Safety and Tolerability Studies for an Anti-Fibrin P2 Monoclonal Antibody for the Treatment of Alzheimer's Disease

抗纤维蛋白 P2 单克隆抗体治疗阿尔茨海默病的安全性和耐受性研究

• 批准号: 10693372
• 负责人: Aaron B Kantor
• 金额: $ 96.63万
• 依托单位: THERINI BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10693372
• 关键词: AD transgenic mice; Address; Adverse effects; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Amino Acids; Amyloid; Amyloid beta-Protein; Animal Model; Antibodies; Antibody Therapy; Automobile Driving; Binding; Biological Assay; Blocking Antibodies; Blood - brain barrier anatomy; Blood Preservation; Blood Proteins; Blood Vessels; Blood coagulation; Brain; Cells; Cerebral Amyloid Angiopathy; Cerebrovascular system; Characteristics; Chemicals; Chronic; Clinical Trials; Coagulation Process; Cognition; Dementia; Deposition; Deterioration; Development; Disease; Disease Progression; Dose; Drug Kinetics; Elderly; Encephalomyelitis; Epitopes; Event; Extravasation; Face; Fibrin; Fibrinogen; Genetic; Health; Hemorrhage; Hemostatic function; Human; ITGAM gene; ITGB2 gene; Image; Immune; Impaired cognition; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Lead; Ligands; Longitudinal Studies; Macrophage; Macrophage-1 Antigen; Mediating; Microglia; Modeling; Molecular; Monitor; Monoclonal Antibodies; Mus; Neurodegenerative Disorders; Neurons; No-Observed-Adverse-Effect Level; Oxidative Stress; Pathology; Patients; Persons; Phase I Clinical Trials; Phase II Clinical Trials; Play; Preparation; Recovery; Regimen; Risk; Rodent; Role; Safety; Senile Plaques; Source; Testing; Tg2576; Therapeutic; Therapeutic Intervention; Toxic effect; Vascular Dementia; Vascular Diseases; brain parenchyma; cerebral atrophy; cerebral microbleeds; cytokine; economic impact; glial activation; immunogenicity; in vivo; intravenous administration; long term recovery; migration; mouse model; neuroinflammation; neuron loss; nonhuman primate; novel; novel therapeutic intervention; novel therapeutics; patient subsets; pre-clinical; preclinical development; preclinical safety; rational design; receptor; research clinical testing; safety assessment; safety study; safety testing; therapeutic target; transgenic model of alzheimer disease; translational approach; β-amyloid burden

ABSTRACT Neuroinflammation is a significant driver of pathology in Alzheimer’s disease (AD) and Alzheimer’s disease related dementia (ADRD). Multiple lines of evidence in patients and in animal models of AD/ADRD point to vascular dysregulation and deposits of fibrin (FN) in the brain and cerebral blood vessels as significant sources of this inflammation. In AD/ADRD patients localized BBB breakdown is an early event and increases with disease progression. Vascular breakdown leads to the extravasation of blood proteins, including fibrinogen (FGN), into the brain and the formation of FN clots in brain parenchyma and cerebral vasculature coincident with Aβ plaques and inflammatory immune cells. In the conversion of FGN to FN a cryptic epitope is exposed on the FN  chain This sequence (Fibγ377-395, also known as FN P2) is a ligand for the CD11b/CD18 receptor on macrophages and microglia, triggering activation of these innate immune cells and secretion of inflammatory mediators. Genetic or chemical depletion of FGN or genetic substitution of 6 key amino acids within FN P2 in the 5xFAD mouse model of AD considerably reduces their level of inflammatory cytokines and the rate of cognitive decline. A mouse monoclonal antibody (mAb), 5B8, discovered by Dr. Katerina Akassoglou (founder of Therini Bio Inc.) binds this cryptic epitope and recapitulates the activity of the genetic FN P2 deletion. 5B8 is highly selective for FN over FGN and does not interfere with normal coagulation. Therini Bio Inc. has humanized 5B8 and demonstrated that the lead humanized anti-FN P2 mAb, termed THN227, retains the selective binding for FN over FGN and does not interfere with normal FN-mediated functions such as hemostasis. In an in vivo fibrino(gen)-induced encephalomyelitis model of neuroinflammation, intravenous administration of THN227 reduced microglial activation, macrophage infiltration, and oxidative stress. In this proposal the lead humanized anti-FN P2 mAb will be tested in several key preclinical and nonclinical safety studies to ensure that the antibody is safe and tolerable for human clinical trials. Prior to the initiation of the proposed studies, we will have tested THN227 and several back-up humanized or fully human anti-FN P2 mAbs in ex vivo assays of immunogenicity and in rodent PK and dose range finding studies. In this proposal, we will first test whether our lead anti-FN P2 mAb induces microhemorrhages in a transgenic AD mouse model. This is an important safety test, as several anti-Aβ mAbs induced amyloid related imaging abnormalities associated with hemorrhage (ARIA-H) in a subset of AD patients in previous clinical trials. We will also establish the safe dose range in nonhuman primates (NHPs) and assess the safety or repeated short-term and chronic dose regimens. These key safety studies will drive the preclinical development of our novel anti-FN P2 mAb approach, establish important safety limitations, supporting an IND application and informing the rational design of early stage clinical trials in AD/ADRD.

