Engineering Event Exhibits Eye diseases Foundations Goals Growth Growth Factor Hemolysis Human In Vitro Individual Infection Inflammatory Injury Intraperitoneal Injections Japanese Population Measures Molecular Monitor Multiple Sclerosis Mus N-terminal Nerve Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurotrophic Tyrosine Kinase Receptor Type 2 Ophthalmology Outcome Pathologic Pathology Patients Peptides Pharmacologic Substance Phase Play Positioning Attribute Production Proteins Protocols documentation Rabies virus Receptor Protein-Tyrosine Kinases Recovery Reporter Rodent Model Role Signal Transduction Synaptic plasticity TMEV Testing Therapeutic Therapeutic antibodies Thrombotic Thrombocytopenic Purpura Tissues Toxicology Treatment Efficacy Validation Variant Virus Diseases base behavioral study blood-brain barrier crossing blood-brain barrier penetration blood-brain barrier permeabilization brain cell complement pathway complement system disability effectiveness testing experimental study good laboratory practice humanized antibody improved in vivo medical schools mouse model murine antibody nanobodies neurogenesis neuroinflammation neuron loss neuronal survival neurotropic nonhuman primate pharmacokinetics and pharmacodynamics prevent response sex synaptic pruning treatment effect treatment planning

项目摘要

Abstract. Central Nervous System (CNS) physical injuries, including bacterial or viral infection, can induce chronic neuroinflammation that is believed to persist for the lifetime of an individual. Among the other inflammatory events, it is recognized that both acute and chronic activation of the complement pathway plays a role in the development of secondary brain injuries by inducing neuronal cell loss and synaptic pruning. Complement over-activation is also firmly implicated in the pathology that underlies the irreversible progression of multiple sclerosis (MS), a common inflammatory and neurodegenerative disease of the CNS. We hypothesize that therapeutic inhibition of the complement system and concurrent stimulation of nerve growth may prevent CNS tissue damage and slow or even block the progression of MS. Currently, the main obstacle for drug delivery to the CNS is the presence of a selectively permeable blood-brain barrier (BBB), limiting blood-borne proteins' entryinto the CNS. To overcome this issue, we have recently developed several potent camelid-derived nanobodies. The first group of nanobodies can inhibit complement activation, whereas the second group comprises tyrosine kinase receptor TrkB agonists that mimic the action of brain-derived neurotrophic factor (BDNF), a growth factor in the brain that promotes neuronal survival, synaptic plasticity and neurogenesis. Here, we propose to engineer these nanobodies further to facilitate their crossing of the BBB, thereby gaining the ability to more effectively inhibit the complement cascade and/or stimulate nerve growth within the CNS. During phase I, bispecific nanobodies will be produced and validated in in vitro cellular functional assays. Therapeutic efficacy will be further validated in a well-characterized murine model of progressive MS, the Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). To this end, mice will be treated with control nanobodies, a complement inhibitor nanobody, TrkB agonistic nanobody, or a combination of the latter two. Once therapeutic efficacy is confirmed in TMEV-IDD, the camelid-derived nanobodies will be humanized to reduce antigenicity in humans. Statistically significant improvement in treated mice monitored as an impact on disability progression and CNS pathology will be the foundation for a phase II submission. The goals of phase II are 1) revalidate the therapeutic efficacy of humanized antibodies in more extensive experiments, including a detailed analysis of the effect of sex, age, dose-ranges and delayed treatments, i.e., later than 30 days post-infection, on disability progression, disease pathology and recovery; 2) to establish manufacturing protocols under current Good Manufacturing Practice conditions and; 3) to define the biological response, PK/PD, dose-ranging and toxicology in multiple model animals, including toxicology studies in non-human primates.

抽象的。中枢神经系统 (CNS) 身体损伤，包括细菌或病毒感染，可诱发据信，慢性神经炎症会持续一个人的一生。其中炎症事件中，人们认识到补体途径的急性和慢性激活都起着重要作用通过诱导神经元细胞丢失和突触修剪在继发性脑损伤的发展中发挥作用。补体过度激活也与不可逆进展的病理学密切相关多发性硬化症（MS）是一种常见的中枢神经系统炎症和神经退行性疾病。我们假设补体系统的治疗性抑制和同时刺激神经生长可能会阻止中枢神经系统组织损伤可减缓甚至阻止多发性硬化症的进展。目前，药物输送到中枢神经系统的主要障碍是选择性渗透血脑的存在屏障（BBB），限制血源性蛋白质进入中枢神经系统。为了解决这个问题，我们最近开发了几种有效的骆驼源纳米抗体。第一组纳米抗体可以抑制补体激活，而第二组包含酪氨酸激酶受体 TrkB 激动剂，模仿脑源性神经营养因子（BDNF），一种大脑中促进神经元存活、突触的生长因子可塑性和神经发生。在这里，我们建议进一步设计这些纳米抗体以促进它们的交叉血脑屏障，从而获得更有效地抑制补体级联和/或刺激神经的能力中枢神经系统内的生长。在第一阶段，将生产双特异性纳米抗体并在体外细胞功能测定中进行验证。治疗效果将在经过充分表征的进行性多发性硬化症小鼠模型中得到进一步验证，泰勒氏鼠脑脊髓炎病毒引起的脱髓鞘病（TMEV-IDD）。为此，小鼠将用对照纳米抗体、补体抑制剂纳米抗体、TrkB激动性纳米抗体或组合处理后两者中。一旦TMEV-IDD的治疗效果得到证实，源自骆驼的纳米抗体将被用于人源化以降低人类的抗原性。监测到治疗小鼠对残疾进展和中枢神经系统的影响具有统计学意义的显着改善病理学将成为第二阶段提交的基础。第二阶段的目标是 1) 重新验证治疗人源化抗体在更广泛的实验中的功效，包括对效果的详细分析性别、年龄、剂量范围和延迟治疗，即感染后 30 天后，关于残疾进展的情况，疾病病理学和康复； 2) 在现行良好制造条件下建立制造协议实习条件和； 3) 定义多种药物的生物反应、PK/PD、剂量范围和毒理学模型动物，包括非人类灵长类动物的毒理学研究。