SBIR-STTR Award

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.

Public Health Relevance Statement:


Public Health Relevance:
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.

Project Terms:
Acute; Affinity; Animal Model; Animals; Antibiotic Therapy; Antibiotics; Antibodies; Antibody Affinity; Area; B-Lymphocytes; Bacteria; Bacterial Infections; base; Binding (Molecular Function); Biomedical Research; Blood specimen; bone; Burkholderia; Cardiac; Catheters; Cell physiology; Cessation of life; Chronic; Chronic Obstructive Airway Disease; Clinical; Clinical Paths; Clinical Treatment; Cystic Fibrosis; Dose; Drug Kinetics; Ear structure; Effectiveness; Endocarditis; Engineering; Ensure; Evaluation; Funding; Funding Mechanisms; Genetic Programming; Gram-Negative Bacteria; Haemophilus influenzae; Heart; heart valve replacement; Heart Valves; Homologous Protein; Hour; Human; human monoclonal antibodies; Immune system; Implant; implantation; improved; In Vitro; in vitro Model; in vivo; Infection; Infective endocarditis; innovation; Investigation; Klebsiella pneumonia bacterium; Light; Los Angeles; Luminescent Proteins; Measures; Mediating; Microbial Biofilms; Modeling; Monitor; Mus; non-invasive imaging; non-invasive monitor; Operative Surgical Procedures; Pharmacodynamics; Phase; Polymers; Proteins; Pseudomonas aeruginosa; public health relevance; Randomized; Rattus; Refractory; Relapse; Research; Research Institute; response; scaffold; Serum; Skin; Small Business Technology Transfer Research; soft tissue; Specificity; Sprague-Dawley Rats; Staphylococcus aureus; Staphylococcus epidermidis; Sterility; Structure; System; Technology; Testing; Therapeutic; Therapeutic antibodies; Time; Toxic effect; Toxicity Tests; Toxicology; Urinary tract; Vancomycin; Work

About 65-80% of serious bacterial infections are biofilm-mediated. Not only do biofilms provide an anchor and physical protection from the immune system 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 substantially between the two states, with bacteria being orders of magnitude less sensitive to antibiotics in the sessile state. Biofilms are 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, which binds the homologs of this protein from both Gram positive and Gram negative bacteria. In Phase I of this project, we used two rodent models of bacterial infection to demonstrate that extraction of the protein from the biofilm by this antibody leads to the biofilm dissolving in vivo as it does in vitro. Therapeutic benefit was seen for treatment of MRSA in both models: a rat model of infective endocarditis and a mouse model of implant infection. In Phase II, we will conduct IND-enabling studies for FDA approval by establishing a manufacturing method under GMP and conducting toxicity testing of the therapeutic antibody. In parallel, we will continue preclinical research to explore alternative indications and dosing regimens. 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 an indication 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. Because the biofilm can be imaged directly (using trans-esophageal echocardiogram technology), efficacy defined by clinical endpoints can be correlated with the mechanism of action. Since the heart valve is readily accessible to antibody delivered intravenously, tissue penetration is not a significant variable for this indication. The combination of high unmet medical need and favorable experimental features makes this indication particularly useful for our initial clinical trials.  

Public Health Relevance Statement:
Narrative Following a successful Phase I in vivo test of a native human monoclonal antibody with specificity for a key protein component of bacterial biofilms, we propose to initiate formal development leading towards an IND. Manufacturing development, toxicity testing, and preclinical dose optimization will be carried out. This antibody offers potential clinical benefit against a wide range of infections that are currently very difficult to treat.

Project Terms:
abstracting; Acinetobacter baumannii; Adverse effects; Animal Model; Animals; Antibiotics; Antibodies; Antibody Affinity; Award; B-Lymphocytes; Bacteria; Bacterial Infections; Binding; Biochemical; Biological Assay; Biological Sciences; catheter related infection; Catheters; cell bank; Cell physiology; Cessation of life; Chinese Hamster Ovary Cell; Clinical; clinical application; Clinical Trials; clinically relevant; Collaborations; Combined Antibiotics; Conduct Clinical Trials; Daptomycin; Data; Derivation procedure; Development; Disease; Dose; Echocardiography; Engineering; Epitope Mapping; Esophageal; extracellular; Funding; Genetic Programming; GMP lots; Gram-Negative Bacteria; Grant; heart valve replacement; Heart Valves; Homologous Gene; Homologous Protein; Human; human disease; Human Genome; human monoclonal antibodies; Image; Immune system; Implant; In Vitro; in vitro activity; in vivo; Indwelling Catheter; Infection; Infective endocarditis; Klebsiella pneumonia bacterium; Laboratories; Lead; Linezolid; manufacturing process; Mediating; Medical; Medical Device; Metabolic; methicillin resistant Staphylococcus aureus; Methods; Microbial Biofilms; Modeling; Monoclonal Antibodies; Morbidity - disease rate; mortality; mouse model; novel; novel therapeutics; Operative Surgical Procedures; Organ; Osteomyelitis; Pathogenesis; Pathology; Penetration; Phase; Polymers; pre-clinical; pre-clinical research; Preparation; Probability; Process; Production; Progress Reports; Proteins; Pseudomonas aeruginosa; Qualifying; Rattus; Refractory; Regimen; Relapse; Reporting; Request for Applications; Research; Resistance; Resources; Rivers; Rodent Model; safety testing; scaffold; Scaffolding Protein; scale up; Secure; Sepsis; Services; Small Business Innovation Research Grant; Small Business Technology Transfer Research; soft tissue; Specificity; stability testing; Staging; Staphylococcus aureus; Structure; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic antibodies; Time; Tissues; tool; Toxicity Tests; Toxicology; Work