Therapeutic Antibodies for Biofilm Infections

生物膜感染的治疗抗体

基本信息

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
项目类别：
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

项目摘要

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.

抽象的疾病预防控制中心估计，有65-80％的临床意义抗药性细菌感染是药物难治性与生物膜形成相关的病原体生理状态的变化。 TRL1068是一个高亲和力（100 PM）本地人类单克隆抗体（MAB），通过提取关键细菌脚手架破坏生物膜蛋白质。表位在广泛的革兰氏阳性的靶蛋白同源物中高度保守和革兰氏阴性细菌，包括所有Eskape病原体。释放的细菌恢复了对抗生素。生物膜破坏已在体外证明金黄色葡萄球菌的体外，几克负物种：铜绿假单胞菌，鲍曼尼杆菌杆菌，克雷伯氏菌肺炎。体内， TRL1068与仅抗生素与抗生素结合使用，已显示出具有统计学意义的功效两种动物模型（小鼠感染植入物和感染性心内膜炎的甲氧西林金黄色葡萄球菌（MRSA）（MRSA）在大鼠中）和在软组织感染的小鼠模型中反对鲍曼尼曲霉的抗药性临床分离。临床毒性风险很低，因为在人蛋白质组中不存在表位，并且将mAb从A克隆到A 健康的人类捐助者。与FDA进行了成功的预定会议，并取得了共同的开发一支经验丰富的团队正在进行活动，该团队部分由NIAID的第二阶段SBIR赠款资助。专业 SBIR资金的目标是开发商业上有用的TRL1068的大型细胞库（MCB）水平以及特定于产品的开发。在合并的CHO细胞转染阶段的表达在上游和下游处理的亚克隆和优化之前，位于预期范围内。这剩余的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资金完成包括毒理学研究，额外动物疗效在内的促临床前发展研究，以及为第1阶段和第2阶段人类临床试验的足够材料制造。带有CRP资金预计将在SBIR第二阶段资金结束后不久开始，我们预计IND将在30个月内提交收到CRP资金后。实际的临床试验费用不会使用SBIR或CRP资金。