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Principal Investigator: Angela Meier
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2023
Award: $1,027,000
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><3-D><3-Dimensional><3D><A baumanni><A baumannii><A baumannii associated pneumonia><A baumannii pneumonia><A baumannii related pneumonia><A baumannii-associated pneumonia><A baumannii-related pneumonia><A. baumanni><A. baumannii><A. baumannii associated pneumonia><A. baumannii pneumonia><A. baumannii related pneumonia><A. baumannii-associated pneumonia><A. baumannii-related pneumonia><A.baumannii><ARDS><Acinetobacter baumanni><Acinetobacter baumannii><Acinetobacter baumannii associated pneumonia><Acinetobacter baumannii pneumonia><Acinetobacter baumannii related pneumonia><Acquired brain injury><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Alveolar Macrophages><Anti-Bacterial Agents><Antibacterial Agents><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antimicrobial Resistance><Antimicrobial resistant><Apoptosis><Apoptosis Pathway><Bacterial Pneumonia><Bacterial Toxins><Binding><Biological Mimetics><Biomimetics><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Serum><Blood donor><Body Tissues><Brain Injuries><COVID-19 virus><COVID19 virus><Carbapenems><Caring><Cell membrane><Cellular injury><Cessation of life><Clinical><Clinical Management><CoV-2><CoV2><Complication><Confined Spaces><Critical Illness><Critically Ill><Cytokines and Inflammatory Response><Cytoplasmic Membrane><Da Nang Lung><Death><Development Plans><Drug Kinetics><Drugs><Early-Stage Clinical Trials><Endothelial Cells><Endothelium><Epithelial Cells><Epithelium><Goals><Grippe><Hospital Admission><Hospital Mortality><Hospitalization><Hospitals><Human><Immune system><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><In-house Mortalities><Infection><Inflammation><Inflammatory><Inflammatory Response><Inflammatory Response Pathway><Influenza><Inhospital Mortality><Intensive Care Units><Intravenous><Invaded><Investigational New Drug Application><Knowledge><Life><Lipid Bilayers><Lipopolysaccharides><Lung><Lung Inflammation><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung damage><Lung infections><MDR P aeruginosa><MDR P. aeruginosa><MDR Pseudomonas aeruginosa><Macrophage><Marrow Neutrophil><Mechanical ventilation><Medical><Medication><Membrane><Mice><Mice Mammals><Miscellaneous Antibiotic><Modern Man><Molecular Interaction><Morbidity><Morbidity - disease rate><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Murine><Mus><Mφ><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Nosocomial pneumonia><Operative Procedures><Operative Surgical Procedures><Organism><Organoids><Oxidative Burst><P aeruginosa><P aeruginosa associated pneumonia><P aeruginosa caused pneumonia><P aeruginosa induced pneumonia><P aeruginosa pneumonia><P aeruginosa-associated pneumonia><P aeruginosa-caused pneumonia><P aeruginosa-induced pneumonia><P. aeruginosa><P. aeruginosa associated pneumonia><P. aeruginosa caused pneumonia><P. aeruginosa induced pneumonia><P. aeruginosa pneumonia><P. aeruginosa-associated pneumonia><P. aeruginosa-caused pneumonia><P. aeruginosa-induced pneumonia><PK/PD><Pathway interactions><Patient Admission><Patients><Phagocytosis><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacodynamics><Pharmacokinetics><Phase 1 Clinical Trials><Phase I Clinical Trials><Plasma Membrane><Pneumonia><Pneumonitis><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Production><Programmed Cell Death><Proliferating><Pseudomonas aeruginosa><Pseudomonas aeruginosa associated pneumonia><Pseudomonas aeruginosa caused pneumonia><Pseudomonas aeruginosa induced pneumonia><Pseudomonas aeruginosa pneumonia><Pseudomonas pyocyanea><Publishing><Pulmonary Inflammation><Pulmonary Macrophages><Receptor Protein><Resistance development><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistance to antimicrobial><Resistant development><Resistant to Multiple Drug><Resistant to multi-drug><Resistant to multidrug><Respiratory Burst><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Septic Shock><Serum><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Shock Lung><Stiff lung><Structure><Structure of parenchyma of lung><Surface><Surgical><Surgical Interventions><Surgical Procedure><Therapeutic><Tissue Preservation><Tissues><Toxic effect><Toxicities><Viral Pneumonia><Work><Wuhan coronavirus><anti-bacterial><anti-microbial resistance><anti-microbial resistant><antibacterial><bacteria pathogen><bacteria pneumonia><bacterial pathogen><biocompatibility><biodegradable polymer><biomaterial compatibility><bioresorbable polymer><brain damage><brain-injured><cell damage><cell injury><cellular damage><clinical development><coronavirus disease 2019 virus><coronavirus disease-19 virus><cytokine><cytotoxic><damage to cells><degradable polymer><developing resistance><drug/agent><experience><extracellular><hCoV19><healthcare-associated pneumonia><hospital acquired pneumonia><hospital associated pneumonia><iPS><iPSC><iPSCs><immune clearance><immune elimination><in vivo><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><injury to cells><innovate><innovation><innovative><leukocyte oxidative burst><lipid bilayer membrane><living system><lung injury><lung preservation><mechanical respiratory assist><mechanically ventilated><membrane structure><mortality><mouse model><multi-drug resistant><multi-drug resistant P. aeruginosa><multi-drug resistant Pseudomonas aeruginosa><multidrug resistant><multidrug resistant P. aeruginosa><multidrug-resistant P. aeruginosa><multidrug-resistant Pseudomonas aeruginosa><murine model><nCoV2><nano><nano particle><nano-sized particle><nanoparticle><nanoparticle therapy><nanosized particle><nanotherapeutic><neutrophil><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathogen><pathogenic bacteria><pathway><pharmacokinetics and pharmacodynamics><phase I protocol><plasmalemma><pneumonia model><pneumonia models><preservation><pulmonary><pulmonary damage><pulmonary infections><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><receptor><resistance to anti-microbial><resistant to anti-microbial><resistant to antimicrobial><response><sepsis patients><septic><septic patients><surgery><therapeutic nanoparticles><three dimensional><ventilator-acquired pneumonia><ventilator-associated pneumonia><wet lung>