Imaging Brain Amyloid with a Bispecific Antibody

描述(申请人提供)：阿尔茨海默病(AD)的痴呆症是由大脑淀粉样蛋白缓慢堆积引起的。因此，开发一种测量大脑淀粉样蛋白的脑部扫描可以识别那些有可能患上阿尔茨海默病的人。早期发现可以导致早期治疗，并推迟症状的出现。据估计，将AD症状出现的时间推迟5年，每年将为美国节省500亿美元的医疗费用。仅在美国，有可能接受AD诊断脑扫描的人数就超过3000万人。这项工作的目标是开发一种阿尔茨海默病(AD)诊断脑扫描。AD是由淀粉样蛋白在大脑中的沉积引起的，如果淀粉样蛋白显像剂可以通过血脑屏障(BBB)运输，就可以开发出诊断AD的脑扫描。本工作将制备一种基因工程双特异性抗体，其中一种是抗人胰岛素受体(HIR)的嵌合单抗，命名为HIRMAb，另一种是针对形成AD斑块的Aβ淀粉样蛋白的单链单链抗体，命名为AbetaMAb。HIRMAb将实现跨血脑屏障的运输，AbetaMAb将结合AD的Abeta斑块，并使大脑淀粉样蛋白成像。该药物将包含一个用于111-铟放射性标记的螯合剂部分，这将使脑淀粉样蛋白的单光子发射计算机断层成像成为可能，这种成像在大多数医院和成像中心都可以广泛获得。在第一阶段，融合基因将被改造，细胞株将被转染，融合蛋白的双功能将被证明，因为将证明融合蛋白既与BBB受体结合，又与AD淀粉样蛋白结合。这项工作将使向FDA提交的IND准备用于测试这种新型的活体脑扫描，这将是第一个专用于AD的诊断测试。AD脑扫描可能会及早发现那些有脑淀粉样蛋白和AD后期发展风险的人，并允许早期药物治疗。

DESCRIPTION (provided by applicant): The dementia of Alzheimer's Disease (AD) is caused by the slow accumulation of brain amyloid. Therefore, the development of a brain scan that measures brain amyloid could identify those individuals at risk for the later development of AD. Early detection can lead to early therapy and delay the onset of symptoms. It is estimated that the delay of the onset of symptoms of AD, for just 5 years, would save $50 billion per year in U.S. health care costs. The number of people who are potential candidates for an AD diagnostic brain scan is in excess of 30 million in United States alone. The goal of this work is the development of an Alzheimer's Disease (AD) diagnostic brain scan. AD is caused by the deposition of amyloid in the brain and a diagnostic brain scan for AD could be developed if amyloid imaging agents were made transportable through the blood brain barrier (BBB). This work will prepare a genetically engineered bispecific antibody, wherein one monoclonal antibody (MAb) is a chimeric MAb to the human insulin receptor (HIR), and designated HIRMAb, and the other MAb is a single chain ScFv antibody directed at the Abeta amyloid that forms the plaque of AD, and is designated AbetaMAb. The HIRMAb will enable transport across the BBB and the AbetaMAb will bind the Abeta plaque of AD and enable imaging of the brain amyloid. The drug will contain a chelator moiety for radiolabeling with 111-indium, which will enable imaging of brain amyloid with single photon emission computed tomography, which is widely available in most hospitals and imaging centers. In phase I, the fusion gene will be engineered, cell lines will be transfected, and the bi-functionality of the fusion protein will be demonstrated, as it will be shown that the fusion protein both binds the BBB receptor and binds the AD amyloid. This work will enable the preparation of an IND to the FDA for testing of this novel in vivo brain scan that will be the first diagnostic test specific for AD. The AD brain scan may allow for early detection of those individuals at risk for later development of brain amyloid and AD, and permit early drug therapy.