Bioengineering of a New Antibody Drug Delivery Technology

新型抗体药物递送技术的生物工程

基本信息

批准号：
8055209
负责人：
RUBEN J. BOADO
金额：
$ 33.48万
依托单位：
ARMAGEN TECHNOLOGIES, INC.
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：
2008-09-15 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8055209
关键词：
Accounting Acquired Immunodeficiency Syndrome Active Immunization Adult Affinity Affinity Chromatography Alzheimer&apos s Disease Amyloid beta-Protein Animals Anions Antibodies Appearance Autopsy Binding Biochemical Biological Assay Biomedical Engineering Bioreactors Biotechnology Blood Blood - brain barrier anatomy Body Weight Bovine Spongiform Encephalopathy Brain Brain Diseases Brain Injuries Carbohydrates Cations Cell Line Cells Cerebrum Chimeric Proteins Chinese Hamster Chinese Hamster Ovary Cell Chromatography Clinical Chemistry Tests Cloning Complex DNA Dementia Development Disease Dose Drug Delivery Systems Drug Kinetics Encephalitis Endotoxins Engineering Enzyme-Linked Immunosorbent Assay Exclusion Filtration Fluorescence Microscopy Future Genetic Engineering Glial Fibrillary Acidic Protein Growth Hematoxylin and Eosin Staining Method Hemorrhage High Pressure Liquid Chromatography Histocytochemistry Human Immunoglobulin G Immunotherapy Injection of therapeutic agent Insulin Receptor Isoelectric Focusing Macaca mulatta Malignant neoplasm of brain Mediating Monoclonal Antibodies Multiple Sclerosis Organ Organ Weight Ovary Parkinson Disease Passive Immunization Peptide Mapping Peptides Perfusion Peripheral Pharmaceutical Preparations Phase Plasma Primates Process Production Progress Reports Protein Binding Proteins Prussian blue Publications Recombinant Fusion Proteins Reference Standards Relative (related person)Reporting Research Senile Plaques Serum-Free Culture Media Site Small Business Innovation Research Grant Symptoms Technology Temperature Testing Therapeutic Monoclonal Antibodies Therapeutic antibodies Time Tissue Stains Toxic effect Toxicology Transgenic Mice Urine West Nile virus Western Blotting Work amyloid peptide base brain tissue drug development fluoro jade human INSR protein immunocytochemistry manufacturing process molecular trojan horse nano neonatal Fc receptor neuropathology new technology novel therapeutics phase 1 study phase 2 study prevent programs receptor receptor binding uptake vector

项目摘要

DESCRIPTION (provided by applicant): Monoclonal antibodies (MAb) are potential new therapeutics for many brain diseases, including Alzheimer's disease (AD), Parkinson's disease, mad cow disease, West Nile encephalitis, neuro- AIDS, brain injury, brain cancer, or multiple sclerosis. In almost all cases, it is necessary that the MAb therapeutic that is administered into the blood be able to access target sites within the brain. However, MAb's are large molecule drugs that do not cross the blood-brain barrier (BBB). The BBB problem prevents the brain drug development of antibody drugs. The proposed research will develop a new technology for antibody drug delivery to brain, which could also be used for other organs, and the new technology will be applied to AD. This work is based on the genetic engineering of a fusion protein comprised of 2 antibodies. One antibody is the therapeutic antibody against the Abeta amyloid peptide of AD, and the other antibody is a drug delivery system, which is directed at an endogenous transporter on the human BBB. The Phase I studies accomplished the following: (1) genetic engineering of a tandem vector expressing the hetero-tetrameric fusion protein, (2) cloning of a permanently transfected host cell line that expresses high levels of the fusion antibody in serum free medium, (3) biochemical and functional characterizion of the fusion antibody, and (4) determination of the plasma pharmacokinetics (PK) and brain uptake of the fusion protein in the adult Rhesus monkey. The phase II studies will accomplish the following: (1) growth of the host cell line in a 50L bioreactor, followed by 3-column downstream processing that can be replicated in a GMP lab; (2) biochemical analysis of the fusion protein with over 15 analytical tests; (3) dose finding PK and toxicity study in Rhesus monkeys. These studies will enable future submission of an IND for human testing of this new fusion protein for AD. PUBLIC HEALTH RELEVANCE: Monoclonal antibodies are powerful new therapeutic products of biotechnology. Antibody drugs could be applied to many serious brain disorders, such as Alzheimer's disease (AD), Parkinson's disease, mad cow disease, West Nile encephalitis, neuro-AIDS, brain injury, brain cancer, or multiple sclerosis. However, antibody drugs cannot be developed for these disorders, because the antibody drugs do not cross the blood-brain barrier (BBB). The present research will develop a new technology for the drug delivery of antibody drugs for the brain, which could be applied to diseases such as AD.

描述（由申请人提供）：单克隆抗体（MAb）是许多脑部疾病的潜在新疗法，包括阿尔茨海默病（AD）、帕金森病、疯牛病、西尼罗河脑炎、神经艾滋病、脑损伤、脑癌或多发性硬化症。几乎在所有情况下，注入血液的单克隆抗体治疗剂必须能够到达大脑内的靶位点。然而，MAb 是大分子药物，不能穿过血脑屏障 (BBB)。 BBB问题阻碍了抗体药物的脑药物开发。拟议的研究将开发一种将抗体药物递送至大脑的新技术，该技术也可用于其他器官，并且该新技术将应用于AD。这项工作基于由 2 种抗体组成的融合蛋白的基因工程。一种抗体是针对 AD 的 Abeta 淀粉样肽的治疗抗体，另一种抗体是药物递送系统，针对人血脑屏障上的内源性转运蛋白。第一阶段研究完成了以下工作：（1）表达异源四聚体融合蛋白的串联载体的基因工程，（2）克隆永久转染的宿主细胞系，该细胞系在无血清培养基中表达高水平的融合抗体，（ 3)融合抗体的生化和功能表征，以及(4)测定成年恒河猴中融合蛋白的血浆药代动力学(PK)和脑摄取。 II期研究将完成以下任务：（1）宿主细胞系在50L生物反应器中生长，然后进行可在GMP实验室复制的3柱下游处理； (2)融合蛋白的生化分析，分析测试超过15项； (3)恒河猴剂量发现PK和毒性研究。这些研究将使未来能够提交 IND，以对这种新的 AD 融合蛋白进行人体测试。公共卫生相关性：单克隆抗体是强大的生物技术新治疗产品。抗体药物可应用于许多严重的脑部疾病，例如阿尔茨海默病（AD）、帕金森病、疯牛病、西尼罗河脑炎、神经艾滋病、脑损伤、脑癌或多发性硬化症。然而，无法开发针对这些疾病的抗体药物，因为抗体药物不能穿过血脑屏障（BBB）。目前的研究将开发一种向大脑输送抗体药物的新技术，该技术可应用于治疗 AD 等疾病。