MAb Passive Vaccination against Acinetobacter baumannii

针对鲍曼不动杆菌的 MAb 被动疫苗接种

• 批准号: 9440295
• 负责人: BRAD J SPELLBERG
• 金额: $ 73.12万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 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/9440295
• 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; Developing 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; 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; killings; macrophage; mouse model; neutrophil; novel; pathogen; prevent; soft tissue; subcutaneous; synergism; virtual

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.

项目总结/摘要 50%的A。来自美国ICU的鲍曼不动杆菌分离株是极端耐药（XDR），远高于其他 病原体这些感染导致10，000和30，000人死亡，以及3.9亿美元的额外医疗费用， 在美国和全球每年7.42亿美元。此外，与其他耐药细菌相比， 抗生素正在研发中，以应对XDR A。鲍曼不动杆菌。迫切需要新的治疗方法。 我们建立了两个单克隆抗体，C8和39，共同结合90%的62个临床分离的A。 鲍曼不动试验。我们已经在XDRA的致死鼠模型中发现了功效。鲍氏菌血症 和吸入性肺炎是A.鲍曼不动杆菌感染此外，C8显示 在致死性A的延迟治疗期间与粘菌素具有显著的协同作用。鲍曼不动杆菌感染（39例尚未检测）。 还提出了尚未表征的其他MAb。我们将确定单克隆抗体的最佳混合物， 广泛靶向菌株，并确定保护机制，以支持未来的人源化和临床试验。 具体目标1：确定关于表面结合和体外杀伤多种细胞的最佳MAb 动杆菌临床分离株鲍曼不动杆菌。我们将定义MAb与同种型对照的表面结合，以广泛地 不同临床分离株A.鲍曼不动杆菌。我们还将确定细菌清除的机制， 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 易感性最后，我们将建立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种感染模型中的体内作用， 多株A.鲍曼不动杆菌，有无抗生素我们将在体内比较单一的 vs.在3个良好建立的感染模型中，在延迟治疗期间，组合MAb与同种型对照; 小鼠菌血症、小鼠肺炎和大鼠伤口感染。我们将评估抗MAb 老鼠体内的抗体然后，我们将确定感染前单克隆抗体预防的有效性，以及如何 长期感染后单克隆抗体治疗仍然有效，并且在长期感染期间多次剂量的单克隆抗体的影响 疗法最后，我们将在每个模型中定义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被动接种的保护机制。我们将 通过在野生型与小鼠中使用最佳MAb与同种型对照进行治疗，确定体内疗效机制 随着宿主效应物的选择性耗尽（例如，补体、巨噬细胞、中性粒细胞和活化Fc γ R与 抑制性Fc β RII）。结果测量将包括存活率、细菌密度和炎症。这些结果 将告知未来的努力，以优化人源化单克隆抗体的功效，并确定替代功效测定。 新的解决方案A.鲍曼不动杆菌感染是一个尚未满足的关键需求。我们将确定一个最佳的单克隆抗体方案， 对多个感染部位（血液、肺、软组织）的保护，定义体外保护相关性，以及 确定保护机制，这将使人源化MAb的未来功效优化成为可能。