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：
10432036
负责人：
Hanping Feng
金额：
$ 100.87万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10432036
关键词：
Advisory Committees Animal Disease Models Animal Model Antibiotic Resistance Antibiotics Antibodies Bacteria Bacterial Drug Resistance Biological Assay Biological Products 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 Monoclonal Antibodies Mus New Zealand Oryctolagus cuniculus Persons 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 manufacturing process novel paragon phase III trial pre-clinical preclinical evaluation product development recurrent infection 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.

抽象的抗菌抗性是全球公共卫生危机。抗生素艰难梭菌是造成的每年在美国有29,000多人死亡，感染对公共卫生构成了紧急威胁全世界。最关心的是，艰难梭菌感染（CDI）和疾病严重程度的发生率迅速近年来，由于抗呼吸高和抗生素抗性菌株的出现。 CDI是引起的通过两个主要的毒素TCDA和TCDB，没有细菌是无毒的。当前标准治疗抗生素是最佳的，并且由于肠道菌群的破坏而伴有高复发率。使用抗体来瞄准主要毒力因素的方法是一种新的治疗选择 CDI。然而，最先进的治疗性抗体bezlotoxumab，一种来自TCDB的单克隆抗体默克，仅显示出与抗生素性明对降低CDI复发的可比作用 III试验。这种不可避免的功效可能是由于靶向毒素和低效力的单个表位抗体。我们已经开发了一种基于4 VHHS的新型四特异性，人源化的抗体FZ001 靶向不同的表位，每个毒素上有两个。 FZ001有效，广泛地中和两种毒素不同的临床分离株，并证明了对原发性和经常性的有效治疗功效小鼠的CDI。 CGMP级CHO系的构建高表达水平的FZ001。在对RFA-AI-16-034的响应，我们建议开发细胞培养参数和分析测定，以及随后的制造过程，以生成GLP毒理学的FZ001。这个项目将允许生成用于未来IND归档和I期的化学，制造和控制（CMC）的关键数据临床试验。