Monoclonal antibody passive vaccination to treat XDR Acinetobacter infections

项目摘要/摘要 在过去的十年里，鲍曼不动杆菌已经成为对抗生素耐药最高的细菌之一。 美国和世界各地的细菌病原体。事实上，70%的鲍曼不动杆菌 临床分离株现在广泛耐药(XDR；即对除粘菌素以外的所有抗生素都有耐药性 或替吉环素)，反映出自2000年以来增长了15倍。熊猫耐药(PDR)引起的感染 鲍曼不动杆菌(对所有可用的抗生素都有抗药性)已经出现，而且还会继续增加。 鉴于缺乏治疗鲍曼不动杆菌的新药。 在缺乏有效抗生素的情况下，接种疫苗是提高A. 鲍曼氏杆菌感染。我们已经发现，接种OmpA疫苗可以保护小鼠免受其他致命的XDR A的伤害。 鲍曼氏杆菌感染(初步数据)。抗体效价与保护相关，免疫血清增强 吞噬细胞对鲍曼不动杆菌的杀灭和免疫血清被动免疫可显著提高免疫效果。 受感染的小鼠存活。最近，人们从A. 鲍曼尼。抗OmpA单抗可有效治疗已确诊的鲍曼不动杆菌感染。同样，单抗 靶向鲍曼不动杆菌胶囊多糖(由Russo博士(Co-I)提出)在治疗食管炎方面有效 鲍曼不动杆菌在伤口感染模型中。因此，我们寻求将针对OmpA的单抗与 包埋胶囊被动接种鲍曼不动杆菌。我们假设单抗的最佳方案是 将被确定为改善静脉注射、肺部和伤口感染的啮齿动物模型的结果。 我们的具体目标是：1)确定单抗表位、表面结合和体外杀伤机制。 鲍曼曲霉(A.baumannii)这些结果将支持选择非冗余的、广泛活跃的单抗进行组合 目标2中的测试；2)确定单抗在静脉和肺感染模型中的最佳有效组合 小鼠，创伤/SC感染的大鼠模型；3)确定细胞和细胞因子的保护机制 通过选择性耗尽特定宿主效应物(如补体、巨噬细胞和 静脉感染和肺部感染过程中的中性粒细胞)。这些机械性的结果将为未来的努力提供信息 为了优化人源化单抗的疗效，并确定替代效力分析方法，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的治疗方法的一个关键的未得到满足的需求。没有新消息 在接下来的十年里，治疗这些感染的抗生素可能会出现。缺少新的抗生素，单抗 在治疗这种感染方面有很大的潜力。一种新的多价单抗被动接种策略将是 而保护机制将通过操纵宿主防御来定义。 效应器和调节表位靶标。在建议的研究完成后，混合的单抗将是 准备好人性化(由私人资本或商业赠款资助)，以支持临床前毒理学研究， 申请IND，并启动对XDR/PDR鲍曼不动杆菌感染患者的I期临床试验。

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.