抽象的 神经炎症是阿尔茨海默病 (AD) 和阿尔茨海默病病理学的重要驱动因素 相关痴呆症（ADRD）。 AD/ADRD 患者和动物模型中的多项证据表明 血管失调以及大脑和脑血管中纤维蛋白 (FN) 的沉积是重要来源 这种炎症。在 AD/ADRD 患者中，局部 BBB 破坏是早期事件，并且随着时间的推移而增加 疾病进展。血管破裂导致血液蛋白质外渗，包括纤维蛋白原 (FGN)，进入大脑并在脑实质和脑血管系统中形成 FN 凝块，这与 Aβ 斑块和炎症免疫细胞。在 FGN 转化为 FN 的过程中，一个神秘的表位暴露在 FN 链 该序列（Fibγ377-395，也称为 FN P2）是 CD11b/CD18 受体的配体 作用于巨噬细胞和小胶质细胞，触发这些先天免疫细胞的激活和炎症的分泌 调解员。 FGN 的遗传或化学耗竭或 FN P2 中 6 个关键氨基酸的遗传取代 AD 的 5xFAD 小鼠模型显着降低了炎症细胞因子的水平以及 AD 的发生率 认知能力下降。小鼠单克隆抗体 (mAb) 5B8，由 Katerina Akassoglou 博士（创始人）发现 Therini Bio Inc. 的 (Therini Bio Inc.) 结合此神秘表位并概括了遗传性 FN P2 缺失的活性。 5B8是 对 FN 的选择性高于 FGN，并且不会干扰正常凝血。 Therini Bio Inc. 已将 5B8 并证明领先的人源化抗 FN P2 mAb（称为 THN227）保留了选择性结合 FN 优于 FGN，并且不会干扰 FN 介导的正常功能，例如止血。在体内 纤维蛋白（gen）诱导的神经炎症脑脊髓炎模型，静脉注射 THN227 减少小胶质细胞活化、巨噬细胞浸润和氧化应激。在这个提案中，主导人性化 抗 FN P2 mAb 将在多项关键的临床前和非临床安全性研究中进行测试，以确保该抗体 对于人体临床试验来说是安全且可耐受的。在开始拟议的研究之前，我们将测试 THN227 和几种备用人源化或全人源抗 FN P2 mAb 的离体免疫原性测定 以及啮齿动物 PK 和剂量范围探索研究。在这个提案中，我们将首先测试我们的领先抗FN P2是否 mAb 在转基因 AD 小鼠模型中诱导微出血。这是一项重要的安全测试，因为有几个 抗 Aβ 单克隆抗体在子集中诱导淀粉样蛋白相关的与出血相关的成像异常 (ARIA-H) 先前临床试验中的 AD 患者。我们还将确定非人类灵长类动物 (NHP) 的安全剂量范围 并评估安全性或重复短期和长期剂量方案。这些关键的安全研究将推动 我们新型抗 FN P2 mAb 方法的临床前开发，建立了重要的安全限制， 支持 IND 申请并为 AD/ADRD 早期临床试验的合理设计提供信息。