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

仿生巨噬细胞膜包被的纳米海绵：一种治疗多重耐药铜绿假单胞菌和鲍曼不动杆菌医院相关肺炎的新疗法

• 批准号: 10674406
• 负责人: Angela Meier
• 金额: $ 102.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674406
• 关键词: 2019-nCoV; 3-Dimensional; Acinetobacter baumannii; Acinetobacter baumannii pneumonia; Acute Respiratory Distress Syndrome; Alveolar Macrophages; Anti-Bacterial Agents; Antibiotics; Antimicrobial Resistance; Apoptosis; Bacterial Pneumonia; Bacterial Toxins; Binding; Biomimetics; Blood donor; Brain Injuries; Carbapenems; Caring; Cell membrane; Cessation of life; Clinical; Clinical Management; Complication; Confined Spaces; Critical Illness; Development Plans; Drug Kinetics; Endothelial Cells; Endothelium; Epithelial Cells; Epithelium; Goals; Hospital Mortality; Hospitalization; Hospitals; Human; Immune system; Immunologics; Infection; Inflammation; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Influenza; Intensive Care Units; Intravenous; Invaded; Investigational New Drug Application; Knowledge; Life; Lipid Bilayers; Lipopolysaccharides; Lung; Lung infections; Macrophage; Mechanical ventilation; Medical; Membrane; Morbidity - disease rate; Multi-Drug Resistance; Mus; Nosocomial pneumonia; Operative Surgical Procedures; Organism; Organoids; Pathway interactions; Patient Admission; Patients; Phagocytosis; Pharmaceutical Preparations; Pharmacodynamics; Phase I Clinical Trials; Pneumonia; Production; Proliferating; Pseudomonas aeruginosa; Pseudomonas aeruginosa pneumonia; Publishing; Pulmonary Inflammation; Resistance development; Respiratory Burst; Septic Shock; Serum; Structure; Structure of parenchyma of lung; Surface; Therapeutic; Tissue Preservation; Tissues; Toxic effect; Viral Pneumonia; Work; biodegradable polymer; biomaterial compatibility; cell injury; clinical development; cytokine; cytotoxic; experience; extracellular; immune clearance; in vivo; induced pluripotent stem cell; innovation; lung injury; lung preservation; mortality; mouse model; multidrug-resistant Pseudomonas aeruginosa; nano; nanoparticle; nanotherapeutic; neutrophil; novel; novel therapeutics; pathogen; pathogenic bacteria; pharmacokinetics and pharmacodynamics; pneumonia model; preservation; receptor; response; septic; septic patients; therapeutic nanoparticles; ventilator-associated pneumonia

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.

项目摘要 肺炎是美国因感染住院的最常见原因，也是最常见的 感染相关死亡的原因。卫生保健相关性肺炎（HAP）的死亡率总体为13%， 重症监护室的病人细菌性肺部感染也是一种常见的并发症， 大手术、创伤和病毒性肺损伤后需要机械通气的患者 肺炎（例如SARS-Cov 2）;此类呼吸机相关肺炎（VAP）的死亡率甚至更严重。 HAP/VAP的两个主要细菌原因是革兰氏阴性医院病原体假单胞菌 铜绿假单胞菌（PA）和鲍曼不动杆菌（AB），这两种菌经常高度耐药， 对最后一线碳青霉烯类耐药。革兰氏阴性细菌HAP/VAP经常并发中性粒细胞- 以及细胞因子驱动的过度炎症和相关的肺损伤-当严重时被称为“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 免疫系统清除严重的细菌性肺炎，同时抑制 导致肺组织破坏的过度炎症。在这里，我们描述了一个高度创新的药物概念， 重症PA和AB型肺炎重症患者具有独特的多重作用机制：仿生 人巨噬细胞膜包被的纳米颗粒（MΦ-NP）。MΦ-NP是用细胞包裹法制备的 膜衍生自人类巨噬细胞周围的可生物降解的聚合物核心，保留其 膜脂双层和完整的表面结构和受体，只是在纳米（~1/50，000） 规模天然的仿生赋予MΦ-NP结合、隔离和中和细菌的能力 毒素、脂多糖（LPS）和宿主衍生的促炎细胞因子，三方作用机制 抑制有害炎症，保持组织完整性，并促进细菌清除。在这里，我们描述了我们的 广泛的先前发表的和初步的结果，强烈支持新的治疗概念的MΦ-NP 治疗重症监护室患者的严重革兰氏细菌肺炎，以及旧金山的 总部位于Diego的Cellics Therapeutics将在途径的每一步支持我们的临床开发计划 研究性新药（IND）申请并进入1期临床试验，以满足这一关键要求。 未满足的医疗需求在目的1中，我们将研究MΦ-NP保护肺上皮和内皮细胞的能力。 在肺炎激发后的屏障完整性和功能，包括在新的3D人iPSC衍生物中的工作 类器官在目的2中，我们将检测MΦ-NP阻断过量肺泡巨噬细胞的能力， 嗜中性粒细胞驱动的炎症，但保留其对MDR革兰氏病原体的抗菌功能。最后 在目标3中，我们将对静脉内（IT）和/或静脉内（IV）MΦ-NP的益处进行体内分析。 治疗对MDR革兰氏阴性菌鼠模型中死亡率、细菌清除率和肺部炎症/损伤的影响 肺炎并进行关键研究以评估MΦ-NP施用的PK/PD和毒性特征。