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.

项目总结/摘要 Abilita Bio是一家创新驱动的生物技术公司，正在为这项发现寻求SBIR第一阶段资金 靶向孤儿G蛋白偶联受体GPR 17和GPR 37的新型治疗性纳米抗体， 解决阿尔茨海默病的神经病理学。超过500万美国人因此而受苦 一种使人衰弱的疾病，它会导致记忆丧失和认知功能的进行性损害。 尽管有大量证据支持淀粉样蛋白β和tau蛋白在阿尔茨海默病中的作用， 在病因病理学方面，针对淀粉样蛋白-β的临床努力几乎没有产生改善认知功能的证据。 或功能结果，强调对新靶点和治疗策略的未满足需求。 最近的影像学研究表明，白色物质的结构变化和潜在的髓鞘， 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蛋白 病理学由于白色物质变化和髓鞘丢失与临床进展的相关性， 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髓鞘再生的药物可能 代表了治疗阿尔茨海默氏症和其他神经退行性疾病的有前途的新疗法。近日更 已经发现两种孤儿G蛋白偶联受体GPR 17和GPR 37， 少突胶质细胞发育，因为它们成熟为髓鞘细胞，这最终影响它们的能力 修复受损的轴突GPR 17和GPR 37信号传导的选择性拮抗剂可以解除阻断 少突胶质细胞检查点，以促进其分化和髓鞘再生活性，这提出了一个新的观点。 有机会修复阿尔茨海默氏症造成的病理损伤。 尽管GPR 17和GPR 37具有潜力，但没有可用的特定药理学试剂可用于治疗。 用于验证阿尔茨海默病的靶点，或作为治疗线索，我们将在 拟议的研究。GPR 17和GPR 37由于其差的生物活性而非常难以给药。 限定的结合口袋、差的功能性折叠和高的组成性活性，这是孤儿的典型特征。 受体。我们将通过使用一种新的方法来解决对选择性靶向调节剂的需求， 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GPR 17， GPR 37用于骆驼免疫和用于骆驼科动物单链发现的噬菌体文库筛选 抗体（纳米抗体）。纳米抗体具有独特的特性，能够识别受体结合 对G蛋白偶联受体的功能调节至关重要的口袋和结构元件， 已通过成功的临床开发得到验证。我们计划找出竞争性和对抗性的 纳米抗体将被重新表征和测试其刺激 少突胶质细胞成熟和髓鞘形成活性。纳米抗体被证实表现出效力和选择性 在这些试验中，将在未来的阶段中在阿尔茨海默病模型中进行体内验证。 II SBIR努力，以临床开发为目的。