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.

项目摘要/摘要 在过去的十年中，鲍曼尼（Baumannii）的杆菌已成为抗生素最高度抗生素之一 美国（美国）和全世界的细菌病原体。确实，> 70％的Baumannii 临床分离株现在具有广泛的耐药性（XDR；即对所有抗生素抗性，除了colistin以外的所有抗生素 或Tigecycline），反映自2000年以来的增长> 15倍。 A. baumannii（对所有可用抗生素的抗药性）已经被看到，并且将继续增加 鉴于在管道中缺乏针对鲍曼尼曲霉的活性。 在没有有效的抗生素的情况下，疫苗接种是提高A的死亡率的有前途的策略。 Baumannii感染。我们发现，用OMPA保护的小鼠疫苗接种了否则致命的XDRA。 Baumannii感染（初步数据）。抗体滴度与保护相关，免疫血清增强 囊细胞杀死鲍曼尼a。 感染小鼠的存活。最近，针对A.的OMPA提出了单克隆抗体（mAb）。 鲍曼尼。抗empa mab有效治疗了已建立的XDR A. Baumannii感染。同样，mabs 靶向鲍曼尼·囊囊囊多糖（由Russo博士（CO-I）提出）在治疗方面有效 A.在伤口感染模型中的鲍曼尼I。因此，我们试图将针对OMPA的mabs结合起来 囊囊是针对XDR A. Baumannii的被动疫苗接种。我们假设MAB的最佳方案 将确定可以改善IV，肺和伤口感染的啮齿动物模型的结果。 我们的具体目的是：1）定义MAB表位，表面结合和体外cidal机制 A. Baumannii。这些结果将支持选择非冗余，广泛活跃的mAb进行组合 在AIM 2中进行测试； 2）在IV中定义mAb的最佳有效组合和感染中的肺模型 小鼠和伤口/SC感染的大鼠模型； 3）定义保护的细胞和细胞因子机制 通过选择性耗竭特定宿主效应子（例如补体，巨噬细胞和 中性粒细胞）在小鼠静脉内和肺部感染期间。这些机械结果将为未来的努力提供信息 为了优化人性化mAB的功效，并定义替代功效测定以在将来的临床试验中测试。 鲍曼尼氏菌感染是对新疗法发展的关键需求。没有新的 在未来十年中，可能会提供治疗这些感染的抗生素。缺乏新的抗生素，mabs 具有巨大的治疗感染潜力。一种新型的多价MAB被动疫苗接种策略将是 针对鲍曼尼a。 效应子和调节表位目标。拟议的研究完成后，mAb的混合物将是 准备人性化（由私人资本或商业赠款资助）支持临床前毒理学研究， 在XDR/PDR A. Baumannii感染患者中提交IND并开始I期临床试验。