IMMUNOTHERAPEUTIC AGENTS TO TREAT ALZHEIMER'S DISEASE

描述：(逐字摘自申请人的摘要)β-淀粉样蛋白和 它形成的大脑斑块可能是直接或间接的原因 阿尔茨海默氏症。这种小的，43个氨基酸残基的多肽是 在中枢神经系统和外周组织中 细胞表面前体蛋白。因此，可溶性β淀粉样蛋白以游离形式存在于 血液和脑脊液，最终以不溶于水的形式沉积 聚集在一起在大脑中形成淀粉样斑块。需要检验的假设 提示针对这种β-淀粉样多肽的特异性抗体 可用于全身或大脑内，以破坏斑块的形成 并有可能溶解现有的斑块。 阿尔茨海默病患者脑内可溶和不可溶的β-淀粉样蛋白 患者似乎处于动态平衡状态，这些也可能与 血流中的β-淀粉样蛋白。因此，斑块的生长将受到抑制。 当这种平衡被取代时，斑块应该会逐渐溶解 降低可溶性β-淀粉样蛋白水平。耗尽将通过使用 结合或永久修饰的高度特异的抗β-淀粉样蛋白抗体 大脑或外周循环中的β-淀粉样蛋白。抗体可能 系统功能，但也可以在大脑内注入或靶向 使用矢量化双特异性抗体传递系统的大脑。 合适的多肽和过渡态多肽类似抗原已经被 旨在产生常规或催化的抗β-淀粉样蛋白 抗体。制备了单抗，并用酶联免疫吸附试验进行了鉴定 和蛋白水解法，以选择那些显示高亲和力结合的 β淀粉样蛋白，或催化活性，或溶解β淀粉样蛋白的能力 集合体。矢量化双特异性抗体是通过偶联 抗转铁蛋白受体抗体的抗β淀粉样抗体，该抗体可以 通过细胞穿透跨越血脑屏障。 全身性和脑内抗淀粉样蛋白抗体将使用 已建立的表达人淀粉样蛋白前体的转基因小鼠群体 蛋白质，并在-11个月龄时在大脑中产生β-淀粉样肽沉积 年龄。β-淀粉样蛋白抗原或抗体将用于年轻人和老年人 周期性ip转基因小鼠。在发病前或发病后注射 斑块的形成。脑内治疗将通过直接输注 去势的小鼠或通过使用矢量化试剂。经过治疗的小鼠将被 在斑块数量和大小方面与对照转基因小鼠进行比较 脑切片和脑提取液中B-淀粉样多肽的水平。这些 专门设计的抗原、抗β-淀粉样蛋白抗体和矢量化 抗β-淀粉样蛋白抗体为免疫治疗提供了新的基础 阿尔茨海默氏症。

DESCRIPTION: (Verbatim from the Applicant's Abstract) Beta-amyloid and the cerebral plaques that it forms are likely either the direct or indirect cause of Alzheimer's disease. This small, 43 amino acid residue peptide is produced in both the central nervous system and peripheral tissues by cleavage from a cell-surface precursor protein. Thus, soluble beta-amyloid exists free in the blood and cerebrospinal fluid and it eventually deposits as ~insoluble" aggregates to form amyloid plaques in the brain. The hypothesis to be tested suggests that specific antibodies directed against this beta-amyloid peptide can be used either systemically or intracerebrally to disrupt plaque formation and possibly dissolve existing plaques. Soluble and insoluble forms of beta-amyloid within the brain of Alzheimer's patients appear to be in dynamic equilibrium and these may also exchange with beta-amyloid in the blood stream. Accordingly, plaque growth will be curtailed and plaques should gradually dissolve when that equilibrium is displaced by reducing soluble beta-amyloid levels. Depletion will be accomplished by using highly specific anti-beta-amyloid antibodies to tie up or permanently modify beta-amyloid in either the brain or peripheral circulation. Antibodies may function systemically but also can be infused intracerebrally or targeted into the brain using a vectorized bispecific antibody delivery system. Appropriate peptide and transition state peptide analog antigens have been designed to generate either conventional or catalytic anti-beta-amyloid antibodies. Monoclonal antibodies have been produced and chacterized by ELISA and proteolytic assays to select those showing high-affinity binding to beta-amyloid, or catalytic activity, or an ability to dissolve beta-amyloid aggregates. Vectorized bispecific antibodies were formed by coupling the anti-beta-amyloid antibodies to an anti-transferrin receptor antibody which can cross the blood-brain barrier by transcytosis. Systemic and intracerebral anti-beta-amyloid antibodies will be tested using an established colony of transgenic mice that express the human amyloid precursor protein and produce beta-amyloid peptide deposits in the brain at -11 months of age. Beta-amyloid antigens or antibodies will be administered to young and old transgenic mice by periodic i.p. injection either before or after the onset of plaque development. Intracerebral treatment will be by direct infusion into cannulated mice or by using the vectorized reagents. Treated mice will be compared to control transgenic mice in terms of the number and size of plaques in brain sections and the level of B-amyloid peptides in brain extracts. These expressly designed antigens, anti-beta-amyloid antibodies and vectorized anti-beta-amyloid antibodies provide a novel basis for the immunotherapy of Alzheimer's disease.