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.

项目概要/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 的新型治疗性纳米抗体 解决阿尔茨海默病的神经病理学问题。超过500万美国人患有此病 使人衰弱的疾病，导致记忆丧失和认知功能逐渐受损。 尽管有大量证据支持 β 淀粉样蛋白和 tau 蛋白在阿尔茨海默病中的作用 病因病理学、β淀粉样蛋白靶向临床努力几乎没有产生认知改善的证据 或功能性结果，强调对新靶点和治疗策略的需求未得到满足。 最近的影像学研究表明，白质结构变化和底层髓磷脂 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 蛋白出现 病理学。由于白质变化和髓磷脂缺失与临床进展有关 阿尔茨海默病，神经胶质细胞负责髓鞘质、少突胶质细胞的产生和修复， 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 代表了阿尔茨海默病和其他神经退行性疾病的有前景的新疗法。近日，有 研究发现，两个孤儿 G 蛋白偶联受体 GPR17 和 GPR37 具有负调节作用 少突胶质细胞在成熟为髓鞘细胞时发育，最终影响其能力 修复受损的轴突。 GPR17 和 GPR37 信号传导的选择性拮抗剂可能会解除阻断 少突胶质细胞检查点促进其分化和髓鞘再生活性，这呈现出 修复阿尔茨海默病造成的病理损伤的机会。 尽管 GPR17 和 GPR37 具有潜力，但尚无特定的药物制剂可用于 用于验证阿尔茨海默病的靶标，或作为治疗线索，我们将在 拟议的研究。 GPR17 和 GPR37 由于其性能较差而极难药物化。 明确的结合口袋、功能折叠差和高组成活性，这是孤儿药的典型特征 受体。我们将通过使用一种新颖的方法来满足选择性靶标调节剂的需求，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库筛选以发现骆驼单链 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 对于 G 蛋白偶联受体的功能调节至关重要的口袋和结构元件 已被成功的临床开发所验证。我们计划发现竞争性和对抗性 纳米抗体将进行药理学表征并测试其刺激能力 少突胶质细胞成熟和髓鞘形成活性。经验证纳米抗体具有效力和选择性 这些测定中的结果将在未来的阶段在阿尔茨海默病模型中进行体内验证 II SBIR 努力，以临床开发为目标。