Therapeutic Antibodies for Biofilm Infections

生物膜感染的治疗抗体

基本信息

批准号：
8979558
负责人：
Lawrence Michael Kauvar
金额：
$ 22.49万
依托单位：
TRELLIS BIOSCIENCE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8979558
关键词：
Acute Affinity Animal Model Animals Antibiotic Therapy Antibiotics Antibodies Antibody Affinity Area B-Lymphocytes Bacteria Bacterial Infections Binding Biomedical Research Blood specimen Burkholderia Cardiac Catheters Cell physiology Cessation of life Chronic Chronic Obstructive Airway Disease Clinical Clinical Paths Clinical Treatment Cystic Fibrosis Dose Drug Kinetics Ear Effectiveness Endocarditis Engineering Ensure Evaluation Funding Funding Mechanisms Genetic Programming Gram-Negative Bacteria Haemophilus influenzae Heart Heart Valves Homologous Protein Hour Human Immune system Implant In Vitro Infection Infective endocarditis Investigation Klebsiella pneumonia bacterium Light Los Angeles Luminescent Proteins Measures Mediating Microbial Biofilms Modeling Monitor Mus Operative Surgical Procedures Pharmacodynamics Phase Polymers Proteins Pseudomonas aeruginosa Randomized Rattus Refractory Relapse Research Research Institute Serum Skin Small Business Technology Transfer Research Specificity Sprague-Dawley Rats Staphylococcus aureus Staphylococcus epidermidis Sterility Structure System Technology Testing Therapeutic Therapeutic antibodies Time Toxic effect Toxicity Tests Toxicology Urinary tract Vancomycin Work base bone heart valve replacement human monoclonal antibodies implantation improved in vitro Model in vivo innovation non-invasive imaging non-invasive monitor public health relevance response scaffold soft tissue

项目摘要

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.

描述（由适用提供）：大约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定和物理保护，而且细菌的生理和遗传编程也在浮游生物（自由浮动）和无柄（固定）状态之间转移。最值得注意的是，抗生素敏感性在两个状态下有所不同，细菌对静态状态下的抗生素敏感不太敏感。生物膜AR已知包括各种聚合物和蛋白质。这些蛋白质之一先前已被证明是锚定聚合物的三维脚手架的。 Trellis使用其专有抗体发现技术来克隆人类B淋巴细胞TRL1068的高亲和力抗体，该抗体结合了该蛋白质的同源物与革兰氏阳性和革兰氏阴性细菌的同源物。该抗体从生物膜中提取蛋白质会导致几个小时内的生物膜在体外溶解，如金黄色葡萄球菌和铜绿假单胞菌所示。拟议的工作将扩展体外表征，包括其他细菌物种，更详细的时间过程和剂量/反应研究。基于这些结果，将使用创新的非侵入性监测系统在大鼠模型中测试抗体，用于感染的心内膜炎，该系统检测到设计用于表达发光蛋白质的细菌。如果成功的话，这项工作将为我们计划寻求II阶段资金的制造和毒性研究提供了令人信服的理由。该抗体可为广泛的感染提供潜在的临床益处目前很难治疗。尤其是感染性心内膜炎是一种明确的指示，当前治疗通常会失败，导致昂贵的心脏瓣膜替代手术，该手术具有显着的继电器（重新建立生物膜保护感染），导致死亡。