R01AI176543

Host Directed Orynotide for MDR Gram Negative Bacterial Infections - Project Summary

The goal of this grant proposal is to advance the preclinical development of a novel macrocyclic peptide, ORYNOTIDE™ MTD12813, for treatment of multidrug resistant (MDR) gram negative bacterial infections, with the initial focus being on infections caused by carbapenem-resistant enterobacteriaceae (CRE).

The emergence of infections by multiple CRE pathogens has created an urgent public health threat, because carbapenems are drugs of last resort for infections caused by an increasing fraction of MDR bacterial pathogens. Just two species, Klebsiella pneumoniae and Escherichia coli, cause an estimated 140,000 nosocomial infections per year in the United States alone, and many are carbapenem resistant.

There is global consensus that new preventive and therapeutic strategies are urgently needed to combat the growing problem of MDR bacterial infections.

The applicants, leaders in the field of -defensin biology, are responding to this need by developing orynotides, a new class of host-directed antimicrobial macrocyclic peptides bioinspired by the structural and biological properties of theta ()-defensins, macrocyclic peptides expressed exclusively in old world monkeys (but not humans).

Exploiting the pleiotropic host defense properties of -defensins, we produced a library of novel orynotides that includes several compounds that are highly effective in MDR gram negative septicemia models.

Hit-to-lead studies identified MTD12813 as the lead orynotide candidate for preclinical development as a first-in-class immunotherapeutic agent for MDR gram negative infections.

In the mouse peritoneal sepsis model, single dose administration of MTD12813 is highly effective (enhanced survival with concomitant bacterial clearance) against multiple strains of CRE-K. pneumoniae and CRE-E. coli, and additionally was shown to be effective in septicemia caused by MDR Acinetobacter baumannii.

Consistent with the range of pathogens against which MTD12813 is active in vivo, we showed that the peptide's mode of action is immunotherapeutic, promoting host-mediated bacterial clearance, stimulating phagocytosis and neutrophil recruitment, while modulating levels of otherwise dysregulated proinflammatory cytokines.

These data indicate that MTD12813 is a novel immunotherapeutic agent effective in the treatment of gram negative bacterial pathogens.

The peptide is readily manufacturable (~1.5 g on hand), highly stable in human plasma and whole blood, resistant to bacterial proteases, and well tolerated when administered by numerous routes.

In the proposed studies, we will advance the preclinical characterization of MTD12813.

Aim 1 studies will include production of GLP MTD12813 and other critical reagents, pharmacokinetic (PK) and PK/pharmacodynamic analyses, and ADME studies.

Aim 2 will focus on illuminating mechanism(s) of action at the cellular and molecular level.

Aim 3 objectives will include preclinical non-GLP safety and toxicokinetic studies in rats and beagle dogs, evaluation of immunogenicity, development of an antidrug antibody assay, and culminate with formal GLP safety studies.

The goal of these aims is to advance the preclinical development of MTD12813 to IND filing with the FDA.

University Of Southern 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]

Los Angeles, California 90033 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 201% from $1,005,952 to $3,025,760.