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Identification of Lamprey Antibodies Capable of Noninvasive Brain Drug Delivery

能够无创脑部药物输送的七鳃鳗抗体的鉴定

基本信息

批准号：
10186832
负责人：
ERIC V SHUSTA
金额：
$ 32.92万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10186832
关键词：
Acquired Immunodeficiency Syndrome Affinity Alzheimer&apos s Disease American Antibodies Antibody Specificity Antibody-drug conjugates Antigen Receptors Binding Biodistribution Biological Products Blood Blood - brain barrier anatomy Blood Circulation Brain Brain-Derived Neurotrophic Factor Carbohydrates Cell membrane Cerebrum Characteristics Clinical Complementary DNA Coupling Data Development Diffuse Disease model Dose Drug Delivery Systems Drug Kinetics Drug Transport Endothelium Exhibits Family Fc Receptor Gene Proteins Generations Genes Goals Hagfish Human Immune Immune system Immunization Immunize Immunoglobulin G Immunoprecipitation Insulin Lampreys Lead Leucine-Rich Repeat Libraries Link Liposomes Low Density Lipoprotein Receptor Low-Density Lipoproteins Lymphocyte Malignant neoplasm of brain Mammals Mediating Medicine Mining Mus Oryctolagus cuniculus Parkinson Disease Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pharmacotherapy Polysaccharides Preparation Proteins Reagent Research Route Side Specificity Stains Stroke Structure Surface System Techniques Technology Therapeutic Transferrin Translating Translations Validation Vertebrates Yeasts base blood-brain barrier permeabilization brain tissue cerebral microvasculature dalton drug candidate drug development high-throughput drug screening immunogenic improved in vivo innovation intravenous administration intravenous injection lipophilicity member nanoparticle nervous system disorder novel novel therapeutics pharmacokinetic model programs receptor response screening small molecule small molecule therapeutics stroke model tandem mass spectrometry targeted delivery therapeutic DNA trafficking transcytosis uptake vector

项目摘要

ABSTRACT Millions of people worldwide suffer from neurological diseases such as Alzheimer's disease, stroke, and brain cancer. Advances in protein/gene profiling techniques and high throughput drug screening technologies have spawned many new drug candidates. However, the blood-brain barrier (BBB) has impeded the development and clinical realization of this new generation of neurotherapeutics by restricting the brain uptake of most small molecule therapeutics, and prohibiting brain uptake of protein- and gene-based medicines. A promising noninvasive brain delivery strategy takes advantage of endogenous BBB transport mechanisms as a means to shuttle drug cargo from the blood to the brain. Such receptor-mediated transport systems can be targeted using the exquisite specificity of antibodies that are in turn linked to a drug payload that can include small molecules, proteins, or DNA therapeutics. After binding to the receptor on the blood side, the antibody- drug conjugate acts as an artificial substrate for the transporter and is transcytosed from the blood, across the BBB, and into the brain. Current approaches have yielded limited brain uptake because the targeted transporters are ubiquitously expressed, and the antibody targeting reagents have a low BBB permeability. Therefore, this proposal is focused on the identification and validation of novel delivery vectors and their cognate BBB transporters that can mediate improved transport efficiency. Rather than deploying traditional mammalian antibody technology, we describe a new strategy that employs lamprey antibodies known as Variable Lymphocyte Receptors (VLRs) to target the BBB. Lampreys and humans last shared a common ancestor >500 million years ago, and due to this tremendous evolutionary divergence, even highly conserved mammalian proteins and carbohydrates are immunogenic in lampreys. By leveraging these unique aspects of the lamprey immune system with innovative screening technologies, we anticipate that the proposed research will provide new BBB-targeting VLRs capable of trafficking into the brain. To achieve these goals, lampreys were immunized with mouse brain microvessel plasma membrane preparations, and staining with the resultant polyclonal antiserum demonstrated that VLRs clearly recognize the in vivo BBB and bind to multiple unique glycan structures. The lymphocyte cDNA of immunized lampreys was then used to create a yeast display library consisting of millions of VLRs that will be screened using an innovative screening approach to select BBB-binding and trafficking monoclonal VLRs. These brain-targeting VLRs will be validated both by pharmacokinetic profiling and their capacity to elicit a pharmacologically- relevant response in a murine stroke model. Finally, the BBB-targeting VLRs will be employed to identify the cognate BBB transporter and any associated glycoforms. Those VLRs exhibiting significant and specific brain uptake would represent new, noninvasive brain drug delivery vectors that could be powerful in the treatment of debilitating neurological disease.

摘要

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）

Antibody-Targeted Liposomes for Enhanced Targeting of the Blood-Brain Barrier.

DOI：
10.1007/s11095-022-03186-1
发表时间：
2022-07
期刊：
PHARMACEUTICAL RESEARCH
影响因子：
3.7
作者：
Ye, Zhou;Gastfriend, Benjamin D.;Umlauf, Benjamin J.;Lynn, David M.;Shusta, Eric, V
通讯作者：
Shusta, Eric, V

Yeast display biopanning identifies human antibodies targeting glioblastoma stem-like cells.