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.

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.尽管通过拮抗与其许多配体的结合来防止flrage激活是一种有吸引力的AD治疗策略，但毒性，低疗效和BBB渗透率较差，对一个小分子，甚至这种孤独的药物候选者的rage靶向治疗测试有限。我们将开发蛋白水解抗体（CATABS），能够使每个cantab的数千种flrage分子失活，作为新的“催化优势”的疗法，有可能作为第一种有效的AD疾病治疗方法。酵母表面展示平台以前用于开发抗原结合ABS（BINDAB）来治疗各种疾病，用于创建催化特定水解FLRAGE的人类catabs。 Flrage Catabs能够催化数千个短寿命的Flrage结合，Flrage水解，产品释放和与另一个Flrage分子相互作用的能力，从而使许多“催化优势”与Flrage结合药物相比。 CATABS的特异性和高剂量功效减少了上面的Flrage拮抗剂试验中副作用的机会。同样，catabs将Bindabs的特异性与每AB灭活的靶标数量更高，这是BBB对蛋白质药物的低渗透性的关键好处。此外，catabs的快速水解和Flrage分子的释放将使药物给药后表达的FLRAGE靶标失活，从而使catabs具有独特的能力来解释Flrage更新。最后，与Flrage拮抗剂不同，catabs不会与Flrage的循环同工型，SRAGE进行长期结合，因此不太可能阻碍血浆中AB的Srage启动清除率。我们将使用一种新颖的图书馆设计方法来构建一种酵母播放的CATAB库，该库将作为多个Flrage Catabs的来源。荧光活化的细胞分选（FACS）将既可以隔离铅flrage catabs，又可以分离出可增强催化性能的速脱股工程。在鼠细胞膜上表达的FLRAGE的catab水解将在体外进行验证。这项工作将导致与Sun Health Research Institute神经炎症实验室（AZ Sun City，AZ）合作进行CATAB工程和AD Mouse模型研究的建议。我们对这些第一个“催化优势”的AD Therapeutics的潜在影响感到兴奋，并渴望启动这项研究。 公共卫生相关性：对阿尔茨海默氏病（AD）没有令人满意的有效治疗，这是一种疾病，遭受了超过450万美国人的影响，并且经济影响超过1000亿美元/年，目前存在。尽管已知晚期糖基化最终产物（RAGE）的受体在AD发作和进展的多个方面都起着作用，但针对这种不良蛋白的靶向疗法的挑战才导致在临床试验中评估了单一的rage靶向治疗方法。我们将开发一种新的以愤怒为目标的治疗剂，能够破坏每个单一治疗分子的愤怒蛋白的副本，并具有令人兴奋的潜力，成为第一个真正有效的AD治疗剂。