Biofilm disrupting antibody to treat respiratory and musculoskeletal infections

总结。 约70%-80%的严重细菌感染是由生物膜介导的。生物膜不仅提供了一个锚 和对细菌细胞的物理保护，但对抗生素的敏感性在自由生活和静止状态下是不同的 细菌，处于静止状态的细菌对抗生素不太敏感。其中一种蛋白质包括 生物膜基质是DNA结合蛋白Hu及其近亲。TRL1068，一个专利人类 Trellis Bioscience分离的单抗结合HU并破坏广泛来源的细菌生物膜 使细菌回复到抗生素敏感状态。在SBIR的资助下，Trellis发现 TRL1068能够大大提高标准护理抗生素治疗细菌感染的疗效 多种动物模型；在存在TRL1068的情况下，与单独使用抗生素相比，CFU的减少可以得到改善 高出2-3个数量级。格子公司已通过GMP制造，初步提升了TRL1068 毒理学方面取得了显著的成功，为提交IND和启动人体测试提供了一条明确的途径。 在这份直接到第二阶段的STTR拨款申请中，Trellis建议与学术和CRO合作 科学家们将扩大被证明可以通过治疗改进的感染范围 TRL1068的使用。我们将调查三个领域。首先，我们将探索该模型的适用性 TRL1068对肌肉骨骼植入物感染的影响；二、我们将探讨吸入的效果 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有用的屏幕。到TRL1068在人体上进行安全测试时， 根据该项目开发的数据将有助于确定最合适的2期临床 这种创新的和有希望的感染控制药物的适应症。

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.