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

Recombinant Fc fusions for treatment of uropathogenic E. coli

用于治疗尿路致病性大肠杆菌的重组 Fc 融合体

基本信息

批准号：
10021217
负责人：
EVGENI Veniaminovic SOKURENKO
金额：
$ 48.69万
依托单位：
PLANET BIOTECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10021217
关键词：
Adhesions Affect Animal Model Antibiotic Resistance Antibiotics Antibodies Bacteria Bacterial Adhesins Bacterial Adhesion Bacterial Attachment Site Bacterial Infections Binding Binding Proteins Biological Assay Budgets C3bi Cell Surface Receptors Cell-Matrix Junction Cells Classical Complement Pathway Clinical Trials Complement Complement 1q Complement 3b Complement Activation Complement Membrane Attack Complex Complement-Dependent Cytotoxicity Dipeptidyl Peptidases Enterobacter Enterobacteriaceae Escherichia coli Escherichia coli Infections Frequencies Future Galactose Goals Human Hybrids IgG1 IgG3 Immune Immunoglobulin G In Vitro Klebsiella Klebsiella Infections Klebsiella pneumoniae Macrophage-1 Antigen Mannose Mediating Membrane Membrane Glycoproteins Modification Molecular Multi-Drug Resistance N-terminal Phagocytes Phagocytosis Phase Plants Point Mutation Polysaccharides Protein Fragment Proteins Public Health Recombinant Proteins Recombinants Research Project Grants Resistance Serum Small Business Innovation Research Grant Surface Testing Urinary tract infection Uropathogenic E. coli Urothelial Cell Urothelium Variant Virulence Factors bacterial resistance community-acquired UTI cost glycosylation hybrid protein improved in vitro activity monomer neutrophil novel pandemic disease pathogen pathogenic bacteria resistant strain type 1 fimbriae

项目摘要

Urinary tract infections (UTIs) are among the most common bacterial infections, affecting 150 million people worldwide each year. In the USA, community-acquired UTIs account for about 11 million cases each year that cost the U.S. public health budget $5 billion annually. Uropathogenic Escherichia coli (UPEC) accounts for up to 80% of UTIs. While UTIs are currently treated with antibiotics, the frequency of multi-drug resistance is increasing, portending a future of untreatable UTIs. A promising alternative to antibiotics is to directly target bacterial virulence factors that are critical for bacterial adhesion to and invasion of uroepithelial cells. These virulence factors include the bacterial adhesin FimH, expressed by the majority of uropathogenic E. coli strains. FimH binds to a specific glycoform, oligomannose-3, carried by an abundant membrane glycoprotein on uroepithelial cells. We have produced a recombinant protein targeting FimH. It is a molecular fusion of human protein, dipeptidyl peptidase 4 (DPP4) with IgG1 Fc (DPP4-Fc), carries eight mannose-containing N-glycans and binds in a mannose-specific manner to FimH. We have shown that that DPP4-Fc promotes killing of uropathogenic E. coli by complement. The purpose of this research project is to demonstrate the ability of DPP4-Fc to promote activation of complement on the surface of antibiotic-resistant uropathogenic E. coli thereby leading to increased bacterial killing by complement and polymorphonuclear cells (PMNs). We will produce three new variants of DPP4-Fc carrying different numbers of N-glycans per monomer and different glycoforms. We will modify the Fc of DPP4-Fc to improve C1q binding and thus increase activation of the classical complement pathway. Modifications will include point mutations and replacement of IgG1 Fc with IgG3 Fc. We will also produce a negative control DPP4-Fc in which the Fc contains two point mutations that abrogate C1q binding and thus has no opsonizing activity. We will test all these new DPP4-Fc variants for their ability to: i) bind to uropathogenic E.coli, Enterobacter and Klebsiella pneumonia strains, ii) inhibit bacterial attachment to urothelial cells, iii) promote serum mediated killing of bacteria and iv) promote opsonophagocytosis of bacteria. We expect that DPP4-Fc can be developed into a novel treatment for uropathogenic E. coli, Enterobacter and Klebsiella infections. Future research projects will test the activity of these molecules in animal models and later in human clinical trials.

尿路感染（uti）是最常见的细菌感染之一，影响1.5亿人