R01AI180050

Development of anti-LPS therapeutic antibodies for the treatment of Pseudomonas aeruginosa infections - Summary

The goal of this proposal is to develop therapeutic antibodies for the treatment of multidrug resistant (MDR) P. aeruginosa infections, with an emphasis on sepsis.

With the rise in antimicrobial resistance around the world we are running out of therapeutic options against MDR P. aeruginosa.

Our laboratory has identified a potential solution to address this problem: a therapeutic antibody cocktail that targets the lipopolysaccharide of P. aeruginosa.

One of the antibodies present in the cocktail (WVU-VDC-S3D4, or S3D4 for short) completely protects mice against lethal sepsis, preventing bacterial dissemination and cytokine storm.

This antibody is also more potent than vaccination with a P. aeruginosa whole cell vaccine or passive immunization with serum from whole cell vaccinated mice.

Most interestingly, S3D4 is also capable of directly killing P. aeruginosa in vitro in the absence of complement or immune cells.

In this proposal, we will characterize the mechanism of action of S3D4, formulate it in an LPS multivalent antibody cocktail, and evaluate efficacy against MDR P. aeruginosa.

To do this, we will evaluate host and bacterial factors involved in S3D4 function (Aims 1 and 2).

We will then combine it as a cocktail with three additional antibodies that target the 6 LPS serogroups that cause 87% of P. aeruginosa bloodstream infection.

Efficacy in vitro and in vivo will be evaluated with MDR clinical isolates (Aim 3).

We will also evaluate efficacy against P. aeruginosa biofilms.

We hypothesize that a multivalent anti-LPS cocktail of antibodies, alone or in combination with standard of care antibiotics, will be efficacious for the prevention and treatment of MDR P. aeruginosa sepsis.

By the completion of these studies, we anticipate to elucidate the mechanism of action of a novel class of antibodies that can directly kill P. aeruginosa in vitro, which will help with the production of additional antibodies with similar functions against other MDR organisms.

We will also produce proof of concept data to support the generation of antibody therapy against P. aeruginosa infections.

Altogether, this project will generate important knowledge to improve the lives of patients affected by this MDR bacterium.

West Virginia University Research Corporation

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]

Morgantown, West Virginia 26506 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 375% from $741,917 to $3,521,872.