Biofilm disrupting antibody to treat respiratory and musculoskeletal infections

生物膜破坏抗体用于治疗呼吸道和肌肉骨骼感染

• 批准号: 10251020
• 负责人: Lawrence Michael Kauvar
• 金额: $ 99.09万
• 依托单位: TRELLIS BIOSCIENCE, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251020
• 关键词: Acute; Address; Adult; Affinity; Animal Model; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antibodies; Applications Grants; Award; Bacteria; Bacterial Infections; Binding; Biological Sciences; Cells; Chemosensitization; Chronic; Clinical; Clinical Trials; Communities; DNA-Binding Proteins; Data; Development; Diabetic Foot Ulcer; Dose; Drug Tolerance; ESKAPE pathogens; Effectiveness; Endocarditis; Epitopes; Escape Mutant; Formulation; Funding; Goals; Gram-Negative Bacteria; Grant; HU Protein; Health; Healthcare Systems; Human; Implant; Infection; Infection Control; Infective endocarditis; Inhalation; Investigation; Legal patent; Life; Link; Lung; Mediating; Metals; Microbial Biofilms; Modeling; Molecular Conformation; Monoclonal Antibodies; Musculoskeletal; Nebulizer; Operative Surgical Procedures; Oropharyngeal; Osteomyelitis; Pacemakers; Patients; Phase; Phase I Clinical Trials; Preparation; Proteins; Proteome; Quality Control; Quality of life; Recurrence; Refractory; Regimen; Replacement Arthroplasty; Research; Respiratory Tract Infections; Risk Factors; Rodent; Scientist; Skin Tissue; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Soft Tissue Infections; Spinal; Staphylococcus aureus; Surveys; Testing; Therapeutic; Time; Tissues; Toxicology; Ventilator; Work; bactericide; chronic infection; chronic wound; clinical lot; cost; design; experimental study; human data; human monoclonal antibodies; implant associated infection; improved; in vitro Assay; in vitro Model; innovation; joint infection; lot production; meetings; pathogenic bacteria; phase II trial; preclinical development; programs; respiratory; safety testing; soft tissue; stability testing; standard of care; success; translational impact; ventilator-associated pneumonia

SUMMARY. 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.

概括。 大约70-80％的严重细菌感染是生物膜介导的。生物膜不仅提供锚 和细菌细胞的物理保护，但抗生素灵敏度在自由生活和无梗之间有所不同 细菌，细菌对无梗状态的抗生素敏感。包含的蛋白质之一 生物膜基质是DNA结合蛋白HU及其近亲。 TRL1068，专利的人 通过格子生物科学分离的单克隆抗体与HU结合并破坏了较广泛起源的细菌生物膜 导致细菌恢复为抗生素敏感态。在SBIR资助下，Trellis发现 TRL1068能够大大提高护理标准抗生素治疗细菌感染的功效 多种动物模型；在TRL1068存在的情况下，仅在抗生素上降低CFU 乘以2-3个数量级。 Trellis通过GMP制造和初步进行了TRL1068的高级TRL1068 毒理学具有明显的成功，为提出IND和人类测试的启动提供了清晰的途径。 在此直接进行II阶段STTR赠款应用程序中，Trellis建议与学术和CRO合作 科学家扩展了通过该感染的范围 使用TRL1068。我们将研究三个调查领域。第一，我们将探讨 TRL1068感染肌肉骨骼植入物；第二，我们将探索吸入的有效性 用于控制呼吸道感染的TRL1068；而且，三，我们将研究体外模型的相关性 作为TRL1068有用性的屏幕。到TRL1068已接受了人类安全性测试时， 根据该项目开发的数据将有助于识别最合适的阶段2临床 这种创新和有前途的感染控制的指示。