权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

New Human Antibodies for CNS Drug Delivery

用于中枢神经系统药物输送的新型人类抗体

基本信息

批准号：
10581615
负责人：
ERIC V SHUSTA
金额：
$ 38.21万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581615
关键词：
Acquired Immunodeficiency Syndrome Alzheimer&apos s Disease American Antibodies Antibody Specificity Antibody-drug conjugates Binding Biodistribution Biological Products Blood Blood - brain barrier anatomy Blood Circulation Brain Brain Diseases Brain-Derived Neurotrophic Factor Cells Cerebrum Characteristics Clinical Coupling Data Development Diffuse Disease Disease model Dose Drug Delivery Systems Drug Efflux Drug Kinetics Drug Transport Endothelium Ensure Exclusion Exhibits Fc Receptor Generations Genes Health Hematological Disease Human Immunoprecipitation In Vitro Insulin Insulin Receptor Libraries Link Liposomes Low Density Lipoprotein Receptor Malignant neoplasm of brain Mediating Medicine Mining Modeling Monitor Mus Neuropeptides Neurotensin Parkinson Disease Patients Persons Phage Display Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacotherapy Property Proteins Reagent Research Route Side Source Specificity Stroke System TFRC gene Techniques Technology Testing Therapeutic Transferrin Translating Translations Validation Vascular Endothelium antibody libraries blood-brain barrier crossing blood-brain barrier permeabilization dalton delivery vehicle drug candidate drug development efflux pump high-throughput drug screening human tissue in vivo induced pluripotent stem cell innovation intravenous administration intravenous injection lipophilicity nanoparticle natural hypothermia nervous system disorder novel novel therapeutics pharmacologic pre-clinical programs receptor response screening small molecule small molecule therapeutics stroke model tandem mass spectrometry targeted delivery targeted treatment therapeutic DNA transcriptome transcytosis uptake

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. However, current approaches have yielded limited brain uptake because the targeted transporters are ubiquitously expressed and the antibody targeting reagents have low BBB permeability. Therefore, this proposal is focused on the identification and validation of a new panel of antibodies and cognate transporters that can mediate BBB crossing of therapeutics. The antibodies were identified by mining a large phage display antibody library against a BBB model comprising human induced pluripotent stem cell- derived brain microvascular endothelial-like cells (BMECs). The barrier characteristics of these BMECs are well- suited to screen large antibody libraries for those antibodies capable of crossing the BBB in vitro. Moreover, at the transcriptome level, the transporter profiles in these cells correlate quite well to freshly isolated human BMECs. Finally, the human sourcing ensures that identified antibodies recognize human BBB transporters. Using this innovative platform, we have identified a panel of high value antibodies that preliminary data indicate are capable of binding both the human and murine BBB and delivering pharmacologically relevant amounts of drug cargo to the murine brain. We propose to further validate these brain targeting antibodies by identifying their cognate transporters. Next, we will determine their pharmacokinetic properties, biodistribution and brain regiospecificity. Finally, the antibodies will be tested for their ability to mediate brain uptake of conjugated drug cargo to normal brain and to diseased brain in the form of a murine stroke model. Those antibodies that exhibit significant and selective brain uptake would represent new, noninvasive drug delivery vectors with potential application in many neurological disease settings.

摘要