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：
10228693
负责人：
DAVID B. WEINER
金额：
$ 95.06万
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/10228693
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

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

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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.

项目摘要高度抗菌抗性（AMR）感染（如多药抗性假单胞菌）的控制是一个严重的全球公共卫生问题。抗多药的铜绿假单胞菌是顶级AMR微型 - 生物体，对感染控制提出了重大挑战。传统的替代干预措施迫切需要抗菌剂。靶向高度保守蛋白的单克隆抗体（mAb）代表一种针对传染病的重要方法。 MAB可以在住院之前立即交付或预防或控制感染的医疗程序。但是，蛋白质mAb递送技术严重受到高生产成本，发展缓慢和长期生产的限制，并且需要几个高剂量管理（mg/kg）。这些限制往往会使蛋白质mAb的递送成为一般的挑战管理并将其管理限制为有限的人口。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基因编码为优化来解决这些关键问题直接在体内给药的DNA平台。 DMAB在体内与直接抗微生物的体内触发水平活动迅速，可以简单而迅速地制造，可能避免冷链要求，并且是与蛋白质IgG相比，成本效益高。在最近的一项研究中，我们证明了工程的DMAB可以有效地输送MAB在体内，以控制小鼠中的MDR P.铜绿假单胞菌感染（Patel，Digianomenico等人。通讯。 2017）。我们的目标是通过进一步增强DMAB技术和将这种方法转化为控制抗生素耐药感染的策略。我们建议增强我们针对MDR P.铜绿的良好表征的DMAB铅系列的特性，并发展具有增强的抗原结合和接收器接合以控制感染的更有效形式。在此提案中，我们将进行重要的研究，以支持这种方法对大型动物的翻译，并最终移动提交。