Imaging Brain Amyloid with a Bispecific Antibody

描述（申请人提供）：阿尔茨海默病（AD）的痴呆是由脑淀粉样蛋白的缓慢积累引起的。因此，测量大脑淀粉样蛋白的大脑扫描的发展可以识别出那些有后期发展为AD风险的个体。早期发现可以导致早期治疗并延迟症状的发作。据估计，AD症状发作的延迟仅5年，每年将节省美国医疗保健费用500亿美元。仅在美国，AD诊断脑扫描的潜在候选人人数就超过3000万。这项工作的目标是开发阿尔茨海默病（AD）诊断大脑扫描。AD是由淀粉样蛋白在脑中的沉积引起的，如果淀粉样蛋白成像剂可通过血脑屏障（BBB）运输，则可以开发AD的诊断脑扫描。本工作将制备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MAb，并命名为HIRMAb，另一种MAb是针对形成AD斑块的A β淀粉样蛋白的单链ScFv抗体，并命名为A β MAb。HIRMAb将能够穿过BBB运输，而AbetaMAb将结合AD的Abeta斑块并能够对脑淀粉样蛋白成像。该药物将含有一个螯合剂部分，用于111-铟的放射性标记，这将使脑淀粉样蛋白的单光子发射计算机断层扫描成像，这是广泛适用于大多数医院和成像中心。在阶段I中，融合基因将被工程化，细胞系将被转染，并且融合蛋白的双功能性将被证明，因为它将显示融合蛋白既结合BBB受体又结合AD淀粉样蛋白。这项工作将为FDA准备IND，用于测试这种新的体内脑扫描，这将是第一个针对AD的诊断测试。AD脑扫描可以允许早期检测那些处于脑淀粉样蛋白和AD后期发展风险中的个体，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.