Biofilm disrupting antibody to treat respiratory and musculoskeletal infections

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 使细菌恢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。一，我们将探索的适用性 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。

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.