RAGE-Proteolyzing Antibodies for Alzheimer's Disease Therapy

用于治疗阿尔茨海默病的 RAGE 蛋白水解抗体

• 批准号: 8164664
• 负责人: Peter J Heinzelman
• 金额: $ 12.43万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8164664
• 关键词: Accounting; Advanced Glycosylation End Products; Adverse effects; Alzheimer' s Disease; American; Antibodies; Binding; Blood - brain barrier anatomy; Cell Separation; Cell membrane; Cell surface; Cities; Clinical Trials; Collaborations; Collection; Disease; Dose; Endothelium; Engineering; Fluorescence-Activated Cell Sorting; Genes; Genetic Recombination; Goals; Health; Human; Hydrolysis; In Vitro; Inflammation; Laboratories; Lead; Length; Libraries; Life; Ligands; Mediating; Membrane; Methods; Microglia; Mus; Mutagenesis; Neurodegenerative Disorders; Neurons; Onset of illness; Oxidative Stress; Penetration; Performance; Permeability; Pharmaceutical Preparations; Plasma; Play; Property; Protein Isoforms; Proteins; Research; Research Institute; Role; Source; Specificity; Staging; Surface; Testing; The Sun; Therapeutic; Toxic effect; Vision; Work; Yeasts; abeta accumulation; antigen binding; base; brain tissue; design; drug candidate; economic impact; effective therapy; falls; in vivo; innovation; mouse model; neuroinflammation; novel; patient safety; prevent; receptor; small molecule; therapeutic evaluation; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): Activation of the full length, membrane bound isoform of the Receptor for Advanced Glycation End Products (flRAGE) on blood brain barrier (BBB) endothelium, neurons and microglia promotes the onset and progression of Alzheimer's Disease (AD) by increasing accumulation of beta-amyloid ( 2) in brain tissue, raising inflammation and elevating oxidative stress. Although preventing activation of flRAGE by antagonizing binding to its many ligands is an attractive AD treatment strategy, toxicity, low efficacy and poor BBB penetration have limited RAGE-targeted therapeutic testing to one small molecule and even this lone drug candidate caused side effects. Wewill develop proteolytic antibodies (CatAbs), able to inactivate thousands of flRAGE molecules per CatAb, as a new class of "catalytically advantaged" therapeutics with the potential to serve as the first effective disease-modifying treatments for AD. A yeast surface display platform, previously used to develop antigen-binding Abs (BindAbs) to treat a range of diseases, will be employed to create human CatAbs catalyzing specific hydrolysis of flRAGE. flRAGE CatAbs' ability to catalyze thousands of cycles of short-lived flRAGE binding, flRAGE hydrolysis, product release and interaction with another flRAGE molecule give CatAbs many "catalytic advantages" over flRAGE-binding drugs. CatAbs' specificity and high dose efficacy reduces the chances of side effects as seen in the flRAGE antagonist trial above. Also, CatAbs pair BindAbs' specificity with a much higher number of targets inactivated per Ab, a key benefit given the BBB's low permeability to protein drugs. Furthermore, CatAbs' rapid hydrolysis and release of flRAGE molecules will allow inactivation of flRAGE targets expressed after drug administration, giving CatAbs a unique ability to account for flRAGE turnover. Finally, unlike flRAGE antagonists, CatAbs will not undergo long-lived binding to flRAGE's circulating isoform, sRAGE, and thus be unlikely to impede sRAGE-promoted clearance of Ab from plasma. We will use a novel library design approach to construct a yeast-displayed CatAb library that will serve as a source of multiple flRAGE CatAbs. Fluorescence Activated Cell Sorting (FACS) will enable both isolation of lead flRAGE CatAbs and subsequent CatAb engineering for enhanced catalytic properties. CatAb hydrolysis of flRAGE expressed on murine cell membranes will be validated in vitro. This work will lead to proposals for follow on CatAb engineering and AD mouse model studies performed in collaboration with the Sun Health Research Institute Neuroinflammation Laboratory (Sun City, AZ). We are excited about the potential impact of these first-ever "catalytically advantaged" AD therapeutics and are eager to initiate this research. PUBLIC HEALTH RELEVANCE: No satisfactorily effective treatment for Alzheimer's Disease (AD), a malady that afflicts more than 4.5 million Americans and has an economic impact exceeding $100 billion/yr, currently exists. Although the Receptor for Advanced Glycation End Products (RAGE) is known to play roles in multiple aspects of AD onset and progression, challenges in targeting therapies to this undesirable protein have led to only a single RAGE-targeted therapeutic being evaluated in clinical trials. We will develop a new class of RAGE-targeted therapeutics that are capable of destroying thousands of copies of the RAGE protein per single therapeutic molecule and hold the exciting potential to be the first truly efficacious AD therapeutics.

