Research Project 2: Therapeutic Human Monoclonal Antibody Treatments for Filoviruses

项目总结/摘要-研究项目2 埃博拉病毒引起人类最严重的出血热，死亡率高达90%。他们还 被认为是生物恐怖主义和生物战的潜在武器。我们已经隔离了数千名 天然存在的人抗体（Ab），可中和埃博拉病毒和马尔堡病毒， 动物模型中的疾病。丝状病毒抗体治疗领域的空白之一是缺乏单克隆抗体。 作用于埃博拉病毒的所有主要致病物种（扎伊尔埃博拉病毒[EBOV]， 本迪布焦埃博拉病毒[BDBV]和苏丹埃博拉病毒[SUDV]。成功治疗的关键要求 使用单克隆抗体（mAb）的丝状病毒感染可包括（A）使用广谱和强效mAb，以及（B） 施用结合高度保守的病毒表位的抗体或mAb的混合物。我们在此提议， 进行泛埃博拉病毒和泛马尔堡病毒人源单克隆抗体的高级开发 治疗学这项工作将与一组非常有前途的抗体一起进行，这些抗体已经在手， 目标是鉴定和选择先导化合物，并推进临床前开发， 随后的IND备案和临床试验。这项工作是围绕几个目标组织的，这些目标旨在比较 保护mAb在体外和体内抵抗各种丝状病毒，并选择领先的候选成员。在 此外，mAb将通过其作用机制、同种型和Fc糖基化含量来表征。细胞 为了发展大规模生产，将完成大规模生产铅候选物的生产线 以及先导候选抗体的纯化方法。我们有一个高度互动的联盟， 在人类抗体发现和工程（范德比尔特）、丝状病毒 生物学和免疫（UTMB）和抗体生产（Mapp Biopharmacology）。这项工作有望产生一个 针对埃博拉病毒具有广泛和有效活性的同类最佳抗体制剂，可用于治疗或 预防人类埃博拉病毒感染。

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.