Therapeutic Antibodies for Biofilm Infections

生物膜感染的治疗抗体

基本信息

批准号：
9201393
负责人：
Lawrence Michael Kauvar
金额：
$ 99.96万
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 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9201393
关键词：
Acinetobacter baumannii Adverse effects Animal Model Animals Antibiotics Antibodies Antibody Affinity Award B-Lymphocytes Bacteria Bacterial Infections Binding Biochemical Biological Assay Biological Sciences Catheters Cell physiology Cessation of life Chinese Hamster Ovary Cell Clinical Clinical Trials Collaborations Combined Antibiotics Conduct Clinical Trials Daptomycin Data Derivation procedure Development Disease Dose Echocardiography Engineering Epitope Mapping Esophageal Funding GMP lots Genetic Programming Gram-Negative Bacteria Grant Heart Valves Homologous Gene Homologous Protein Human Human Genome Image Immune system Implant In Vitro Indwelling Catheter Infection Infective endocarditis Klebsiella pneumonia bacterium Laboratories Lead Linezolid Mediating Medical Medical Device Metabolic Methods Microbial Biofilms Modeling Monoclonal Antibodies Morbidity - disease rate Operative Surgical Procedures Organ Osteomyelitis Pathogenesis Pathology Penetration Phase Polymers Preparation Probability Process Production Progress Reports Proteins Pseudomonas aeruginosa Qualifying Rattus Refractory Regimen Relapse Reporting Request for Applications Research Resistance Resources Rivers Rodent Model Scaffolding Protein Secure Sepsis Services Small Business Innovation Research Grant Small Business Technology Transfer Research Specificity Staging Staphylococcus aureus Structure Technology Testing Therapeutic Therapeutic Agents Therapeutic antibodies Time Tissues Toxicity Tests Toxicology Work abstracting catheter related infection cell bank clinical application clinically relevant extracellular heart valve replacement human disease human monoclonal antibodies in vitro activity in vivo manufacturing process methicillin resistant Staphylococcus aureus mortality mouse model novel novel therapeutics pre-clinical pre-clinical research safety testing scaffold scale up soft tissue stability testing tool

项目摘要

Abstract About 65-80% of serious bacterial infections are biofilm-mediated. Not only do biofilms provide an anchor and physical protection from the immune system 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 substantially between the two states, with bacteria being orders of magnitude less sensitive to antibiotics in the sessile state. Biofilms are 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, which binds the homologs of this protein from both Gram positive and Gram negative bacteria. In Phase I of this project, we used two rodent models of bacterial infection to demonstrate that extraction of the protein from the biofilm by this antibody leads to the biofilm dissolving in vivo as it does in vitro. Therapeutic benefit was seen for treatment of MRSA in both models: a rat model of infective endocarditis and a mouse model of implant infection. In Phase II, we will conduct IND-enabling studies for FDA approval by establishing a manufacturing method under GMP and conducting toxicity testing of the therapeutic antibody. In parallel, we will continue preclinical research to explore alternative indications and dosing regimens. 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 an indication 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. Because the biofilm can be imaged directly (using trans-esophageal echocardiogram technology), efficacy defined by clinical endpoints can be correlated with the mechanism of action. Since the heart valve is readily accessible to antibody delivered intravenously, tissue penetration is not a significant variable for this indication. The combination of high unmet medical need and favorable experimental features makes this indication particularly useful for our initial clinical trials.

摘要大约 65-80% 的严重细菌感染是生物膜介导的。生物膜不仅提供细菌细胞免受免疫系统的锚定和物理保护，但生理学和遗传细菌的编程也在浮游（自由漂浮）和固着（静止）状态之间转换。最值得注意的是，这两个州之间的抗生素敏感性差异很大，细菌的数量级为在固着状态下对抗生素的敏感性较低。已知生物膜包括多种聚合物和蛋白质。其中一种蛋白质先前已被证明可以锚定三维聚合物的支架。 Trellis 使用其专有的抗体发现技术克隆了一种高来自人 B 淋巴细胞的亲和抗体 TRL1068，它与来自两种细胞的该蛋白的同源物结合革兰氏阳性菌和革兰氏阴性菌。在该项目的第一阶段，我们使用了两种啮齿动物模型细菌感染，以证明通过该抗体从生物膜中提取蛋白质会导致生物膜在体内和在体外一样溶解。在两种情况下均观察到 MRSA 治疗的治疗效果模型：感染性心内膜炎大鼠模型和植入物感染小鼠模型。在第二阶段，我们将通过建立符合 GMP 的生产方法，进行 IND 授权研究以获取 FDA 批准对治疗性抗体进行毒性测试。与此同时，我们将继续进行临床前研究探索替代适应症和给药方案。该抗体针对以下疾病提供了潜在的临床益处：目前很难治疗的广泛感染。感染性心内膜炎尤其是当前治疗经常失败的适应症，导致昂贵的心脏瓣膜置换手术具有显着的复发率（生物膜保护感染的重新建立），导致死亡。因为生物膜可以直接成像（使用经食管超声心动图技术），确定功效临床终点可以与作用机制相关联。由于心脏瓣膜很容易静脉内输送的抗体可接近，组织渗透性对此不是一个重要变量指示。高度未满足的医疗需求和有利的实验特征相结合使得这适应症对于我们的初步临床试验特别有用。