Imaging Brain Amyloid with a Bispecific Antibody

描述（由申请人提供）：阿尔茨海默病（AD）的痴呆是由大脑淀粉样蛋白缓慢积累引起的。因此，开发一种脑部扫描技术，测量大脑淀粉样蛋白，可以识别出那些有老年痴呆症后期发展风险的个体。早期发现可以导致早期治疗和延迟症状的发作。据估计，延迟阿尔茨海默病症状的发作，仅仅5年，每年将节省500亿美元的美国医疗保健费用。仅在美国，可能需要进行AD诊断性脑部扫描的人数就超过了3000万。这项工作的目标是开发一种诊断阿尔茨海默病（AD）的脑部扫描。阿尔茨海默病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，则可以开发诊断性阿尔茨海默病的脑部扫描。本研究将制备一种基因工程双特异性抗体，其中一种单克隆抗体（MAb）是针对人胰岛素受体（HIR）的嵌合单抗，命名为HIRMAb，另一种单链单克隆抗体（MAb）是针对形成AD斑块的Abeta淀粉样蛋白的单链ScFv抗体，命名为AbetaMAb。HIRMAb将使运输跨越血脑屏障，AbetaMAb将结合阿尔茨海默病的β斑块，并使脑淀粉样蛋白成像。该药物将包含一个螯合剂片段，用于111-铟的放射性标记，这将使单光子发射计算机断层扫描能够成像脑淀粉样蛋白，这在大多数医院和成像中心广泛使用。在第一阶段，融合基因将被改造，细胞系将被转染，融合蛋白的双功能将被证明，因为它将被证明融合蛋白既结合血脑屏障受体又结合AD淀粉样蛋白。这项工作将为FDA准备IND，以测试这种新型体内脑扫描，这将是AD的第一个专门诊断测试。阿尔茨海默病脑部扫描可能允许早期发现那些有脑淀粉样蛋白和阿尔茨海默病后期发展风险的个体，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.