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: 8822414
• 负责人: BRAD J SPELLBERG
• 金额: $ 0.55万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8822414
• 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.

项目总结/摘要 在过去的十年中，鲍曼不动杆菌已经成为最高度耐药的细菌之一， 细菌病原体在美国（US）和整个世界。70%以上的A。鲍曼不 临床分离株目前具有广泛的耐药性（XDR;即对除粘菌素外的所有抗生素都具有耐药性 或替加环素），反映自2000年以来增加>15倍。泛耐药（PDR）引起的感染 A.鲍曼不动杆菌（对所有可用的抗生素都有耐药性）已经出现，并将继续增加 由于缺乏新的药物在管道中的活动对A。鲍曼不动杆菌。 在缺乏有效抗生素的情况下，接种疫苗是一种很有希望的策略，以提高死亡率。 鲍曼不动杆菌感染。我们已经发现，用OmpA接种保护小鼠免受其他致命的XDR A。 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 调理吞噬杀伤A.和免疫血清被动接种明显改善了 感染小鼠的存活率。最近，从A. 鲍曼不动杆菌。抗OmpA单克隆抗体有效治疗已建立的XDR A。鲍曼不动杆菌感染同样，MAbs 以A.鲍曼不动杆菌荚膜多糖（由Russo博士（Co-I）提出）在治疗 A.伤口感染模型中的鲍曼不动杆菌。因此，我们寻求将针对OmpA的单克隆抗体与针对OmpA的单克隆抗体进行联合收割机组合， 胶囊作为抗XDR A的被动疫苗接种。鲍曼不动杆菌。我们假设单克隆抗体的最佳方案 将被鉴定为改善IV、肺和伤口感染的啮齿动物模型中的结果。 我们的具体目标是：1）确定单克隆抗体的表位，表面结合，和体外杀伤机制， A.鲍曼不动杆菌。这些结果将支持选择非冗余的、广泛活性的MAb用于组合 目的2中的测试; 2）定义MAb在iv和肺部感染模型中的最佳有效组合， 小鼠和创伤/SC感染的大鼠模型; 3）定义保护创伤/SC感染的细胞和细胞因子机制。 通过选择性耗尽特异性宿主效应物（例如，补体、巨噬细胞和 嗜中性粒细胞）。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以在未来的临床试验中进行测试。 A.鲍曼不动杆菌感染是开发新治疗方法的关键的未满足的需求。没有新 治疗这些感染的抗生素可能在未来十年内问世。缺乏新的抗生素，MAb 对治疗此类感染具有巨大潜力。一种新的多价单克隆抗体被动疫苗接种策略将是 定义为A。鲍曼不动杆菌，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。在完成拟议的研究后， 准备进行人源化（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，并在XDR/PDR A患者中启动I期临床试验。鲍曼不动杆菌感染。