Development of highly potent human monoclonal for RSV immuno-prophylaxis

开发用于 RSV 免疫预防的高效人单克隆抗体

基本信息

批准号：
10208698
负责人：
Larry Zeitlin
金额：
$ 80.1万
依托单位：
MAPP BIOPHARMACEUTICAL, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208698
关键词：
2 year old Adult Age-Years Antibodies Asthma Biological Products Bioreactors Caring Cell Line Child Childhood Chinese Hamster Ovary Cell Chronic Clinical Complex Congestive Heart Failure Cost Effectiveness Analysis Cotton Rats Country Data Developing Countries Development Disease Dose Drug Kinetics Elderly Formulation Future Generations Goals Half-Life Health Benefit Hospitalization Hospitals Human Immune response In Vitro Industry Standard Infant Influenza A virus Lead Lebanon Life Lower respiratory tract structure Lung diseases Medical Medicine Monoclonal Antibodies Nursing Homes Palivizumab Pharmaceutical Preparations Phase Population Price Production Public Health Rehabilitation therapy Research Respiratory Syncytial Virus Vaccines Respiratory Tract Diseases Respiratory syncytial virus Respiratory syncytial virus RSV F glycoprotein Savings Seasons Serum Structure Technology Testing Texas Tissues Toxicology Universities Wheezing austin base burden of illness cell bank clinical development college cost cross reactivity high risk high risk infant human monoclonal antibodies humanized mouse immunoprophylaxis improved in vivo in vivo evaluation lead candidate murine antibody neonate prevent prophylactic response success vaccination outcome

项目摘要

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.

项目概要呼吸道合胞病毒 (RSV) 是美国婴儿住院的主要原因，该疾病老年人的负担与非大流行性甲型流感相似。传统策略未能产生有效的 RSV 疫苗，并且在某些情况下，某些疫苗接种会导致疾病加剧，这强调了尽管可以使用预防性抗体（帕利珠单抗、 MedImmune 销售的人源化小鼠单克隆抗体 Synagis®），其高成本和有限的功效已被此外，由于成本高昂，帕利珠单抗无法被儿童使用。发展中国家，并且在 5 个人口最多的国家中的 4 个国家无法使用 – 超过世界的一半人口无法获得此类治疗。通过降低成本，无疑会提高公共卫生效益和全球范围内的可及性德克萨斯大学奥斯汀分校 Adimab（黎巴嫩，新罕布什尔州）、爱因斯坦医学院（纽约州布朗克斯）和 Mapp Biopharmaceutical, Inc.（加利福尼亚州圣地亚哥），合作开发了一种全人源、高效的单克隆抗体，可以按 RSV 单剂量给药使用更有效的单克隆抗体（即较低剂量），但可以减少给药频率（由于血清延长）。半衰期），该团队的目标是大幅降低 RSV 的价格并提高其可用性此外，市场竞争也可能有助于降低成本并增加成本。全球可及性，特别是因为帕利珠单抗目前在 RSV 市场上处于垄断地位。我们的努力确定了 3 个主要候选药物（来自 445 个 mAb 组），所有这些候选药物在体外都显着更有效此外，这些单克隆抗体与阿斯利康的第二种单克隆抗体具有相似的中和活性。针对测试的 5 种 RSV 菌株的新一代 RSV mAb MEDI8897（目前处于临床开发后期）迄今为止，在第一阶段的努力取得成功后，我们提出了第二阶段的以下具体目标：1) 根据针对临床小组的中和活性的广度和效力来选择主要候选者分离；2) 生成适合 GMP 生产的 CHO 细胞系；3) 进行 IND 生产研究；4) 开展 IND 支持研究。