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.

描述（由申请人提供）：阿尔茨海默氏病的痴呆症（AD）与大脑中淀粉样蛋白斑块的沉积相关，并且迫切需要新药将大脑中的斑块分解。最有效的斑块分解药物是抗淀粉样抗体（AAAS）。但是，AAA必须物理接触斑块以引起分解，并且斑块位于血脑屏障（BBB）后面的大脑中。与其他大分子药物一样，AAA在没有BBB破坏的情况下不会越过BBB。 AAA治疗在转基因小鼠模型或AD的人类中的副作用是ABETA淀粉样蛋白肽的血浆浓度的急剧增加，这与小鼠的脑微毛脑和人体血管脑水肿的脑毛发症有关。需要的是新一代的AAA，既可以穿透BBB而不会破坏BBB，又不会引起血浆淀粉样蛋白肽，脑水肿或BBB破坏的升高。在目前的工作中，对AAA进行了重新设计，以通过转铁蛋白受体（TFR）上的受体介导的转运穿过小鼠BBB。 AAA的单个链FV（SCFV）形式进行了设计，SCFV与鼠标TFR的基因工程嵌合单克隆抗体（MAB）的重链的羧基末端融合在一起，并且该融合蛋白被指定为CTFRMAB-SCFV。将融合蛋白长期施用至双转基因AD小鼠，治疗导致脑AB1-42降低40％，而血浆AB1-42无增加，并且没有脑微毛发。在拟议的工作中，将在AD的双转基因和三重转基因小鼠模型中进行剂量反应研究。此外，AD转基因小鼠将用双重生物疗法与大脑穿透AAA和脑穿透性肿瘤坏死因子（TNF）-Alpha抑制剂进行治疗。 AAA治疗加速了大脑中淀粉样蛋白斑块的分解，而大脑穿透TNF抑制剂的大脑会减少AD转基因小鼠模型大脑中淀粉样蛋白斑块的产生。公共卫生相关性：阿尔茨海默氏病的痴呆与大脑中淀粉样蛋白斑块的沉积相关，并且迫切需要新药将大脑中的斑块分解。最有效的斑块分解药物是抗淀粉样抗体（AAAS）。在目前的工作中，AAA经过重新设计，以通过转铁蛋白受体上的受体介导的转运跨越血脑屏障（BBB）。该药物开发计划的目的是AAA的工程，该AAA在没有BBB破坏的情况下渗透到大脑，并减少了脑淀粉样菌斑，而不会导致血浆淀粉样蛋白肽或大脑微肺炎的升高。

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

Receptor-mediated abeta amyloid antibody targeting to Alzheimer's disease mouse brain.