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: 10460560
• 负责人: Lawrence Michael Kauvar
• 金额: $ 98.93万
• 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/10460560
• 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。生物膜不仅提供锚定作用 以及对细菌细胞的物理保护，但自由生活和固着的抗生素敏感性不同 细菌，细菌在固着状态下对抗生素不太敏感。其中一种蛋白质包含 生物膜基质是DNA结合蛋白HU及其近亲。 TRL1068，人类专利 由 Trellis Bioscience 分离的单克隆抗体，与 HU 结合并破坏广泛来源的细菌生物膜 导致细菌恢复到对抗生素敏感的状态。在 SBIR 资助下，Trellis 发现 TRL1068能够大大增强标准护理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，与单独使用抗生素相比，可以改善 CFU 的减少 2-3 个数量级。 Trellis已通过GMP制造和初步试验推进了TRL1068 毒理学取得了显着的成功，为提交 IND 和启动人体测试提供了明确的途径。 在这份直接进入第二阶段 STTR 拨款申请中，Trellis 建议与学术界和 CRO 合作 科学家们通过以下方法扩大了已证明可以改善治疗的感染范围 使用TRL1068。我们将调查三个调查领域。一、我们将探讨其适用性 TRL1068 治疗肌肉骨骼植入物的感染；二、我们将探究吸入的功效 TRL1068用于控制呼吸道感染；第三，我们将研究体外模型的相关性 作为 TRL1068 用途的屏幕。当TRL1068经过人体安全性测试时， 该项目开发的数据将有助于确定最合适的 2 期临床 这种创新且有前途的感染控制剂的适应症。