Phase II year
2020
(last award dollars: 2021)
Phase II Amount
$2,979,414
About 70-80% of serious bacterial infections are biofilm-mediated. Not only do biofilms provide an anchor and physical protection for bacterial cells, but antibiotic sensitivity differs between free living and sessile bacteria, with bacteria being less sensitive to antibiotics in the sessile state. One of the proteins comprising the biofilm matrix is the DNA binding protein HU and its close relatives. TRL1068, a patented human monoclonal antibody isolated by Trellis Bioscience, binds to HU and disrupts bacterial biofilms of wide origins causing the bacteria to revert to the antibiotic-sensitive state. Under SBIR funding, Trellis has discovered that TRL1068 is able to greatly enhance the efficacy of standard of care antibiotics to treat bacterial infection in multiple animal models; in the presence of TRL1068, reduction of CFUs over antibiotic alone can be improved by 2-3 orders of magnitude. Trellis has advanced TRL1068 through GMP manufacturing and preliminary toxicology with marked success, providing a clear path to filing an IND and initiation of human testing. In this Direct to Phase II STTR grant application, Trellis proposes to collaborate with academic and CRO scientists to extend the range of infections shown to be amenable to therapeutic improvement through the use of TRL1068. We will investigate three fields of investigation. One, we will explore the applicability of TRL1068 to infections of musculoskeletal implants; two, we will explore the effectiveness of inhaled TRL1068 for control of respiratory infections; and, three, we will investigate the relevance of in vitro models as screens for TRL1068 usefulness. By the time that TRL1068 has been tested for safety in humans, the data developed under this project will assist in the identification of the most appropriate Phase 2 clinical indications for this innovative and promising agent for infection control.
Public Health Relevance Statement: NARRATIVE. TRL1068, a patented human monoclonal antibody discovered by Trellis Bioscience, disrupts bacterial biofilms to make antibiotics more effective in controlling recalcitrant infection. Animal models have demonstrated improved treatment of infectious endocarditis caused by Staphylococcus aureus and implant-associated infection by Gram negative bacteria. Experiments proposed in the current application are designed to test the suitability of TRL1068 for use in treatment of infections associated with joint replacement and infections of the respiratory tract, building on prior work showing efficacy in infective endocarditis and infected soft tissue implants. The average cost of each infected total joint replacement is more than $140,000, rising to more than $900,000 for each spinal implant. Oropharyngeal (OP) colonization is a major risk factor for ventilator-associated pneumonia (VAP): 23% of the patients with OP colonization evolved to VAP, vs. only 3.3% in patients without OP colonization. If effective clinically in these indications, TRL1068 will address a currently intractable problem that currently costs the US healthcare system $10 billion annually.
Project Terms: Acute; Address; Adult; Affinity; Animal Model; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antibodies; Applications Grants; Award; Bacteria; Bacterial Infections; bactericide; Binding; Biological Sciences; Cells; Chemosensitization; Chronic; chronic infection; chronic wound; Clinical; clinical lot; Clinical Trials; Communities; cost; Data; design; Development; Diabetic Foot Ulcer; DNA-Binding Proteins; Dose; Drug Tolerance; Effectiveness; Endocarditis; Epitopes; Escape Mutant; ESKAPE pathogens; experimental study; Formulation; Funding; Goals; Gram-Negative Bacteria; Grant; Health; Healthcare Systems; HU Protein; Human; human data; human monoclonal antibodies; Implant; implant associated infection; improved; in vitro Assay; in vitro Model; Infection; Infection Control; Infective endocarditis; Inhalation; innovation; Investigation; joint infection; Legal patent; Life; Link; lot production; Lung; Mediating; meetings; Metals; Microbial Biofilms; Modeling; Molecular Conformation; Monoclonal Antibodies; Musculoskeletal; Nebulizer; Operative Surgical Procedures; Oropharyngeal; Osteomyelitis; Pacemakers; pathogenic bacteria; Patients; Phase; Phase I Clinical Trials; phase II trial; preclinical development; Preparation; programs; Proteins; Proteome; Quality Control; Quality of life; Recurrence; Refractory; Regimen; Replacement Arthroplasty; Research; respiratory; Respiratory Tract Infections; Risk Factors; Rodent; safety testing; Scientist; Skin Tissue; Small Business Innovation Research Grant; Small Business Technology Transfer Research; soft tissue; Soft Tissue Infections; Spinal; stability testing; standard of care; Staphylococcus aureus; success; Surveys; Testing; Therapeutic; Time; Tissues; Toxicology; translational impact; Ventilator; ventilator-associated pneumonia; Work
