Immunomodulation targeting abnormal conformation and the influence of apoE

针对异常构象的免疫调节及apoE的影响

• 批准号: 10621851
• 负责人: Fernando goni
• 金额: $ 47.4万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621851
• 关键词: 3xTg-AD mouse; APP-PS1; Active Immunization; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Animal Model; Animals; Antibodies; Antibody Binding Sites; Antibody Response; Apolipoprotein E; Apolipoproteins; Autoimmune; Behavioral; Binding; Binding Sites; Biochemical; Biological Markers; Blood - brain barrier anatomy; Blood Vessels; Brain; Cerebral Amyloid Angiopathy; Cerebrovascular system; Characteristics; Clinical Trials; Cognitive; Complication; Crossbreeding; Elderly; Female; Future; Hemorrhage; Human; Image; Immune Targeting; Immunization; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Immunotherapy; Injections; Intraperitoneal Injections; Kinetics; Knock-in; Legal patent; Mass Spectrum Analysis; Measures; Mediating; Modeling; Molecular Conformation; Monoclonal Antibodies; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Passive Immunization; Passive Immunotherapy; Pathogenesis; Pathologic; Pathology; Peptoids; Peripheral; Permeability; Proteome; Proteomics; Reporting; Safety; Senile Plaques; Sterility; Structure; Testing; Therapeutic Effect; Toxic effect; Vaccination; Western Blotting; abeta oligomer; amyloid structure; autoimmune toxicity; beta pleated sheet; blood-brain barrier crossing; blood-brain barrier penetration; cognitive testing; conformer; extracellular; human tissue; hyperphosphorylated tau; immunological intervention; immunoregulation; innovation; insight; male; misfolded protein; monomer; mouse model; nanomolar; neuropathology; novel strategies; prion-like; side effect; small molecule; tau Proteins; tau aggregation; vascular abnormality

SUMMARY The neuropathology of AD includes fibrillary amyloid β (Aβ) in plaques, cerebral amyloid angiopathy (CAA), and hyperphosphorylated tau fibrils in neurofibrillary tangles (NFT). However, the most toxic species are Aβ and tau oligomers characterized by generic structural β-sheet secondary structure. These misfolded Aβ and tau conformers are suitable targets for immunological intervention, although numerous clinical trials thus far have failed due to: 1) autoimmune toxicity; 2) lack of specific concomitant targeting of oligomeric Aβ and tau species; and 3) Amyloid Related Imaging Abnormalities (ARIA), particularly among apolipoprotein (apo)E4 carriers, thought to be associated with fibrillar vessel amyloid clearance. To overcome these limitations, we developed innovative antibody combining sites (aβComAb paratopes) that only recognize the dominant β- sheet secondary structure of misfolded proteins, a generic characteristic of all pathologic oligomers found in neurodegenerative diseases. Our preliminary results show that some aβComAb combining sites on either IgM or IgG class can, without side effects, penetrate the BBB of an AD Tg mouse model with pre-existing Aβ and tau pathology, achieve significant cognitive rescue, reduce levels of Aβ and tau pathological oligomers, and in a CAA AD Tg mouse model (TgSwDI) act without ARIA-like toxicity (both models on murine apoE background). In this project, we will test the hypothesis that aβComAbs (IgM or IgG), unlike mAbs directed against Aβ sequences (6E10), can be infused safely and produce modifying therapeutic effects without vascular ARIA-like toxicity in 3xTg and the vascular TgSwDI or APP/PS1dE9 mouse models cross-bred to human apoE2, E3, or E4 backgrounds. Furthermore, we anticipate that the vascular amyloid proteomes of these mice will resemble those that Projects 1 and 2 associate with different apoE backgrounds, treatments, and presence or absence of microhemorrhages. This information is critically needed to elucidate the mechanism associated with ARIA and select aβComAbs paratopes for future clinical trials. The specific aims are to: 1) Produce and characterize IgM and IgG forms of combining sites (AβComAb paratopes) that specifically recognize the β-sheet secondary structures of toxic oligomers. 2) Determine the biochemical and histochemical interaction of the four aβComAbs from Aim 1 with the brain vasculature of peripherally infused TgSwDI mice crossed on KI human ApoE2, E3, and E4 backgrounds. 3) Determine behavioral, histochemical, and biochemical changes after passive immunotherapy with two AβComAb paratopes on an IgM and an IgG selected from Aim 2, in 3xTg, Tg APP/PS1dE9, and TgSwDI mice crossed on KI human ApoE2, E3, and E4 backgrounds.

概括 AD的神经病理包括斑块中的原纤维淀粉样β（Aβ），脑淀粉样血管病（CAA）， 和神经纤维缠结（NFT）中的高磷酸化tau纤维。但是，最有毒物种是Aβ 和以通用结构β-折叠二级结构为特征的Tau低聚物。这些错误折叠的Aβ和 tau构象异构体是免疫干预的合适靶标，尽管到目前为止进行了许多临床试验 由于以下原因失败：1）自身免疫性毒性； 2）缺乏寡聚Aβ和tau的特异性同时靶向 物种; 3）淀粉样蛋白相关的成像异常（ARIA），特别是在载脂蛋白（APO）E4中 载体被认为与纤维血管淀粉样蛋白清除相关。为了克服这些限制，我们 开发了创新的抗体组合位点（AβComab占地），仅识别主要的β- 错误折叠蛋白的片次结构，这是所有病理低聚物的通用特征 神经退行性疾病。我们的初步结果表明，某些Aβcomab在任一IGM上的位点组合 或IgG类无需副作用，可以穿透具有预先存在的Aβ的AD TG小鼠模型的BBB tau病理学，实现明显的认知救援，降低Aβ和TAU病理低聚物的水平，以及 CAA AD TG小鼠模型（TGSWDI）无类似芳香的毒性（这两个模型 背景）。在这个项目中，我们将检验以下假设，即Aβcomab（IgM或IgG）与指向的mAb不同 针对Aβ序列（6E10），可以安全感染，并产生修饰的治疗作用而没有 3XTG和血管TGSWDI或APP/PS1DE9鼠标模型的血管ARIA样毒性杂交 到人类APOE2，E3或E4背景。此外，我们预计血管淀粉样蛋白 这些小鼠的蛋白质组织类似于项目1和2与不同的APOE相关的蛋白质组织 背景，治疗，存在或不存在微生物检查。此信息至关重要 需要阐明与ARIA相关的机制，并选择AβComabs用于未来的临床 试验。具体目的是： 1）产生并表征IgM和IgG形式的组合位点（AβComab占地）的形式 识别有毒寡聚物的β-折叠二级结构。 2）确定来自AIM 1与大脑的四个AβComab的生化和组织化学相互作用 在Ki Human ApoE2，E3和E4背景上跨越周围注入的TGSWDI小鼠的脉管系统。 3）确定被动免疫治疗后的行为，组织化学和生化变化 在IGM上的AβComab占膜片和从AIM 2，3XTG，TG APP/PS1DE9和TGSWDI小鼠中选择的IgG 在Ki Human ApoE2，E3和E4背景上交叉。