Therapeutic antibody for RSV

 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20万例死亡和300万例幼儿住院。用单克隆抗体（mAb），Synagis（TM）（Medimmune，Inc.），在15年前就被证明对减少早产儿感染并发症有效，但在更大的足月婴儿群体中作为感染后治疗尚未显示出有效性。目前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。使用筛选单个人类B细胞的专有技术，Trellis克隆了一种天然的人类mAb 3D 3，克服了Synagis的局限性，在暴露后的动物中提供了前所未有的治疗反应。新的mAb靶向一种不同的包膜糖蛋白，这种糖蛋白与破坏宿主免疫反应有关。该抗体对高度保守的表位具有1 pM的亲和力。它在体外有补体存在的情况下具有直接的抗病毒活性，其效力比补体高100倍。 Synagis在小鼠模型中，3D 3显示出作为直接抗病毒剂和作为阻断与临床病理学相关的肺部炎症的药剂的有效活性。这种双重活性在性质上不同于Synagis或任何正在研究的用于治疗RSV的小分子抗病毒药物。正如对天然人抗体的预期，3D 3显示不与一组人组织结合。在选择前，它已在稳定转化的CHO细胞中以0.3 g/L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。本直接II期提案的目标是开发一个表达细胞的主细胞库，该细胞具有生产商业上有用水平（>2 g/L）的3D 3的能力，并开发启动人体试验所需的分析和毒理学数据（IND数据包）。

 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).