Therapeutic antibody for RSV

RSV 治疗性抗体

• 批准号: 9046676
• 负责人: Lawrence Michael Kauvar
• 金额: $ 126.88万
• 依托单位: TRELLIS BIOSCIENCE, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9046676
• 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; Clinical Pathology; Clinical Trials; Collaborations; Complement; Cost Savings; Cost-Benefit Analysis; Costs and Benefits; Cytomegalovirus; Data; Development; Drug Industry; Epitopes; Funding; GTP-Binding Proteins; Glycoproteins; Goals; Hospitalization; Human; Immune; Immune response; Immune system; Infant; Infection; Influenza; 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 Tract Diseases; Respiratory physiology; Respiratory syncytial virus; Rivers; Services; Small Business Innovation Research Grant; Staging; System; Technology; Testing; Therapeutic Monoclonal Antibodies; Therapeutic antibodies; Tissues; Toxicology; Vaccines; Viral; Virus Diseases; Work; analytical method; cell bank; 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

 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。 15 年前，单克隆抗体 (mAb) Synagis(tm) (Medimmune, Inc.) 的免疫预防已被证明可有效减少早产儿的感染并发症，但作为感染后治疗，它尚未在大量足月婴儿中显示出有效性。迄今为止，还没有安全有效的抗病毒药物，也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 使用筛选单个人类 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，为暴露后的动物提供了前所未有的治疗反应。新的单克隆抗体针对一种不同的包膜糖蛋白，这种糖蛋白与宿主免疫反应的破坏有关。该抗体对高度保守的表位具有 1 pM 的亲和力。在补体存在的情况下，它在体外具有直接抗病毒活性，其效力比补体强100倍 辛纳吉斯。在小鼠模型中，3D3 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 或任何正在研究的治疗 RSV 的小分子抗病毒药物有本质上的不同。正如对天然人类抗体所预期的那样，3D3 未显示出与一组人体组织的结合。在选择之前，它已在稳定转化的 CHO 细胞中以 0.3 g/L 的浓度表达，表明产生高表达细胞系的可行性。因此，通常与第一阶段 SBIR 研究相关的所有目标都已实现。该 Direct II 期提案的目标是开发一个表达细胞的主细胞库，能够以商业有用水平 (>2 g/L) 生产 3D3，并开发启动人体测试所需的分析和毒理学数据（IND 数据包）。