Research Project 2: Therapeutic Human Monoclonal Antibody Treatments for Filoviruses

研究项目2：丝状病毒的治疗性人单克隆抗体治疗

• 批准号: 10576280
• 负责人: James E Crowe
• 金额: $ 246.43万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-08 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576280
• 关键词: Research; Project; Therapeutic; Human; Monoclonal

PROJECT SUMMARY/ABSTRACT – Research Project 2 Ebolaviruses cause the most severe hemorrhagic fevers in humans, with mortality rates up to 90%. They also are considered potential weapons for bioterrorism and biological warfare. We have isolated thousands of naturally-occurring human antibodies (Abs) that neutralize ebolaviruses and marburgviruses and protect against disease in animal models. One of the gaps in the field of filovirus antibody therapeutics is the lack of monoclonal antibodies that act against all of the major pathogenic species of ebolavirus (Zaire ebolavirus [EBOV], Bundibugyo ebolavirus [BDBV] and Sudan ebolavirus [SUDV]. The key requirements for successful treatment of filovirus infections with monoclonal antibodies (mAbs) may include (A) use of broad and potent mAbs, and (B) administration of an antibody or cocktail of mAbs binding to highly conserved viral epitopes. We propose here to perform advanced development of pan-ebolavirus and pan-marburgvirus human monoclonal antibody therapeutics. The work will be conducted with a panel of highly promising antibodies that are in hand, with the goal of identifying and selecting lead compounds and advancing preclinical development in preparation for a subsequent IND filing and clinical testing. The work is organized around several aims that seek to compare the protection of mAbs against various filoviruses in vitro and in vivo, and to select lead candidate members. In addition, mAbs will be characterized by their mechanism of action, isotype, and Fc glycosylation content. Cell lines for large-scale production of the lead candidates will be done in an effort to develop large-scale production and purification methods for the lead candidate antibodies. We have a highly interactive consortium of investigators with complementary expertise in human antibody discovery and engineering (Vanderbilt), filovirus biology and immunity (UTMB) and antibody production (Mapp Biopharmaceutical). The work promises to yield a best-in-class antibody preparation for broad and potent activity against ebolaviruses that can be used to treat or prevent human ebolavirus infections.

项目摘要/摘要 - 研究项目2 埃博拉病毒导致人类最严重的出血性发作，死亡率高达90％。他们也是 被认为是生物恐怖和生物战争的潜在武器。我们已经孤立了数千个 自然存在的人类抗体（ABS）中和埃博氏病毒和马堡病毒并预防 动物模型中的疾病。丝状病毒抗体治疗领域的差距之一是缺乏单克隆 对所有主要致病性埃博氏病毒（Zaire Ebolavirus [ebov]， Bundibugyo埃博氏病毒[BDBV]和苏丹埃博拉病毒[SUDV]。成功治疗的关键要求 用单克隆抗体（mAb）感染的丝状病毒感染可能包括（a）使用宽和潜在的mAb，以及（b） 施用与高度组成的病毒表位结合的mAb的抗体或鸡尾酒。我们在这里建议 执行泛弹病毒和泛马堡病毒人类单克隆抗体的先进开发 治疗。这项工作将使用一组高度有前途的抗体进行，其中包括 识别和选择铅化合物并推进临床前开发的目标 随后的IND归档和临床测试。这项工作是围绕几个试图比较的目标 保护mAB在体外和体内对各种丝状病毒的保护，并选择主要候选人成员。 此外，mAB的作用机理，同型和FC糖基化含量的特征。细胞 将进行大规模生产的主要候选人的线路，以开发大规模生产 和铅候选抗体的纯化方法。我们有一个高度互动的联盟 人类抗体发现与工程（Vanderbilt）的专业知识的调查人员，FILOVIRUS 生物学和免疫（UTMB）和抗体产生（MAPP Biopharmaceutical）。这项工作承诺会产生 一流的抗体制备，用于针对可用于治疗或 预防人类埃博拉病毒感染。