Therapeutic Antibodies for Biofilm Infections

生物膜感染的治疗抗体

• 批准号: 9407282
• 负责人: Lawrence Michael Kauvar
• 金额: $ 100万
• 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: 2015-07-28 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9407282
• 关键词: Acinetobacter baumannii; Address; Affinity; Animal Model; Antibiotic Resistance; Antibiotics; B-Lymphocytes; Bacteria; Bacterial Infections; Bacterial Proteins; Binding; Biological Assay; Biological Sciences; Biotechnology; Cells; Centers for Disease Control and Prevention (U.S.); Chemosensitization; Chinese Hamster Ovary Cell; Clinical; Clinical Trials; Cloning; Collaborations; Communicable Diseases; Contracts; Cytomegalovirus; Data Analytics; Development; Disease; Drug Industry; Drug resistance; Epitopes; Failure; Family; Funding; Goals; Gram-Negative Bacteria; Grant; Homologous Protein; Human; Human Resources; Implant; In Vitro; Infection; Infective endocarditis; Inflammatory; Influenza; Klebsiella pneumonia bacterium; Link; Malignant Neoplasms; Microbial Biofilms; Modeling; Molecular Conformation; Monoclonal Antibodies; Mus; National Institute of Allergy and Infectious Disease; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase II Clinical Trials; Physiological; Preparation; Process; Production; Property; Prophylactic treatment; Proteins; Proteome; Pseudomonas aeruginosa; Publications; Publishing; Rattus; Readiness; Reference Standards; Refractory; Respiratory syncytial virus; Risk; Rodent Model; Scaffolding Protein; Small Business Innovation Research Grant; Soft Tissue Infections; Staphylococcus aureus; System; Technology; Testing; Therapeutic antibodies; Tissues; Toxic effect; Toxicology; Transfection; Vendor; Viral; Virus; Work; animal efficacy; cell bank; clinical development; clinical lot; clinical material; clinically significant; commercialization; cross reactivity; efficacy study; experience; human monoclonal antibodies; human tissue; in vivo; innovation; killings; meetings; methicillin resistant Staphylococcus aureus; mouse model; neutralizing antibody; pathogen; preclinical development; preclinical safety; product development; programs; quorum sensing; safety study; scale up; translational scientist

Abstract The CDC estimates that 65-80% of clinically significant drug resistant bacterial infections are drug refractory due to a change in physiological state of pathogens associated with biofilm formation. TRL1068 is a high affinity (100 pM) native human monoclonal antibody (mAb) that disrupts biofilms by extracting a key bacterial scaffolding protein. The epitope is highly conserved in the target protein homologs across a broad spectrum of gram positive and gram negative bacteria, including all ESKAPE pathogens. The released bacteria regain sensitivity to antibiotics. Biofilm disruption has been demonstrated in vitro for Staphylococcus aureus and for several gram negative species: Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae. In vivo, TRL1068 in combination with an antibiotic vs. antibiotic alone has shown statistically significant efficacy against methicillin resistant S. aureus (MRSA) in two animal models (infected implants in mice and infective endocarditis in rats) and against a drug resistant clinical isolate of A. baumannii in a mouse model of soft tissue infection. Clinical toxicity risk is low, as the epitope is not present in the human proteome and the mAb was cloned from a healthy human donor. A successful pre-IND meeting with the FDA has been held and IND-enabling development activities are underway by an experienced team funded in part by a Phase II SBIR grant from NIAID. The major goal of the SBIR funding is to develop a Master Cell Bank (MCB) producing TRL1068 at commercially useful levels along with development of product specific assays. Expression at the pooled CHO cell transfection stage is within the expected range prior to subcloning and optimization of upstream and downstream processing. The remaining SBIR work has low risk of failure and will be completed in Q3 2017. We now seek CRP funding to complete the IND-enabling preclinical development including toxicology studies, additional animal efficacy studies, and manufacturing of sufficient material for Phase 1 and Phase 2 human clinical trials. With CRP funding projected to start shortly after the end of the SBIR Phase II funding, we anticipate IND filing within 30 months after receipt of CRP funding. No SBIR or CRP funding will be used for actual clinical trial expenses.

摘要 CDC估计，65-80%的临床显著的耐药细菌感染是药物难治性的， 涉及与生物膜形成相关的病原体生理状态的变化。TRL 1068是一种高亲和力（100 pM）天然人单克隆抗体（mAb），其通过提取关键细菌支架来破坏生物膜 蛋白该表位在广谱革兰氏阳性菌中的靶蛋白同源物中高度保守。 和革兰氏阴性菌，包括所有ESKAPE病原体。释放的细菌重新对 抗生素已经在体外证明了金黄色葡萄球菌和几克 阴性菌种：铜绿假单胞菌、鲍曼不动杆菌、肺炎克雷伯菌。在体内， TRL 1068与抗生素的组合相对于单独的抗生素已经显示出针对以下的统计学显著的功效： 耐甲氧西林金黄色葡萄金黄色葡萄球菌（MRSA）在两种动物模型（感染的植入物在小鼠和感染性心内膜炎 在大鼠中）和抗A.鲍曼不动杆菌在软组织感染的小鼠模型中。 临床毒性风险较低，因为表位不存在于人蛋白质组中，并且mAb是从一个 健康的人类捐赠者与FDA成功举行了IND前会议， 活动正在由一个经验丰富的团队进行，部分资金来自NIAID的第二阶段SBIR赠款。主要 SBIR基金的目标是开发一个主细胞库（MCB），以商业上有用的速度生产TRL 1068。 沿着产品特异性检测的发展。合并CHO细胞转染阶段的表达 在亚克隆和优化上游和下游加工之前，的 剩余SBIR工作的失败风险较低，将于2017年第三季度完成。我们现在寻求CRP资金， 完成IND使能临床前开发，包括毒理学研究、其他动物疗效 研究和生产足够的材料用于1期和2期人体临床试验。有CRP供资 预计将在SBIR第二阶段资助结束后不久开始，我们预计IND申请将在30个月内完成 收到CRP资金后。SBIR或CRP资金将不用于实际临床试验费用。