Therapeutic Antibodies for Biofilm Infections

 描述（由申请人提供）：约70-80%的严重细菌感染是生物膜介导的。生物膜不仅为细菌细胞提供了锚和物理保护，而且细菌的生理学和遗传编程也在浮游（自由漂浮）和固着（静止）状态之间转变。最值得注意的是，抗生素敏感性在两种状态之间存在差异，细菌在固着状态下对抗生素不太敏感。已知生物膜包括多种聚合物和蛋白质。这些蛋白质中的一种先前已经显示出锚聚合物的三维支架。Trellis利用其专有的抗体发现技术，从人B淋巴细胞中克隆了一种高亲和力抗体TRL 1068，该抗体结合来自革兰氏阳性和革兰氏阴性细菌的这种蛋白质的同源物。通过该抗体从生物膜中提取蛋白质导致生物膜在体外几小时内溶解，如金黄色葡萄球菌和铜绿假单胞菌所示。拟定工作将扩展体外表征，以包括其他细菌菌种、更详细的时间进程和剂量/反应研究。基于这些结果，然后将使用一种创新的非侵入性监测系统在感染性心内膜炎的大鼠模型中测试抗体，该系统检测经工程改造以表达发光蛋白的细菌。如果成功，这项工作将提供一个令人信服的理由，推动TRL 1068进入IND使能制造和毒性研究，我们计划寻求II期资金。这种抗体提供了针对广泛的感染的潜在临床益处， 特别是感染性心内膜炎是一种明确的适应症，目前的治疗经常失败，导致昂贵的心脏瓣膜置换手术，其具有显著的复发率（生物膜保护感染的重建），导致死亡。

 DESCRIPTION (provided by applicant): About 70-80% of serious bacterial infections are biofilm-mediated. Not only do biofilms provide an anchor and physical protection for bacterial cells, but the physiology and genetic programming of bacteria also shifts between the planktonic (free floating) and sessile (stationary) states. Most notably, antibiotic sensitivity differs betwen the two states, with bacteria being less sensitive to antibiotics in the sessile state. Biofilms ar known to include a variety of polymers and proteins. One of these proteins has previously been shown to anchor the three dimensional scaffolding of the polymers. Trellis has used its proprietary antibody discovery technology to clone a high affinity antibody from human B lymphocytes, TRL1068, that binds the homologs of this protein from both gram positive and gram negative bacteria. Extraction of the protein from the biofilm by this antibody leads to the biofilm dissolving in a few hours in vitro, as shown for both Staphylococcus aureus and Pseudomonas aeruginosa. The proposed work will extend the in vitro characterization to include additional bacterial species, more detailed time course and dose/response studies. Based on those results, the antibody will then be tested in a rat model for infective endocarditis using an innovative non-invasive monitoring system that detects bacteria engineered to express a luminescent protein. If successful, this work will provide a compelling rationale to advance TRL1068 into IND-enabling manufacturing and toxicity studies for which we plan to seek Phase II funding. This antibody offers potential clinical benefit against a wide range of infections that are currently very difficult to treat. Infective endocarditis in particular is a well-defined indiction for which current therapy often fails, leading to expensive heart valve replacement surgery that has a significant relapse rate (re-establishment of the biofilm protected infection) leading to death.