MAb Passive Vaccination against Acinetobacter baumannii

针对鲍曼不动杆菌的 MAb 被动疫苗接种

基本信息

批准号：
10228579
负责人：
BRAD J SPELLBERG
金额：
$ 69.42万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-25 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10228579
关键词：
Acinetobacter baumannii Anti-Bacterial Agents Antibiotic susceptibility Antibiotics Antibodies Aspiration Pneumonia Bacteria Binding Biological Assay Blood Cessation of life Clinical Clinical Trials Colistin Complement Critical Illness Data Death Rate Developed Countries Development Dose Drug resistance Escape Mutant Exhibits Frequencies Future Grant Health Care Costs Human Immune system Immunization In Vitro Infection Infectious Skin Diseases Inflammation Letters Lung Lung infections Methods Modeling Monoclonal Antibody Therapy Mus Outcome Measure Passive Immunization Patients Phagocytes Pneumonia Prophylactic treatment Proteins Rattus Regimen Resistance Risk Factors Rodent Sepsis Serial Passage Serum Site Surface TLR4 gene Testing Vaccinated Vaccination Vaccine Therapy Vaccines Virulence Wound Infection bacterial resistance base density human monoclonal antibodies immune clearance improved improved outcome in vivo infection rate macrophage mouse model neutrophil novel pathogen prevent soft tissue subcutaneous synergism virtual

项目摘要

Project Summary/Abstract Fifty percent of A. baumannii isolates from US ICUs are extreme drug resistant (XDR), far higher than for other pathogens. These infections result in 10,000 and 30,000 deaths and excess healthcare costs of $390 million and $742 million in the US and globally, annually. Furthermore, in contrast to other resistant bacteria, virtually no antibiotics are in the pipeline to deal with XDR A. baumannii. New treatments are critically needed. We established two MAbs, C8 and 39, that collectively bind to 90% of the 62 clinical isolates of A. baumannii tested. We have found efficacy in lethal murine models of XDR A. baumannii bacteremic sepsis and aspiration pneumonia, the two most common sites of A. baumannii infection. Furthermore, C8 exhibits substantial synergy with colistin during delayed therapy for lethal A. baumannii infection (39 is not yet tested). Other MAbs have also been raised that are not yet characterized. We will define an optimal mixture of MAbs to target strains broadly, and define mechanisms of protection to support future humanization and clinical trials. Specific Aim 1: Define optimal MAbs with respect to surface binding and in vitro killing of multiple clinical isolates of A. baumannii. We will define surface binding of the MAbs vs. isotype controls to broadly diverse clinical isolates of A. baumannii. We will also identify the mechanism of bacterial clearance by the MAbs, the potential for and frequency of bacterial escape mutants, and the impact of MAbs on antibiotic susceptibility. Finally, we will establish the antigenic targets of the MAbs. Specific Aim 2: Define the in vivo effects of the optimal MAbs in 3 models of infection and against multiple strains of A. baumannii, with and without antibiotics. We will compare in vivo efficacy of single vs. combination MAbs vs. isotype control during delayed therapy in 3 well-established models of infection; mouse bacteremic sepsis, mouse pneumonia, and rat wound infection. We will evauate for anti-MAb antibodies in rats. We will then determine how early prior to infection MAb prophylaxis is effective, and how long post-infection MAb therapy remains effective, and the impact of multiple doses of MAbs during prolonged therapy. Finally, we will define interactions between MAbs and antibacterial therapy in each model. Specific Aim 3: Define the mechanisms of protection of optimal MAb passive vaccination. We will define the in vivo mechanisms of efficacy by treating with optimal MAb vs. isotype control in wild-type vs. mice with selective depletion of host effectors (e.g., complement, macrophages, neutrophils, and activating FcR vs. inhibitory FcRII). Outcome measures will include survival, bacterial density, and inflammation. These results will inform future efforts to optimize the efficacy of humanized MAbs, and identify surrogate efficacy assays. Novel solutions for A. baumannii infections are a critical unmet need. We will identify an optimal MAb regimen protective across multiple sites of infection (blood, lung, soft tissue), define in vitro correlates of protection, and determine the mechanisms of protection, which will enable future efficacy optimization of humanized MAbs.

项目概要/摘要美国 ICU 分离出的鲍曼不动杆菌中有 50% 具有极端耐药性 (XDR)，远高于其他菌株这些感染导致 10,000 人和 30,000 人死亡以及 3.9 亿美元的额外医疗费用此外，与其他耐药细菌相比，美国和全球每年的销售额为 7.42 亿美元。正在开发抗生素来治疗 XDR 鲍曼不动杆菌，迫切需要新的治疗方法。我们建立了两种 MAb，C8 和 39，它们总共与 62 种临床分离的 A 菌株中的 90% 结合。我们已经在 XDR 鲍曼不动杆菌菌血症败血症的致死小鼠模型中发现了功效。和吸入性肺炎是鲍曼不动杆菌感染的两个最常见部位。此外，C8 也有表现。在致命鲍曼不动杆菌感染的延迟治疗期间与粘菌素有显着的协同作用（39 尚未测试）。还提出了其他尚未表征的 MAb，我们将定义 MAb 的最佳混合物。广泛针对感染，并定义保护机制以支持未来的人源化和临床试验。具体目标 1：确定表面结合和体外杀灭多种细菌的最佳 MAb 我们将广泛定义 MAb 与同种型对照的表面结合。我们还将确定鲍曼不动杆菌的细菌清除机制。单克隆抗体、细菌逃逸突变体的潜力和频率以及单克隆抗体对抗生素的影响最后，我们将确定单克隆抗体的抗原靶标。具体目标 2：确定最佳单克隆抗体在 3 种感染模型和抗感染模型中的体内作用我们将比较单一鲍曼不动杆菌菌株的体内功效，无论是否使用抗生素。在 3 种成熟的感染模型中延迟治疗期间与组合单克隆抗体与同型对照相比；我们将评估小鼠菌血症败血症、小鼠肺炎和大鼠伤口感染。然后我们将确定在感染前多早使用单克隆抗体预防是有效的，以及如何进行预防。感染后长时间的单克隆抗体治疗仍然有效，并且在长时间感染期间多剂量单克隆抗体的影响最后，我们将定义每个模型中单克隆抗体和抗菌治疗之间的相互作用。具体目标 3：确定最佳 MAb 被动疫苗接种的保护机制。通过在野生型小鼠和小鼠中使用 MAb 与同种型对照治疗来确定最佳疗效的体内机制选择性耗尽宿主效应子（例如补体、巨噬细胞、中性粒细胞和激活 FcR 与 FcR）抑制性 Fc-RII）。结果指标包括存活率、细菌密度和炎症。将为未来优化人源化单克隆抗体功效并确定替代功效测定的努力提供信息。鲍曼不动杆菌感染的新解决方案是一个未满足的关键需求，我们将确定最佳的单克隆抗体治疗方案。跨多个感染部位（血液、肺、软组织）提供保护，定义体外保护的相关性，以及确定保护机制，这将使人源化单克隆抗体未来的功效优化。