Monoclonal antibody passive vaccination to treat XDR Acinetobacter infections

单克隆抗体被动疫苗接种治疗 XDR 不动杆菌感染

• 批准号: 8896096
• 负责人: BRAD J SPELLBERG
• 金额: $ 42.82万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896096
• 关键词: Acinetobacter Infections; Acinetobacter baumannii; Antibiotic Resistance; Antibiotics; Antibodies; Antigens; Bacteria; Bacterial Antibiotic Resistance; Binding; Biological Assay; Businesses; Capital; Carbohydrates; Clinical; Clinical Trials; Colistin; Complement; Data; Death Rate; Development; Epitopes; Extreme drug resistant tuberculosis; Funding; Future; Grant; Head; Heating; Host Defense; Host Defense Mechanism; Human; Immune; Immune Sera; Immune system; Immunoglobulin Class Switching; In Vitro; Infection; Inflammatory Response; Intravenous; Lung; Mediating; Modeling; Monoclonal Antibodies; Multi-Drug Resistance; Mus; Organism; Outcome; Patients; Phagocytes; Pharmaceutical Preparations; Phase I Clinical Trials; Polysaccharides; Proteins; Rattus; Recombinants; Regimen; Resistance; Rodent Model; Serotyping; Serum; Specificity; Surface; Testing; Time; United States; Vaccination; Vaccines; Variant; Wound Infection; abstracting; base; capsule; clinical toxicology; cytokine; humanized monoclonal antibodies; improved; in vivo; in vivo Model; killings; macrophage; mortality; neutrophil; novel; pathogen; pre-clinical; programs; subcutaneous; tigecycline; vaccination strategy; wound

Project Summary/Abstract In the last decade, Acinetobacter baumannii has emerged as one of the most highly antibiotic-resistant bacterial pathogens in the United States (US) and throughout the world. Indeed, >70% of A. baumannii clinical isolates are now extensively drug resistant (XDR; i.e. resistant to all antibiotics except colistin or tigecycline), reflecting a >15-fold increase since 2000. Infections caused by pandrug-resistant (PDR) A. baumannii (resistant to all available antibiotics) are already being seen, and will continue to increase given the lack of new drugs in the pipeline with activity against A. baumannii. In the absence of effective antibiotics, vaccination is a promising strategy to improve mortality of A. baumannii infections. We have found that vaccination with OmpA protected mice from otherwise lethal XDR A. baumannii infection (preliminary data). Antibody titers correlated with protection, immune serum enhanced opsonophagocytic killing of A. baumannii, and passive vaccination with immune serum markedly improved the survival of infected mice. Most recently, monoclonal antibodies (MAbs) were raised against OmpA from A. baumannii. Anti-OmpA MAbs effectively treated established XDR A. baumannii infection. Likewise, MAbs targeting A. baumannii capsular polysaccharide (raised by Dr. Russo (Co-I)) were effective in the treatment of A. baumannii in a wound infection model. Thus, we seek to combine MAbs directed against OmpA and capsule as passive vaccination against XDR A. baumannii. We hypothesize that an optimal regimen of MAbs will be identified that improves outcomes in rodent models of iv, lung, and wound infection. Our specific aims are to: 1) Define MAb epitopes, surface binding, and in vitro cidal mechanism against A. baumannii. These results will support selection of non-redundant, broadly active MAbs for combination testing in Aim 2; 2) Define an optimally effective combination of MAbs in iv and lung models of infection in mice, and a rat model of wound/SC infection; 3) Define the cellular and cytokine mechanisms of protection of MAb passive vaccination by selective depletion of specific host effectors (e.g., complement, macrophages, and neutrophils) during intravenous and lung infection in mice. These mechanistic results will inform future efforts to optimize the efficacy of humanized MAbs, and define surrogate efficacy assays to test in future clinical trials. A. baumannii infections are a critical unmet need for development of novel treatments. No new antibiotics to treat these infections will likely be available in the coming decade. Absent new antibiotics, MAbs are of great potential to treat such infections. A novel multivalent MAb passive vaccination strategy will be defined against A. baumannii, and mechanisms of protection will be defined by manipulating host defense effectors and modulating epitope targets. Upon completion of the proposed studies, a mixture of MAbs will be ready for humanization (funded by private capital or business grants) to support pre-clinical toxicology studies, filing an IND, and initiation of phase I clinical trials in patients with XDR/PDR A. baumannii infections.

项目概要/摘要 在过去的十年中，鲍曼不动杆菌已成为抗生素耐药性最高的细菌之一 美国 (US) 和世界各地的细菌病原体。事实上，>70% 的鲍曼不动杆菌 临床分离株现在具有广泛耐药性（XDR；即对除粘菌素之外的所有抗生素具有耐药性） 或替加环素），自 2000 年以来增加了 15 倍以上。 全耐药 (PDR) 引起的感染 鲍曼不动杆菌（对所有可用抗生素具有耐药性）已经出现，并将继续增加 鉴于正在研发的新药缺乏针对鲍曼不动杆菌的活性。 在缺乏有效抗生素的情况下，疫苗接种是降低曲霉死亡率的一种有前景的策略。 鲍曼不动杆菌感染。我们发现，接种 OmpA 疫苗可以保护小鼠免受致命的 XDR A 侵害。 鲍曼不动杆菌感染（初步数据）。抗体滴度与保护相关，免疫血清增强 调理吞噬杀死鲍曼不动杆菌，并被动接种免疫血清可显着改善 受感染小鼠的存活率。最近，针对来自 A. 的 OmpA 产生了单克隆抗体 (MAb)。 鲍曼氏菌。抗 OmpA 单克隆抗体可有效治疗 XDR 鲍曼不动杆菌感染。同样，单克隆抗体 靶向鲍曼不动杆菌荚膜多糖（由 Russo 博士（Co-I）提出）可有效治疗 伤口感染模型中的鲍曼不动杆菌。因此，我们寻求将针对 OmpA 的单克隆抗体与 胶囊作为针对 XDR 鲍曼不动杆菌的被动疫苗接种。我们假设单克隆抗体的最佳方案 将确定可以改善啮齿动物模型的静脉、肺部和伤口感染的结果。 我们的具体目标是： 1) 定义 MAb 表位、表面结合和体外杀伤机制 鲍曼不动杆菌。这些结果将支持选择非冗余、具有广泛活性的单克隆抗体进行组合 目标 2 中的测试； 2) 确定静脉注射和肺部感染模型中单克隆抗体的最佳有效组合 小鼠和大鼠伤口/SC感染模型； 3) 定义细胞和细胞因子的保护机制 通过选择性消耗特定宿主效应物（例如补体、巨噬细胞和 小鼠静脉内和肺部感染期间的中性粒细胞）。这些机械结果将为未来的努力提供信息 优化人源化单克隆抗体的功效，并定义替代功效测定法以在未来的临床试验中进行测试。 鲍曼不动杆菌感染是开发新疗法的一个关键的未满足需求。没有新的 治疗这些感染的抗生素可能会在未来十年内上市。缺乏新的抗生素、单克隆抗体 具有治疗此类感染的巨大潜力。一种新型多价 MAb 被动疫苗接种策略将是 针对鲍曼不动杆菌定义，保护机制将通过操纵宿主防御来定义 效应子和调节表位靶标。完成拟议的研究后，单克隆抗体混合物将被 准备人性化（由私人资本或商业赠款资助）以支持临床前毒理学研究， 提交 IND 申请，并启动 XDR/PDR 鲍曼不动杆菌感染患者的 I 期临床试验。