Therapeutic antibody for RSV

RSV 治疗性抗体

基本信息

批准号：
9212746
负责人：
Lawrence Michael Kauvar
金额：
$ 149.96万
依托单位：
TRELLIS BIOSCIENCE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2017-10-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9212746
关键词：
Advanced Development Advanced Manufacturing Technology Affinity Age Animals Anti-Inflammatory Agents Anti-inflammatory Antibodies Antiviral Agents B-Lymphocytes Binding Biological Models Biological Sciences Bioreactors Biotechnology Cell Line Cells Cessation of life Child Chinese Hamster Ovary Cell Clinical Pathology Clinical Trials Collaborations Complement Cost Savings Cost-Benefit Analysis Costs and Benefits Cytomegalovirus Data Data Analytics Development Disease Drug Industry Epitopes Funding G-substrate GTP-Binding Proteins Glycoproteins Goals Hospitalization Human Immune Immune response Infant Infection Influenza Innate Immune System Investigation Laboratories Legal patent Licensing Link Lower respiratory tract structure Lung Inflammation Medical Monoclonal Antibodies National Institute of Allergy and Infectious Disease Nature Palivizumab Pathology Pharmaceutical Preparations Phase Population Premature Birth Preparation Probability Process Production Productivity Property Prophylactic treatment Proteins Publishing Research Respiratory Syncytial Virus Infections Respiratory physiology Respiratory syncytial virus Rivers Services Small Business Innovation Research Grant Standardization System Technology Testing Therapeutic Monoclonal Antibodies Therapeutic antibodies Tissues Toxicology Vaccines Viral Virus Diseases Work analytical method cell bank clinical candidate clinical development commercialization cost experience flasks human monoclonal antibodies human tissue in vitro activity innovation mouse model novel novel strategies prevent process optimization programs public health relevance response screening shear stress small molecule

项目摘要

DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease, leading annually to 200,000 deaths and 3 million hospitalizations of young children worldwide. Immune prophylaxis with a monoclonal antibody (mAb), Synagis(tm) (Medimmune, Inc.), was shown to be effective 15 years ago to reduce complications of infection in premature birth infants, but it has not shown efficacy as a post-infection treatment in the much larger population of full term infants. No safe and effective antiviral drugs are available and no effective vaccine has been produced to date. Accordingly, there remains a large unmet medical need. Using a proprietary technology for screening single human B cells, Trellis has cloned a native human mAb, 3D3 that overcomes the limitations of Synagis, providing unprecedented curative responses in animals post exposure. The new mAb targets a different envelope glycoprotein, one that has been implicated in sabotage of the host immune response. This antibody has an affinity of 1 pM for a highly conserved epitope. It has direct antiviral activity in vitro in the presence of complement, with potency 100-fold better than Synagis. In mouse models, 3D3 has shown potent activity as both a direct antiviral agent and as an agent to block the lung inflammation linked to clinical pathology. This dual activity is qualitatively different from Synagis, or from any of the small molecule antiviral drugs under investigation for treating RSV. As expected for a native human antibody, 3D3 showed no binding to a panel of human tissues. It has been expressed in stably transformed CHO cells at 0.3 g/L prior to selection, indicating feasibility of generating a high expressing cell line. Thus,all of the goals normally associated with Phase I SBIR research have been achieved. The goals of this Direct Phase II proposal are to develop a Master Cell Bank of expressing cells with the capacity of producing 3D3 at commercially useful levels (>2 g/L), and to develop the analytical and toxicological data needed for initiation of human testing (IND data package).

描述（由申请人提供）：呼吸道合胞病毒 (RSV) 是下呼吸道疾病的主要原因，每年导致全球 20 万人死亡和 300 万人住院，使用单克隆抗体 (mAb) Synagis(tm) 进行免疫预防。 ) ) (Medimmune, Inc.) 15年前就被证明可以有效减少早产儿感染并发症，但它尚未显示出对大量足月婴儿的感染后治疗的有效性，并且迄今为止还没有生产出有效的疫苗。因此，仍然存在大量未满足的医疗需求。 Trellis 采用筛选单个人类 B 细胞的专有技术，克隆了一种天然人类单克隆抗体 3D3，它克服了 Synagis 的局限性，在暴露后为动物提供了前所未有的治疗反应，这种新单克隆抗体针对的是一种不同的包膜糖蛋白。该抗体对保守表位的亲和力为 1 pM，在补体存在的情况下具有直接抗病毒活性，其效力是其 100 倍。 Synagis 在小鼠模型中显示出作为直接抗病毒剂和阻断与临床病理相关的肺部炎症的有效活性，这种双重活性与 Synagis 或任何小分子抗病毒药物都有本质上的不同。正如对天然人抗体的预期一样，3D3 在选择前已在稳定转化的 CHO 细胞中以 0.3 g/L 的浓度表达，这表明 3D3 的可行性。因此，通常与第一阶段 SBIR 研究相关的所有目标都已实现，该直接第二阶段提案的目标是开发具有商业生产 3D3 能力的表达细胞主细胞库。有用水平（> 2 g/L），并开发启动人体测试所需的分析和毒理学数据（IND 数据包）。