A Novel Humanized Tetra-specific Antibody against Clostridium difficile Infection

一种抗艰难梭菌感染的新型人源化四特异性抗体

基本信息

批准号：
9362547
负责人：
Hanping Feng
金额：
$ 146.06万
依托单位：
FZATA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9362547
关键词：
Advisory Committees Animal Disease Models Animal Model Antibiotic Resistance Antibiotics Antibodies Bacteria Bacterial Drug Resistance Biological Assay Businesses Cell Culture Techniques Cell Line Cells Certification Cessation of life Chemicals Chinese Hamster Ovary Cell Clinical Clostridium difficile Collaborations Cyclic GMP Data Development Development Plans Dose Drug Kinetics Engineering Epitopes Future Generations Goals Half-Life Hamsters In Vitro Incidence Infection Laboratories Lead Methods Mono-S Monoclonal Antibodies Mus New Zealand Oryctolagus cuniculus Pharmaceutical Preparations Phase I Clinical Trials Process Production Public Health Recurrence Reference Standards Regulation Running Serum Services Severity of illness Specificity Superbug Technology Transfer Testing Therapeutic Therapeutic antibodies Toxic effect Toxicology Toxin Treatment Efficacy Validation Viral Virulence Factors base biophysical properties cell bank clinical development clinically relevant effective therapy gut microbiota humanized antibody in vivo intravenous administration killings manufacturing process novel paragon phase III trial pre-clinical preclinical evaluation product development resistant strain response scale up standard care therapeutic protein

项目摘要

Abstract Antibacterial resistance is a global public health crisis. Antibiotic-resistant Clostridium difficile is responsible for more than 29,000 deaths in the US each year and the infection represents an urgent threat to public health worldwide. Of most concern is that the incidence of C. difficile infection (CDI) and disease severity is rapidly increasing in recent years due to the emergence of hypervirulent and antibiotic-resistant strains. CDI is caused by two major toxins TcdA and TcdB, absent which the bacterium is avirulent. Current standard treatment with antibiotics is sub-optimal and accompanied by a high recurrence rate due to the disruption of gut microbiota. Approaches using antibodies to target the major virulence factors represent a new treatment option against CDI. However, the most advanced therapeutic antibody bezlotoxumab, an anti-TcdB monoclonal antibody from Merck, only showed a comparable effect as antibiotic fidaxomicin on reducing CDI recurrence in recent Phase III trials. This less-than-desirable efficacy is likely due to targeting a single epitope of the toxin and low potency of the antibody. We have developed a novel tetra-specific, humanized antibody FZ001 based on 4 VHHs targeting distinct epitopes, two on each of the toxins. FZ001 potently and broadly neutralizes both toxins from different clinical isolates and demonstrates a potent therapeutic efficacy against both primary and recurrent CDI in mice. cGMP-grade CHO lines have been constructed with a high expression level of FZ001. In response to RFA-AI-16-034, we propose to develop cell culture parameters and analytic assays and subsequent manufacturing process in order to generate FZ001 for GLP toxicology. This project will allow the generation of the critical data of chemical, manufacturing, and control (CMC) for future IND filing and Phase I clinical trials.

抽象的抗菌素耐药性是一个全球性的公共卫生危机。抗生素耐药性艰难梭菌是造成美国每年有超过 29,000 人死亡，这种感染对公共健康构成了紧迫威胁全世界。最令人担忧的是，艰难梭菌感染 (CDI) 的发病率和疾病严重程度正在迅速增加近年来，由于高毒力和抗生素耐药菌株的出现，这种情况有所增加。 CDI引起由两种主要毒素 TcdA 和 TcdB 产生，没有这两种毒素，细菌就无毒力。目前的标准治疗方法是抗生素效果不佳，并且由于肠道微生物群被破坏而导致高复发率。使用抗体靶向主要毒力因子的方法代表了一种新的治疗选择 CDI。然而，最先进的治疗性抗体 bezlotoxumab 是一种抗 TcdB 单克隆抗体，来自默克 (Merck) 在最近阶段仅显示出与抗生素非达霉素 (fidaxomicin) 在减少 CDI 复发方面相当的效果三、试验。这种不太理想的功效可能是由于针对毒素的单一表位且效力较低的抗体。我们开发了一种基于 4 个 VHH 的新型四特异性人源化抗体 FZ001 针对不同的表位，每种毒素有两个表位。 FZ001 有效且广泛地中和来自不同的临床分离株，并表现出对原发性和复发性的有效治疗效果小鼠 CDI。已构建具有高表达水平的 FZ001 的 cGMP 级 CHO 系。在响应 RFA-AI-16-034，我们建议开发细胞培养参数和分析方法，后续制造过程，以生成用于 GLP 毒理学的 FZ001。该项目将允许生成化学、制造和控制 (CMC) 的关键数据，用于未来 IND 申报和第一阶段临床试验。