Development of highly potent human monoclonal for RSV immuno-prophylaxis

项目摘要 呼吸道合胞病毒（RSV）是美国婴儿住院的主要原因，和疾病 老年人的负担与非大流行性甲型流感相似。传统的战略未能产生 有效的RSV疫苗，在某些情况下，疫苗接种导致疾病加重，强调了 这是人类对RSV免疫应答的复杂性。虽然预防性抗体是可用的（帕利珠单抗， 由MedImmune以Synagis®销售的人源化小鼠mAb），其高成本和适度的功效已经 限制其用于高危婴儿。此外，由于这种高成本，帕利珠单抗对于儿童来说是不可获得的。 发展中国家，5个人口最多的国家中有4个没有，占世界人口的一半以上。 人口无法获得这类治疗。 通过降低成本，无疑将提高公共卫生效益和全球可及性 RSV免疫预防。在这个第二阶段的建议，得克萨斯大学奥斯汀分校，阿迪玛（黎巴嫩， NH）、爱因斯坦医学院（纽约州布朗克斯）和Mapp生物制药公司。(San Diego，CA）， 合作开发一种完全人源化的、高效的mAb， 赛季使用更有效的mAb（即较低剂量），可以降低给药频率（由于延长血清 半衰期），该团队的目标是大幅降低RSV的价格并增加其可用性 免疫预防。此外，市场竞争也有助于降低成本， 在全球范围内，特别是因为帕利珠单抗目前垄断了RSV市场。我们的第一阶段 努力确定了3种主要候选药物（来自一组445种mAb），所有这些药物在体外的效力都明显更强 在体内比帕利珠单抗更有效。此外，这些mAb具有与阿斯利康的第二mAb类似的中和活性。 抗5种检测RSV毒株的第二代RSV mAb MEDI 8897（目前处于后期临床开发阶段） 迄今在这些第一阶段的努力取得成功之后，我们为第二阶段提出以下具体目标： 根据针对一组临床试验的中和活性的广度和效力选择先导候选药物。 分离株; 2）生成适用于GMP生产的CHO细胞系; 3）生产IND使能 研究; 4）开展IND赋能研究。

PROJECT SUMMARY Respiratory syncytial virus (RSV) is a leading cause of infant hospitalizations in the U.S., and the disease burden among the elderly is similar to non-pandemic influenza A. Traditional strategies have failed to generate an effective RSV vaccine, and in some instances vaccination resulted in enhanced disease, underscoring the complexity of the human immune response to RSV. Although a prophylactic antibody is available (palivizumab, a humanized mouse mAb marketed by MedImmune as Synagis®), its high cost and modest efficacy have restricted its use to high-risk infants. Moreover, due to this high cost, palivizumab is inaccessible to children in developing nations and is unavailable in 4 of the 5 most populous countries – more than half the world’s population does not have access to this type of treatment. The public health benefit and the worldwide accessibility would undoubtedly be improved by lowering the cost of RSV immunoprophylaxis. In this Phase 2 proposal, the University of Texas at Austin, Adimab (Lebanon, NH), Einstein College of Medicine (The Bronx, NY) and Mapp Biopharmaceutical, Inc. (San Diego, CA), teamed to develop a fully human, highly potent mAb that can be administered in a single dose per RSV season. With a more potent mAb (i.e. lower dose) that can be dosed less frequently (due to extended serum half-life), the team’s objective is to dramatically lower the price and increase the availability of RSV immunoprophylaxis. In addition, competition in the marketplace may also help to reduce costs and increase accessibility globally, especially since palivizumab currently has a monopoly on the RSV market. Our Phase 1 effort identified 3 lead candidates (from a panel of 445 mAbs), all of which are dramatically more potent in vitro and in vivo than palivizumab. Further, these mAbs have similar neutralization activity to AstraZeneca’s second generation RSV mAb MEDI8897 (currently in late stage clinical development) against the 5 RSV strains tested to date. After the success of these Phase 1 efforts, we propose the following Specific Aims for Phase 2: 1) Select a lead candidate based on breadth and potency of neutralization activity against a panel of clinical isolates; 2) Generate a CHO cell line appropriate for GMP manufacture; 3) Manufacture for IND-enabling studies; 4) Conduct IND-enabling studies.