Bacterial Pneumonia Therapeutic Antibody Safety Trial

Abstract Biofilm is a major contributor to clinical antibiotic resistance, as biofilm-associated (sessile) bacteria show up to 1000-fold lower sensitivity to antibiotics than free growing (planktonic) forms. The CDC estimates that 70% of clinically significant antibiotic failure is due to biofilm, including infections associated with implants, catheters, and tissue adhesions. TRL1068 is a native human monoclonal antibody (mAb) that is highly effective for disrupting biofilm and thereby enhancing the bactericidal activity of conventional antibiotics. The antibody target is conserved across both Gram positive and negative bacteria species. With prior SBIR funding, we demonstrated efficacy in five rodent models. With CARB-X funding, we initiated clinical development for patients with a prosthetic joint infection (PJI): TRL1068-101 (ClinicalTrials.gov NCT04763759). Standard of care for such patients includes replacement of the infected implant with an antibiotic eluting spacer for 8 weeks followed by a second surgery to implant a fresh prosthesis. A planned interim analysis demonstrated positive safety data, and established that the antibody penetrates into the synovial space. The bacterial burden on the explanted prosthesis was quantified following a standardized sonication method from the Mayo Clinic in a standardized volume of Ringer solution. After 7 days of treatment with TRL1068, 6 of 8 patients (75%) had a bacterial biofilm burden below 100 CFU/mL sonication fluid, and for 2 of them the adherent bacteria were below the limit of detection. The reduction and removal of biofilm in these eight PJI patients compares favorably to historical data (n=60) for which implants from only 15% of PJI patients were below 100 CFU/mL sonication fluid. In one of the animal models above, TRL1068 was administered directly to the respiratory system and was shown to be effective for bacterial pneumonia. Here, we propose to conduct a Phase 1 safety trial in healthy adult volunteers for TRL1068 formulated for nebulized delivery as an inhaled therapeutic to treat bronchial infections. We have previously developed an inhaled formulation for our influenza therapeutic mAb program (near-IND). Direct administration of TRL1068 to the airways should provide superior efficacy at a substantially reduced dose.