Development of highly potent human monoclonal for RSV immuno-prophylaxis

项目总结 呼吸道合胞病毒(RSV)是美国婴儿住院的主要原因，这种疾病 老年人的负担类似于非大流行性甲型流感传统策略未能产生 一种有效的RSV疫苗，在某些情况下，接种疫苗会导致疾病加剧，突显出 人类对RSV免疫反应的复杂性。尽管预防性抗体是可用的(Palivizumab， 一种人源化的小鼠单抗，由医学免疫公司销售为Synagis®)，其成本高，疗效适中 仅限高危婴儿使用。此外，由于成本较高，儿童无法获得帕利维珠单抗。 在5个人口最多的国家中，有4个国家没有这种服务--占世界人口总数的一半以上 人口无法获得这种类型的治疗。 通过降低成本，公共卫生效益和全球可及性无疑将得到改善 呼吸道合胞病毒的免疫预防。在这份第二阶段的提案中，德克萨斯大学奥斯汀分校阿迪马布分校(黎巴嫩， 爱因斯坦医学院(纽约布朗克斯)和Mapp生物制药公司(加利福尼亚州圣地亚哥)， 合作开发一种完全人类的、高度有效的单抗，可以在每个RSV单剂注射 赛季到了。具有更强的单抗(即较低的剂量)，可以较少地给药(由于延长的血清 半衰期)，该团队的目标是大幅降低价格并增加RSV的可用性 免疫预防。此外，市场竞争也可能有助于降低成本和增加成本 全球可获得性，特别是因为Palivizumab目前垄断了RSV市场。我们的第一阶段 努力确定了3个主要候选抗体(从445个单抗中)，所有这些在体外都明显更有效 在活体内比帕利维珠单抗更有效。此外，这些单抗与阿斯利康的第二个单抗具有类似的中和活性 针对所测试的5个RSV毒株的一代RSV单抗MEDI8897(目前处于临床后期开发阶段) 到目前为止。在这些第一阶段的努力取得成功后，我们为第二阶段提出了以下具体目标：1) 根据针对临床专家小组的中和活动的广度和效力选择领先候选人 分离株；2)获得适合GMP生产的CHO细胞系；3)生产用于IND使能的CHO细胞 研究；4)进行支持IND的研究。

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.