Discovery of therapeutic nanobodies targeting the G protein-coupled receptors in the brain for the treatment of Alzheimer Disease

发现针对大脑中 G 蛋白偶联受体的治疗性纳米抗体可用于治疗阿尔茨海默病

• 批准号: 9910106
• 负责人: Mauro Mileni
• 金额: $ 41.48万
• 依托单位: ABILITA BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910106
• 关键词: Address; Affect; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid; Amyloid beta-Protein; Antibodies; Antigen Receptors; Antigens; Axon; Bacteriophages; Binding; Biological Assay; Biotechnology; Brain; Brain Diseases; Cells; Clinical; Cognitive; Demyelinations; Development; Directed Molecular Evolution; Disease; Drug Targeting; Elements; Evolution; Exhibits; Failure; Funding; Future; Future Generations; G-Protein-Coupled Receptors; G-substrate; GPR17 gene; Immunization; Impaired cognition; Libraries; Llama; Membrane Proteins; Memory Loss; Molecular Conformation; Morphology; Mutation; Myelin; Neurodegenerative Disorders; Neuroglia; Oligodendroglia; Orphan; Pathogenicity; Pathologic; Pathology; Patients; Phage Display; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Process; Production; Property; Proteins; Reporting; Research; Risk; Role; Senile Plaques; Signal Transduction; Small Business Innovation Research Grant; Structural defect; Structure; Technology; Testing; Therapeutic; Therapeutic antibodies; United States; Validation; Variant; aging population; axon injury; base; clinical development; cognitive function; design; functional outcomes; gray matter; imaging study; improved; in vitro Model; in vivo; innovation; myelination; nanobodies; neuroimaging; neuropathology; novel; novel strategies; novel therapeutics; oligodendrocyte progenitor; preclinical development; receptor; receptor binding; remyelination; repaired; screening; targeted treatment; tau Proteins; tau aggregation; therapeutic development; tool; white matter; white matter change

Project Summary/Abstract Abilita Bio, an innovation-driven biotechnology company, is seeking SBIR Phase I funding for the discovery of novel therapeutic nanobodies targeting the orphan G protein-coupled receptors GPR17 and GPR37, to address the neuropathology of Alzheimer’s disease. More than 5 million Americans suffer from this debilitating disease, which causes memory loss and the progressive impairment of cognitive functions. Despite an abundance of evidence supporting the role of amyloid-β and tau in Alzheimer’s disease etiopathology, amyloid-β targeted clinical efforts have generated little evidence of improvement in cognitive or functional outcomes, which emphasizes the unmet need for novel targets and therapeutic strategies. Recent imaging studies have demonstrated that white matter structural changes and underlying myelin abnormalities are significant components of Alzheimer’s disease and may precede overt amyloid and tau pathologies. Due to the association of white matter changes and myelin loss with the clinical progression of Alzheimer’s disease, the glial cells responsible for the production and repair of myelin, oligodendrocytes, may be critically affected. Therefore, drugs that promote oligodendrocyte maturation and remyelination may represent promising new treatments for Alzheimer’s and other neurodegenerative diseases. Recently, it has been found that two orphan G protein-coupled receptors, GPR17 and GPR37, act to negatively regulate oligodendrocyte development as they mature to myelinating cells, which and ultimately affects their capacity to repair damaged axons. Selective antagonists of GPR17 and GPR37 signaling may unblock oligodendrocyte checkpoints to promote their differentiation and remyelinating activity, which presents an opportunity to repair the pathological damage caused by Alzheimer’s. Despite the potential of GPR17 and GPR37, no specific pharmacological agents are available that can be used to validate the targets in Alzheimer’s disease, or serve as therapeutic leads, which we will address in the proposed research. GPR17 and GPR37 have been exceedingly difficult to drug due to their poorly defined binding pockets, poor functional folding and high constitutively activity, which is typical for orphan receptors. We will address the need for selective target modulators by using a novel approach, where we will use our innovative directed evolution-based protein stabilization technology to optimize GPR17 and GPR37 for use in llama immunization and phage library screening for the discovery of camelid single chain antibodies (nanobodies). Nanobodies have unique properties that enable the recognition of receptor binding pockets and structural elements critical for the functional modulation of G protein-coupled receptors and have been validated by successful clinical development. We plan to discover both agonistic and antagonistic nanobodies that will be pharmacologically characterized and tested for their ability to stimulate oligodendrocyte maturation and myelination activity. Nanobodies verified to exhibit potency and selectivity in these assays will be taken forward to in vivo validation in Alzheimer’s Disease models in a future Phase II SBIR effort, with the aim of clinical development.

项目摘要/摘要 Abilita Bio是一家创新驱动的生物技术公司，正在为这一发现寻求SBIR第一阶段资金 靶向孤儿G蛋白偶联受体GPR17和GPR37的新型治疗性纳米体，以 阐述阿尔茨海默病的神经病理学。500多万美国人患有此病 导致记忆力丧失和认知功能进行性损害的衰弱疾病。 尽管有大量证据支持淀粉样蛋白β和tau在阿尔茨海默病中的作用 病因学，淀粉样蛋白-β靶向临床研究几乎没有发现认知能力改善的证据 或功能结果，强调对新靶点和治疗策略的未得到满足的需求。 最近的成像研究表明，白质结构的变化和潜在的髓鞘 异常是阿尔茨海默病的重要组成部分，可能先于明显的淀粉样蛋白和tau 病理学。由于白质改变和髓鞘丢失与临床进展有关 阿尔茨海默病，负责产生和修复髓鞘的神经胶质细胞，少突胶质细胞， 可能会受到严重影响。因此，促进少突胶质细胞成熟和再髓鞘形成的药物可能 代表着治疗阿尔茨海默氏症和其他神经退行性疾病的有希望的新疗法。最近，它已经 已发现两个孤儿G蛋白偶联受体GPR17和GPR37起负性调节作用 少突胶质细胞在成熟后发育成髓鞘细胞，这最终会影响其能力 修复受损的轴突。GPR17和GPR37信号的选择性拮抗剂可能解除阻断 少突胶质细胞检查点，以促进其分化和重新髓鞘活动，这提出了一种 有机会修复阿尔茨海默氏症造成的病理损害。 尽管GPR17和GPR37具有潜力，但目前还没有特定的药理药物可以 用于验证阿尔茨海默病的靶点，或作为治疗线索，我们将在 建议的研究。由于GPR17和GPR37的质量很差，给药带来了极大的困难 有明确的捆绑口袋，折叠功能差，结构性活动高，这是孤儿的典型特征 感受器。我们将通过使用一种新的方法来解决对选择性目标调制器的需求，其中我们 将使用我们创新的基于定向进化的蛋白质稳定技术来优化GPR17和 GPR37用于骆驼免疫和噬菌体文库筛选发现骆驼单链 抗体(纳米抗体)。纳米抗体具有独特的性质，能够识别受体结合 对G蛋白偶联受体和G蛋白偶联受体功能调节至关重要的口袋和结构元件 已经被成功的临床开发所证实。我们计划同时发现激进性和对抗性 将进行药理学表征并测试其刺激能力的纳米抗体 少突胶质细胞成熟和髓鞘形成活性。纳米体被证实具有效力和选择性 在这些测试中，阿尔茨海默病模型的体内验证将在未来阶段进行 II SBIR努力，以临床开发为目标。