Host-Directed Immunotherapy: A One Health Approach

Project SummaryThe alarming rise of antibiotic resistant strains of bacteria have outpaced the development of new antibioticscapable of treating them. There is obvious concern over the transmission and spread of these resistant strainswithin the human population, but there is now considerable evidence of their transmission from infectedanimals to humans. The broad ramifications of this troubling public health scenario underscore the urgentneed for a new therapeutic strategy that extends beyond the use of conventional antibiotics and theirlimitations in the face of rapid bacterial mutation that give rise to resistant strains. A particularly promisingtherapeutic approach to provide this unmet need is mobilizing innate immune responses with a safe andeffective immune stimulatory molecule. Such ?host-directed immunotherapy? not only will invoke the body'sinherent first line of defense against infection, but will also contribute few/no mutational pressures since thistherapy is not imposed directly on the bacteria in the manner of antibiotics. The potential of host-directedimmunotherapy against resistant bacterial and viral infections in mice has been demonstrated by theadministration of our lead immune stimulatory candidate EP67, a response selective decapeptide agonist ofthe C5a receptor (C5aR/CD88) derived from the biologically active C-terminal region of human complementcomponent C5a (C5a65-74). Against this backdrop, the long-term goal is to establish EP67 (or an improvedanalogue) as an FDA-approved therapeutic for the treatment of antibiotic-resistant infections via the safe andeffective induction of host innate immunity through the C5a/C5aR network on antigen presenting cells.The principal objective of this R01 project, which is an important step toward this goal, is to move the leadcandidate EP67 (or analogue) along an IND-leading pathway that strengthens such designation by the FDA.This objective will be approached by the following specific aims: 1) Down-select from our lead candidate EP67by refining/enhancing the structure-function attributes of EP67 from a series of analogues with residuesubstitutions for Pro at position 7; 2) Demonstrate therapeutic efficacy of EP67/analogue in inducing host-innate immune responses against local and systemic methicillin-resistant Staphylococcus aureus (MRSA)infections in the human-relevant porcine model; and 3) Initiate safety/toxicity/pharmacokinetic studies ofEP67/analogue in industry standard murine models. The team assembled for this project will bring thetechnological, clinical, regulatory, and product development expertise necessary for an IND application andsustainability through the FDA regulatory process leading to clinical trials. This will have a positive impact inthe field by bringing to the forefront the concept of host-directed immunotherapy as a safe and effectivestrategy for treating antibiotic resistant infections within the therapeutic framework of ?One Health?.