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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

基本信息

批准号：
9909128
负责人：
Lawrence Michael Kauvar
金额：
$ 99.92万
依托单位：
TRELLIS BIOSCIENCE, INC.
依托单位国家：
美国
项目类别：
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/9909128
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

项目摘要

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.

摘要约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物理保护细菌细胞，但抗生素敏感性不同之间的自由生活和固着细菌，细菌在固着状态下对抗生素不太敏感。其中一种蛋白质，生物膜基质是DNA结合蛋白HU及其近亲。TRL 1068，一种专利人类由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使细菌回复到对抗生素敏感的状态。在SBIR的资助下，Trellis发现， TRL 1068能够大大增强标准护理抗生素治疗细菌感染的功效，多个动物模型;在TRL 1068的存在下，可以改善CFU相对于单独抗生素的减少 2-3个数量级。Trellis通过GMP生产和初步测试，毒理学取得了显著的成功，为提交IND和启动人体试验提供了明确的途径。在这份直接进入第二阶段STTR资助申请中，Trellis建议与学术和CRO合作科学家扩大感染的范围，通过使用TRL 1068。我们将研究三个调查领域。第一，我们将探讨 TRL 1068对肌肉骨骼植入物感染的影响;二，我们将探讨吸入 TRL 1068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TRL 1068有用性的筛选。到TRL 1068在人体中进行安全性测试时，在本项目下开发的数据将有助于确定最合适的2期临床这种创新和有前途的感染控制剂的适应症。