Therapeutic antibody for RSV

 描述(申请人提供)：呼吸道合胞病毒(RSV)是导致下呼吸道疾病的主要原因，每年导致全球20万名幼儿死亡和300万人住院。15年前，用单抗(MAb)Synagis(Tm)(Medimmune，Inc.)免疫预防被证明能有效地减少早产儿感染的并发症，但在更多的足月婴儿中，它并没有显示出作为感染后治疗的有效性。到目前为止，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，仍有大量未得到满足的医疗需求。利用一项筛选单个人类B细胞的专利技术，Trellis克隆了一种原生人类单抗3D3，它克服了Synagis的限制，在暴露后的动物中提供了前所未有的治疗反应。新的单抗针对的是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的亲和力为1 pm。在补体存在的情况下，它在体外具有直接的抗病毒活性，其效力是 希纳吉斯。在小鼠模型中，3D3显示出强大的活性，既是直接的抗病毒药物，也是阻断与临床病理有关的肺部炎症的药物。这种双重活性在性质上不同于Synagis或任何正在研究的治疗RSV的小分子抗病毒药物。与预期的天然人类抗体一样，3D3显示不与一组人类组织结合。筛选前已在稳定转化的CHO细胞中以0.3g/L的速度表达，表明建立高效表达细胞系是可行的。因此，通常与第一阶段SBIR研究相关的所有目标都已实现。这一直接二期计划的目标是开发一个表达细胞的主细胞库，具有以商业用途水平生产3D3的能力(&gt；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)。

 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).