About 70-80% of serious bacterial infections are biofilm-mediated. Not only do biofilms provide an anchor and physical protection for bacterial cells, but the physiology and genetic programming of bacteria also shifts between the planktonic (free floating) and sessile (stationary) states. Most notably, antibiotic sensitivity differs betwen the two states, with bacteria being less sensitive to antibiotics in the sessile state. Biofilms ar known to include a variety of polymers and proteins. One of these proteins has previously been shown to anchor the three dimensional scaffolding of the polymers. Trellis has used its proprietary antibody discovery technology to clone a high affinity antibody from human B lymphocytes, TRL1068, that binds the homologs of this protein from both gram positive and gram negative bacteria. Extraction of the protein from the biofilm by this antibody leads to the biofilm dissolving in a few hours in vitro, as shown for both Staphylococcus aureus and Pseudomonas aeruginosa. The proposed work will extend the in vitro characterization to include additional bacterial species, more detailed time course and dose/response studies. Based on those results, the antibody will then be tested in a rat model for infective endocarditis using an innovative non-invasive monitoring system that detects bacteria engineered to express a luminescent protein. If successful, this work will provide a compelling rationale to advance TRL1068 into IND-enabling manufacturing and toxicity studies for which we plan to seek Phase II funding. This antibody offers potential clinical benefit against a wide range of infections that are currently very difficult to treat. Infective endocarditis in particular is a well-defined indiction for which current therapy often fails, leading to expensive heart valve replacement surgery that has a significant relapse rate (re-establishment of the biofilm protected infection) leading to death.
This project will extend to an animal model studies on a native human monoclonal antibody with specificity for a key protein component of bacterial biofilms. Antibody mediated extraction of the protein leads to dissolution of the biofilm within a few hours, thereby increasing antibiotic efficacy. This antibody offers potential clinical benefit against a wide range of infections that are currently very difficult to treat.
| Estellés, Angeles; Woischnig, Anne-Kathrin; Liu, Keyi et al. (2016) A High-Affinity Native Human Antibody Disrupts Biofilm from Staphylococcus aureus Bacteria and Potentiates Antibiotic Efficacy in a Mouse Implant Infection Model. Antimicrob Agents Chemother 60:2292-301 |
