IMMUNOTHERAPEUTIC AGENTS TO TREAT ALZHEIMER'S DISEASE

描述：（逐字来自申请人的摘要）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 老年痴呆症这种小的，43个氨基酸残基的肽产生 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-淀粉样蛋白游离存在于细胞中。 血液和脑脊髓液中，它最终沉积为“不溶性” 在大脑中聚集形成淀粉样斑块。待测试的假设 表明针对β-淀粉样肽的特异性抗体 可用于全身或脑内破坏斑块形成 并可能溶解现有的斑块。 阿尔茨海默氏症患者脑内可溶性和不溶性β-淀粉样蛋白 患者似乎处于动态平衡状态，这些也可能与 血液中的β-淀粉样蛋白因此，斑块的生长将被抑制 当平衡被破坏时，斑块会逐渐溶解， 降低可溶性β-淀粉样蛋白水平。消耗将通过使用 高度特异性的抗β-淀粉样蛋白抗体， 大脑或外周循环中的β-淀粉样蛋白。抗体可以 还可以脑内输注或靶向注入 使用载体化的双特异性抗体递送系统来治疗脑。 合适的肽和过渡态肽类似物抗原已经被制备。 设计用于产生常规或催化抗β-淀粉样蛋白 抗体的制备了单克隆抗体，并进行了ELISA鉴定 和蛋白水解测定，以选择那些显示高亲和力结合 或催化活性，或溶解β-淀粉样蛋白的能力 集料.通过偶联抗体形成载体化双特异性抗体。 抗转铁蛋白受体抗体的抗β-淀粉样蛋白抗体， 通过胞吞作用穿过血脑屏障 将使用免疫组织化学方法检测全身和脑内抗β-淀粉样蛋白抗体。 建立表达人淀粉样蛋白前体的转基因小鼠群 蛋白质和产生β-淀粉样肽沉积在大脑中的-11个月的 年龄β-淀粉样蛋白抗原或抗体将给予年轻人和老年人 转基因小鼠通过周期性腹膜内注射之前或之后的发病 斑块发育脑内治疗将通过直接输注至 插管小鼠或通过使用载体化试剂。治疗小鼠将 与对照转基因小鼠相比， 以及脑提取物中B-淀粉样肽的水平。这些 明确设计的抗原、抗β-淀粉样蛋白抗体和载体化 抗β-淀粉样蛋白抗体为免疫治疗提供了新的基础， 老年痴呆症

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.