Biomimetic Macrophage Membrane-Coated Nanosponges: A Novel Therapeutic for Multidrug-Resistant Pseudomonas aeruginosa and Acinetobacter baumannii Hospital-Associated Pneumonia

项目总结 肺炎是美国因感染而导致住院的最常见原因，也是最常见的 感染相关死亡原因。医疗保健相关肺炎(HAP)的死亡率总体为13%，36% 在住进ICU的患者中。细菌性肺部感染也是延迟性肺炎的常见并发症。 大手术、创伤和病毒所致严重肺损伤患者术后需要机械通气 肺炎(如SARS-Cov2)；这种呼吸机相关肺炎(VAP)的死亡率更严重。 引起HAP/VAP的两大主要病原菌是革兰氏阴性杆菌和假单胞菌 铜绿假单胞菌(PA)和鲍曼不动杆菌(AB)，两者都经常高度耐药，并可发展为 对末线碳青霉烯类抗生素耐药。革兰氏阴性细菌HAP/VAP常合并中性粒细胞- 以及细胞因子引起的过度炎症和相关的肺损伤--当病情严重时被称为“急性” 呼吸窘迫综合征“(ARDS)。没有标准的临床证明的疗法来支持宿主 免疫系统在清除重症细菌性肺炎的同时抑制 导致肺组织破坏的过度炎症。在这里，我们描述了一种高度创新的药物概念 重症PA和AB肺炎患者具有独特的多重作用机制：仿生学 人巨噬细胞膜包裹纳米粒(MΦ-NP)。MΦ-NP是通过包裹细胞制成的 从人巨噬细胞衍生的膜围绕可生物降解的聚合物核心，保留其 膜脂双层和表面结构和受体的完整谱系，仅在纳米(~1/50,000) 比例。天然仿生赋予MΦ-NP结合、隔离和中和细菌的能力 毒素、内毒素和宿主来源的促炎细胞因子--三方作用机制 抑制有害炎症，保存组织完整性，促进细菌清除。在这里，我们描述我们的 广泛的先前发表的和初步的结果，有力地支持MΦ-NP的新治疗概念 用于治疗ICU患者的严重革兰氏肺炎，以及旧金山久经考验的团队如何 迭戈细胞治疗公司将在我们的临床发展计划的每一步提供支持 走向研究性新药(IND)应用和进入第一阶段临床试验，以满足这一关键 未得到满足的医疗需求。在目标1中，我们将研究MΦ-NP对肺上皮和内皮细胞的保护能力 肺炎挑战下屏障的完整性和功能，包括在新型3D人类IPSC中的工作 有机化合物。在目标2中，我们将检测MΦ-NP阻断过度的肺泡巨噬细胞和 中性粒细胞驱动的炎症，但保留其对多药耐药革兰氏病原体的抗菌功能。终于 在目标3中，我们将对气管内(IT)和/或静脉(IV)MΦ-NP的益处进行活体分析 对多药耐药小鼠模型的死亡率、细菌清除和肺部炎症/损伤的治疗 并进行关键研究以评估PK/PD和MΦ-NP给药的毒性。

PROJECT SUMMARY Pneumonia is the most common cause of hospitalization due to infection in the US and the most common cause of infection-related death. Mortality in healthcare-associated pneumonia (HAP) is 13% overall and 36% in patients admitted to the ICU. Bacterial lung infections are also a frequent complication of prolonged mechanical ventilation required in patients after major surgery, traume, and severe lung injury due to viral pneumonias (e.g. SARS-Cov2); mortality in such ventilator-associated pneumonias (VAP) is even more grave. Two leading bacterial causes of HAP/VAP are the Gram-negative nosocomial pathogens Pseudomonas aeruginosa (PA) and Acinetobacter baumannii (AB), both frequently highly multidrug-resistant and can develop resistance to last line carbapenems. Gram-negative bacterial HAP/VAP is frequently complicated by neutrophil- and cytokine driven hyperinflammation and associated lung damage—which when severe is designated “acute respiratory distress syndrome” (ARDS). There are no standard clinically proven therapies to support the host immune system in clearing severe bacterial pneumonia while simultaneously suppressing the hyperinflammation that leads to lung tissue destruction. Here we describe a highly innovative drug concept for critically ill patients with severe PA and AB pneumonia with a unique multifold mechanism of action: biomimetic human macrophage membrane-coated nanoparticles (MΦ-NP). MΦ-NP are made by wrapping cell membranes derived from human macrophages around biodegradable polymeric cores, retaining their membrane lipid bilayer and full repertoire of surface structures and receptors, just on a nano (~1/50,000th) scale. The natural biomimicry imparts to the MΦ-NP the ability to bind, sequester and neutralize bacterial toxins, lipopolysaccharide (LPS), and host-derived proinflammatory cytokines, a tripartite mechanism of action to curb harmful inflammation, preserved tissue integrity, and facilitate bacterial clearance. Here we describe our extensive prior published and preliminary results that strongly support the novel therapeutic concept of MΦ-NP for the treatment of severe Gram- bacterial pneumonia in ICU patients, and how the proven team at San Diego-based Cellics Therapeutics will support our Clinical Development Plan at every step of the pathway toward an investigational new drug (IND) application and entry into Phase 1 clinical trials to meet this critical unmet medical need. In Aim 1 we will study the capacity of MΦ-NP to preserve lung epithelial and endothelial barrier integrity and function upon pneumonia challenge, including work in novel 3D human iPSC derived organoids. In Aim 2, we will examine the ability of MΦ-NP to block excessive alveolar macrophage and neutrophil-driven inflammation but preserve their antibacterial function against MDR Gram- pathogens. Finally in Aim 3, we will conduct in vivo analysis of the benefits of intratracheal (IT) and/or intravenous (IV) MΦ-NP therapy on mortality, bacterial clearance, and lung inflammation/damage in murine models of MDR Gram- pneumonia and perform key studies to assess PK/PD and toxicity profile of MΦ-NP administration.