Therapeutic Antibodies for Biofilm Infections

生物膜感染的治疗抗体

• 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
• 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

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.

摘要约65-80%的严重细菌感染是由生物膜介导的。生物膜不仅提供了一种 锚定和物理保护来自免疫系统的细菌细胞，但生理和遗传 细菌的编程也会在浮游状态(自由漂浮)和静止状态(静止)之间转换。 最值得注意的是，抗生素敏感性在两个州之间有很大差异，细菌的顺序是 在无柄状态下对抗生素的敏感度较低。已知的生物膜包括各种 聚合物和蛋白质。这些蛋白质中的一种先前已被证明锚定三维 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，它结合来自两个细胞的该蛋白的同源物 革兰氏阳性菌和革兰氏阴性菌。在这个项目的第一阶段，我们使用了两个啮齿动物模型 细菌感染证明这种抗体从生物膜中提取蛋白质会导致 生物膜在体内溶解，就像在体外一样。在这两种情况下，MRSA的治疗都有好处 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，我们会 通过建立符合GMP和FDA批准的制造方法，进行IND支持研究 进行治疗性抗体的毒性测试。同时，我们将继续进行临床前研究，以 探索其他适应症和给药方案。这种抗体具有潜在的临床疗效。 广泛的感染，目前很难治疗。尤其是感染性心内膜炎是一种 目前治疗经常失败的适应症，导致昂贵的心脏瓣膜置换手术 有显著的复发率(重新建立生物膜保护性感染)，导致死亡。因为 生物膜可以直接成像(使用经食道超声心动图技术)，疗效定义 临床终点可与其作用机制相关联。因为心脏瓣膜很容易 可通过静脉注射的抗体，组织穿透性不是一个重要的变量 指示。高度未得到满足的医疗需求和有利的实验特征相结合，使这一点 适应症对我们的初步临床试验特别有用。