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Novel DNA encoded monoclonal antibodies (DMAbs) for control of Antimicrobial Resistant (AMR) Pseudomonas aeruginosa infection

用于控制抗菌素耐药性 (AMR) 铜绿假单胞菌感染的新型 DNA 编码单克隆抗体 (DMAb)

基本信息

批准号：
10004562
负责人：
DAVID B. WEINER
金额：
$ 115.33万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004562
关键词：
Acinetobacter baumannii Address Affinity Animal Model Animals Anti-Bacterial Agents Antibiotic Resistance Antibiotics Antigen Receptors Antimicrobial Resistance Bacteria Burn injury Categories Cell Degranulation Centers for Disease Control and Prevention (U.S.)Clinic Cold Chains Communicable Diseases Communication Communities DNA DNA delivery Data Development Directed Molecular Evolution Dose Drug resistance Drug resistant Pseudomonas aeruginosa ESKAPE pathogens Engineering Enterobacter Enterococcus faecium Formulation Genes Goals Half-Life Hospitalization IgG Receptors Immunoglobulin G Infection Infection Control Intervention Klebsiella pneumoniae Lead Length Medical Modeling Modification Monitor Monoclonal Antibodies Mus National Institute of Allergy and Infectious Disease Natural Killer Cells Nature Nosocomial Infections Oryctolagus cuniculus Pharmacologic Substance Phase Population Population Heterogeneity Procedures Production Property Proteins Pseudomonas aeruginosa Pseudomonas aeruginosa infection Public Health Publishing Regimen Resistance Serum Staphylococcus aureus Technology The Wistar Institute Therapeutic Time Translating Translations Work World Health Organization antibiotic resistant infections antigen binding antimicrobial antimicrobial resistant infection antimicrobial resistant pathogen clinical development cost cost effective cytotoxic design in silico in vivo innovation lead optimization lead series microorganism multidrug-resistant Pseudomonas aeruginosa nonhuman primate novel novel strategies novel therapeutics preclinical study prevent priority pathogen research clinical testing respiratory skin wound synthetic construct

项目摘要

Project Summary The control of highly antimicrobial resistant (AMR) infections like multi-drug resistant Pseudomonas aeruginosa is a serious global public health concern. Multi-drug resistant P. aeruginosa are one of the top AMR micro- organisms, presenting a major challenge for infection control. Alternative interventions to traditional antimicrobials are urgently needed. Monoclonal antibodies (mAbs) targeting highly conserved proteins represent an important approach against infectious diseases. MAbs can be delivered immediately prior to hospitalization or a medical procedure to prevent or control infection. However, protein mAb delivery technology is severely limited by high manufacturing costs, slow development and long-term production, and a requirement for several high-dose administrations (mg/kg). These limitations tend to make protein mAb delivery a challenge for general administration and restrict its administration to limited populations. Our team has developed DMAb technology, a transformative approach that addresses these critical issues through encoding mAb genes into an optimized DNA platform that is administered directly in vivo. DMAbs reach protective levels in vivo with direct antimicrobial activity rapidly, can be manufactured simply and quickly, can likely avoid cold chain requirements, and are highly cost-effective compared to protein IgG. In a recent study, we demonstrated that engineered DMAbs can effectively deliver mAb in vivo to control MDR P. aeruginosa infection in mice (Patel, DiGiandomenico et al Nat. Comm. 2017). Our goal is to build on this work, through further enhancement in DMAb technology and to translate this approach into a strategy for control of antibiotic resistant infections. We are proposing to enhance the properties of our well-characterized DMAb lead-series directed against MDR P. aeruginosa and to develop more potent forms with enhanced antigen binding and receptor engagement to control infection. In this proposal, we will perform important studies to support translation of this approach to larger animals and ultimately to move to IND submission.

项目摘要高度耐药（AMR）感染的控制，如多重耐药铜绿假单胞菌是一个严重的全球公共卫生问题。多重耐药铜绿假单胞菌是最常见的耐药性微生物之一微生物，对感染控制提出了重大挑战。替代传统的干预措施针对高度保守蛋白质的单克隆抗体（mAb）代表了单克隆抗体是一种重要的抗传染病方法。单克隆抗体可以在住院前立即递送或预防或控制感染的医疗程序。然而，蛋白质mAb递送技术受到严重的限制。受高制造成本、缓慢开发和长期生产的限制，这些限制往往使蛋白质mAb递送成为一般免疫治疗的挑战。管理和限制其管理有限的人群。我们的团队已经开发了DMAb技术，一种变革性的方法，通过将mAb基因编码到优化的 DNA平台直接体内给药。DMAbs在体内达到保护水平，活性迅速，可以简单快速地制造，可以避免冷链要求，并且在最近的一项研究中，我们证明了工程DMAbs可以有效地在体内递送mAb以控制小鼠中MDR铜绿假单胞菌感染（Patel，DiGiandomenico等Nat. Comm. 2017）。我们的目标是在这项工作的基础上，通过进一步增强DMAb技术，将这一方法转化为控制抗生素耐药性感染的战略。我们建议加强我们充分表征的针对MDR铜绿假单胞菌的DMAb先导化合物系列的特性，具有增强的抗原结合和受体接合以控制感染的更有效的形式。在该提议中，我们将进行重要的研究，以支持将这种方法转化为更大的动物，并最终将其提交IND。