R01AI176554

Biomimetic Macrophage Membrane-Coated Nanosponges: A Novel Therapeutic for Multidrug-Resistant Pseudomonas aeruginosa and Acinetobacter baumannii Hospital-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, trauma, 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 (MF-NP). MF-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 MF-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, preserve tissue integrity, and facilitate bacterial clearance.

Here we describe our extensive prior published and preliminary results that strongly support the novel therapeutic concept of MF-NP for the treatment of severe gram-negative 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 MF-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 MF-NP to block excessive alveolar macrophage and neutrophil-driven inflammation but preserve their antibacterial function against MDR gram-negative pathogens.

Finally, in Aim 3, we will conduct in vivo analysis of the benefits of intratracheal (IT) and/or intravenous (IV) MF-NP therapy on mortality, bacterial clearance, and lung inflammation/damage in murine models of MDR gram-negative pneumonia and perform key studies to assess PK/PD and toxicity profile of MF-NP administration.

San Diego University Of California

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

La Jolla, California 92093 United States

Single Zip Code

Partnerships for the Development of Novel Therapeutics to Combat Select Antibiotic Resistant Bacteria and Fungi (R01 Clinical Trial Not Allowed) (RFA-AI-22-028)

Amendment Since initial award the total obligations have increased 195% from $1,027,000 to $3,027,494.