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Monoclonal Antibody Drug Development for Alzheimer's Disease

阿尔茨海默病单克隆抗体药物开发

基本信息

批准号：
8366196
负责人：
William M Pardridge
金额：
$ 31.57万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-15 至 2013-06-27
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8366196
关键词：
Adverse effects Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Antibodies Antibody Therapy Binding Binding Sites Biological Response Modifier Therapy Blood Blood - brain barrier anatomy Brain Brain Edema Cerebrum Chimeric Proteins Clinical Trials Confocal Microscopy Dementia Deposition Development Dose Engineering Enzyme-Linked Immunosorbent Assay Excision Extracellular Domain Generations Goals Head Hemorrhage Histocytochemistry Human Hybridomas IgG1 Immunoglobulin Variable Region Immunotherapeutic agent Injection of therapeutic agent Intravenous Light Measures Mediating Monoclonal Antibodies Mus Patients Peptides Peripheral Pharmaceutical Preparations Plasma Production Protein Binding Prussian blue Rattus Receptors, Tumor Necrosis Factor, Type II Research Saline Senile Plaques Structure Tail Taste Perception Tertiary Protein Structure Testing Therapeutic antibodies Thioflavin S Tissues Transferrin Receptor Transgenic Mice Transgenic Organisms Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Vasogenic Brain Edema Work abeta deposition amyloid peptide drug development inhibitor/antagonist intravenous injection morris water maze mouse model neonatal Fc receptor neurobehavior prevent programs receptor response treatment duration tumor necrosis factor-alpha inhibitor

项目摘要

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.

说明（申请人提供）：阿尔茨海默病（AD）的痴呆与脑内淀粉样斑块的存款相关，迫切需要能解聚脑内斑块的新药。最有效的斑块解聚药物是抗淀粉样蛋白抗体（AAA）。然而，AAA必须物理接触斑块以引起解聚，并且斑块位于血脑屏障（BBB）后面的脑中。与其他大分子药物一样，AAA在没有BBB破坏的情况下不会穿过BBB。在转基因小鼠模型或患有AD的人类中，AAA治疗的副作用是A β淀粉样肽的血浆浓度急剧增加，并且这与小鼠的脑微出血和人类的血管源性脑水肿相关。所需要的是新一代的AAA，其既能穿透BBB而不破坏屏障，又不会引起血浆淀粉样肽升高或脑水肿或BBB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BBB。AAA的单链Fv（ScFv）形式被工程化，并且ScFv融合到针对小鼠TfR的基因工程嵌合单克隆抗体（MAb）的重链的羧基末端，并且该融合蛋白被命名为cTfRMAb-ScFv。将融合蛋白长期给予双转基因AD小鼠，治疗导致脑Ab 1 -42降低40%，而血浆Ab 1 - 42没有增加，也没有脑微出血。在拟定的工作中，将在AD的双转基因和三转基因小鼠模型中进行剂量反应研究。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（TNF）-α抑制剂双重生物治疗。AAA治疗剂加速脑中淀粉样斑块的解聚，而脑穿透性TNF抑制剂减少AD转基因小鼠模型脑中淀粉样斑块的产生。公共卫生相关性：阿尔茨海默病的痴呆与脑内淀粉样斑块的沉积有关，迫切需要新的药物来解聚脑内的斑块。最有效的斑块解聚药物是抗淀粉样蛋白抗体（AAA）。在本工作中，AAA被重新设计为通过转铁蛋白受体上的受体介导的转运穿过血脑屏障（BBB）。该药物开发计划的目标是设计AAA，其在没有BBB破坏的情况下具有脑穿透性，并减少脑淀粉样蛋白斑块，而不引起血浆淀粉样蛋白肽升高或脑微出血。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Engineering and expression of a chimeric transferrin receptor monoclonal antibody for blood-brain barrier delivery in the mouse.

DOI：
10.1002/bit.22135
发表时间：
2009-03-01
期刊：
BIOTECHNOLOGY AND BIOENGINEERING
影响因子：
3.8
作者：
Boado, Ruben J.;Zhang, Yun;Wang, Yuntao;Pardridge, William M.
通讯作者：
Pardridge, William M.

Alzheimer's disease drug development and the problem of the blood-brain barrier.

DOI：
10.1016/j.jalz.2009.06.003
发表时间：
2009-09
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
0
作者：
Pardridge WM
通讯作者：
Pardridge WM

Pharmacokinetics and brain uptake of an IgG-TNF decoy receptor fusion protein following intravenous, intraperitoneal, and subcutaneous administration in mice.

小鼠静脉内、腹膜内和皮下给药后 IgG-TNF 诱饵受体融合蛋白的药代动力学和脑摄取。

DOI：
10.1021/mp400004a
发表时间：
2013
期刊：
Molecular pharmaceutics
影响因子：
4.9
作者：
Sumbria,RachitaK;Zhou,Qing-Hui;Hui,EricKa-Wai;Lu,JeffZhiqiang;Boado,RubenJ;Pardridge,WilliamM
通讯作者：
Pardridge,WilliamM

Pharmacokinetics and brain uptake of a genetically engineered bifunctional fusion antibody targeting the mouse transferrin receptor.