Monoclonal Antibody Drug Development for Alzheimer's Disease

描述(申请人提供)：阿尔茨海默病(AD)的痴呆与大脑中淀粉样斑块的沉积有关，迫切需要新药来解聚大脑中的斑块。最有效的斑块解聚药物是抗淀粉样抗体(AAA)。然而，AAA必须物理接触斑块才能引起解聚，斑块驻留在血脑屏障(BBB)后面的大脑中。与其他大分子药物一样，AAAS在没有血脑屏障破坏的情况下不会越过血脑屏障。无论是在转基因小鼠模型中，还是在患有AD的人类中，AAA治疗的副作用都是血浆中Aβ淀粉样肽浓度的急剧增加，这与小鼠的脑微出血和人类的血管源性脑水肿有关。需要的是新一代的AAA，它既能穿透血脑屏障而不破坏屏障，又不会导致血浆淀粉样肽升高或脑水肿或血脑屏障破坏。在目前的工作中，AAA被重新设计为通过转铁蛋白受体(TFR)上的受体介导的转运穿过小鼠的血脑屏障。设计了AAA的单链抗体(ScFv)形式，并将其与抗小鼠TfR的基因工程嵌合单抗(MAb)重链的羧基末端融合，命名为cTfRMAb-scFv。将该融合蛋白长期应用于双转基因AD小鼠，治疗后脑组织中AB1-42的含量下降了40%，而血浆中的AB1-42没有增加，也没有脑内微出血。在这项拟议的工作中，将在双转基因和三转基因AD小鼠模型上进行剂量反应研究。此外，AD转基因小鼠将接受脑穿透性AAA和脑穿透性肿瘤坏死因子-α抑制剂的双重生物治疗。AAA治疗可加速AD转基因小鼠脑内淀粉样斑块的解聚，而脑穿透性肿瘤坏死因子抑制剂可减少AD转基因小鼠脑内淀粉样斑块的产生。 公共卫生相关性：阿尔茨海默病的痴呆与大脑中淀粉样斑块的沉积有关，迫切需要新药来解聚大脑中的斑块。最有效的斑块解聚药物是抗淀粉样抗体(AAA)。在目前的工作中，AAA被重新设计为通过转铁蛋白受体上的受体介导的转运来穿越血脑屏障(BBB)。该药物开发计划的目标是设计一种AAA，在没有血脑屏障破坏的情况下穿透大脑，减少大脑淀粉样斑块，而不会导致血浆淀粉样多肽升高或大脑微出血。

DESCRIPTION (provided by applicant): The dementia of Alzheimer's disease (AD) correlates with the deposit of amyloid plaques in brain, and there is an urgent need for new drugs that disaggregate the plaque in brain. The most potent plaque disaggregation drugs are anti-amyloid antibodies (AAAs). However, the AAA must physically contact the plaque to cause disaggregation, and the plaque resides in brain behind the blood-brain barrier (BBB). AAAs, like other large molecule drugs, do not cross the BBB in the absence of BBB disruption. A side effect of AAA therapy in either transgenic mouse models, or in humans with AD, is a dramatic increase in the plasma concentration of Abeta amyloid peptides, and this is associated with cerebral micro-hemorrhage in mice and vasogenic brain edema in humans. What is needed is a new generation of AAAs that both penetrate the BBB without barrier disruption, and do not cause elevations in plasma amyloid peptides or brain edema or BBB disruption. In the present work, an AAA is re-engineered to cross the mouse BBB via receptor-mediated transport on the transferrin receptor (TfR). A single chain Fv (ScFv) form of the AAA is engineered, and the ScFv is fused to the carboxyl terminus of the heavy chain of a genetically engineered chimeric monoclonal antibody (MAb) against the mouse TfR, and this fusion protein is designated cTfRMAb-ScFv. The fusion protein was administered chronically to double transgenic AD mice and treatment caused a 40% decrease in brain Ab1-42 with no increase in plasma Ab1-42 and no cerebral micro-hemorrhage. In the proposed work, a dose response study will be performed in both the double transgenic and the triple transgenic mouse models of AD. In addition, AD transgenic mice will be treated with dual biologic therapy with the brain penetrating AAA and a brain penetrating tumor necrosis factor (TNF)-alpha inhibitor. The AAA therapeutic accelerates the disaggregation of amyloid plaque in brain, while the brain penetrating TNF-inhibitor diminishes the production of amyloid plaque in brain of AD transgenic mouse models. PUBLIC HEALTH RELEVANCE: The dementia of Alzheimer's disease correlates with the deposition of amyloid plaques in brain, and there is an urgent need for new drugs that disaggregate the plaque in brain. The most potent plaque disaggregation drugs are anti-amyloid antibodies (AAAs). In the present work, an AAA is re- engineered to cross the blood-brain barrier (BBB) via receptor-mediated transport on the transferrin receptor. The goal of this drug development program is the engineering of an AAA that is brain penetrating in the absence of BBB disruption, and reduces brain amyloid plaque without causing elevations in plasma amyloid peptides or cerebral micro-hemorrhage.