描述（由申请人提供）：血脑屏障（BBB）内皮、神经元和小胶质细胞上的高级糖基化终末产物受体（flRAGE）的全长膜结合亚型的激活通过增加脑组织中β-淀粉样蛋白（2）的积累、引发炎症和升高氧化应激来促进阿尔茨海默病（AD）的发病和进展。虽然通过拮抗 flRAGE 与多种配体的结合来防止 flRAGE 的激活是一种有吸引力的 AD 治疗策略，但毒性、低效和血脑屏障渗透性差限制了针对一个小分子的 RAGE 靶向治疗测试，甚至这种单独的候选药物也会引起副作用。我们将开发蛋白水解抗体 (CatAb)，每个 CatAb 能够灭活数千个 flRAGE 分子，作为一类新型“催化优势”疗法，有可能成为第一个有效的 AD 疾病缓解疗法。酵母表面展示平台先前用于开发抗原结合抗体 (BindAbs) 以治疗一系列疾病，该平台将用于创建催化 flRAGE 特异性水解的人类 CatAbs。 flRAGE CatAbs 能够催化数千个短期 flRAGE 结合、flRAGE 水解、产物释放以及与另一个 flRAGE 分子相互作用的循环，这使得 CatAbs 比 flRAGE 结合药物具有许多“催化优势”。 CatAb 的特异性和高剂量功效降低了副作用的可能性，如上述 flRAGE 拮抗剂试验中所见。此外，CatAbs 将 BindAbs 的特异性与每个 Ab 灭活的靶标数量要高得多，这是考虑到 BBB 对蛋白质药物的低渗透性的一个关键优势。此外，CatAbs 的快速水解和 flRAGE 分子的释放将使给药后表达的 flRAGE 靶标失活，从而使 CatAbs 具有解释 flRAGE 周转的独特能力。最后，与 flRAGE 拮抗剂不同，CatAb 不会与 flRAGE 的循环亚型 sRAGE 长期结合，因此不太可能阻碍 sRAGE 促进的 Ab 从血浆中清除。我们将使用一种新颖的文库设计方法来构建酵母展示的 CatAb 文库，该文库将作为多种 flRAGE CatAb 的来源。荧光激活细胞分选 (FACS) 将能够分离先导 flRAGE CatAbs 和随后的 CatAb 工程以增强催化性能。 CatAb 对小鼠细胞膜上表达的 flRAGE 的水解将在体外进行验证。这项工作将提出与太阳健康研究所神经炎症实验室（亚利桑那州太阳城）合作进行的 CatAb 工程和 AD 小鼠模型研究的后续建议。我们对这些首个“具有催化优势”的 AD 疗法的潜在影响感到兴奋，并渴望启动这项研究。 公共健康相关性：目前阿尔茨海默病 (AD) 尚无令人满意的有效治疗方法，这种疾病困扰着超过 450 万美国人，每年造成的经济影响超过 1000 亿美元。尽管已知高级糖基化终末产物受体 (RAGE) 在 AD 发病和进展的多个方面发挥作用，但针对这种不良蛋白质的靶向治疗面临的挑战导致临床试验中仅对单一 RAGE 靶向治疗进行评估。我们将开发一类新的 RAGE 靶向疗法，该疗法能够破坏每个治疗分子的数千个 RAGE 蛋白拷贝，并具有成为第一个真正有效的 AD 疗法的令人兴奋的潜力。