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

A MERS-CoV Receptor Decoy

MERS-CoV 受体诱饵

基本信息

批准号：
9127085
负责人：
KEITH WYCOFF
金额：
$ 77.34万
依托单位：
PLANET BIOTECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9127085
关键词：
Active Sites Affinity Amino Acids Antibodies Binding Binding Proteins Biotechnology Camels Case Fatality Rates Cell Surface Proteins Cells Cessation of life Contracts Coronavirus Coronavirus Infections Coronavirus spike protein Country Development Dipeptidyl Peptidases Dose Drug Kinetics Enzyme-Linked Immunosorbent Assay Evaluation Extracellular Domain Fc Immunoglobulins Glucose Half-Life Health Human Hydrolase IgA1 IgA2 IgG1 Immunoglobulin Isotypes Immunoglobulins Infection Laboratories Lead Link Middle East Middle East Respiratory Syndrome Coronavirus Modeling Mus Mutate Mutation Peptide Hydrolases Phase Physiological Processes Planets Plants Polysaccharides Process Production Protein S Proteins Rattus Recombinant Proteins Route Safety Serum Site Surface Syndrome System Testing Toxicology Variant Virus base coronavirus receptor design efficacy testing epidemiology study improved in vivo inhibitor/antagonist intraperitoneal novel therapeutics pandemic disease phase 1 study phase 2 study protective efficacy receptor respiratory scale up transmission process

项目摘要

DESCRIPTION (provided by applicant): Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly emerging human health threat with a ~35% case fatality rate. MERS-CoV uses dipeptidyl peptidase 4 (DPP4), a cell surface protein, to enter and infect cells. During our Phase I study, using a transient plant expression system, we produced fusions of human DPP4 and the human immunoglobulin Fc sequences of IgG1, IgA1 and IgA2, to produce "receptor decoys" to block cellular infection with MERS-CoV. We demonstrated that DPP4-Fc binds to the S1 domain of MERS-CoV S protein, and that DPP4-Fc is a more potent inhibitor of MERS-CoV cellular infection than soluble DPP4. We showed that a DPP4-Fc fusion based on IgA1 might possibly be more effective than one based on IgG1. In addition, we demonstrated that binding and virus neutralization could be improved by more than 10-fold by modifying a single amino acid where human DPP4 and MERS-CoV spike protein contact. DPP4-Fc is also expected to have superior pharmacokinetics, as Fc will confer a long circulating half-life and the ability to be delivered to airway mucosal surfaces, the site of MERS-CoV infection. In a phase II study, we will produce new DPP4-Fc constructs to improve DPP4's affinity for MERS-CoV spike protein, and eliminate DPP4's peptidase activity by mutating the active site. We will optimize new constructs to improve expression in plants and to produce DPP4-Fc with human-like N-linked glycans. New DPP4-Fc fusions will be ranked for MERS-CoV spike protein-binding by ELISA and tested for the ability to neutralize MERS-CoV infection in susceptible cells. The best performing DPP4-Fc variants will be tested for protective efficacy in a mouse MERS model, evaluating both intraperitoneal and intranasal routes of administration. We will scale up production and purification of our lead molecule to purify 7 grams of DPP4-Fc, which will be used for a pilot 2-week repeat-dose safety/toxicology study in rats. We will evaluate safety and quantify DPP4-Fc in serum to obtain pharmacokinetic parameters. We will also screen for anti-DPP4-Fc antibodies in these studies.