Mammalian and Plant-derived Antibody-based Therapies against Sudan Ebolavirus

描述（由申请人提供）：埃博拉病毒对美国军队和普通民众构成重大威胁，特别是在赤道非洲的流行地区。这种NIAID A类生物防御病原体是一种潜在的生物威胁剂，未发表的报告表明，前苏联曾试图将这类病毒武器化。在所有种类的埃博拉病毒中，扎伊尔病毒（EBOV）和苏丹病毒（SUDV）造成的疫情最多，占所有埃博拉病毒相关死亡人数的94%。由于没有针对埃博拉病毒感染的经批准的预防性疫苗或治疗方法，支持性护理仍然是治疗埃博拉病毒感染患者的唯一选择。从历史上看，抗体免疫疗法作为埃博拉病毒感染的暴露后治疗在很大程度上被忽视，主要原因是保护非人灵长类动物（NHPs）免受埃博拉病毒攻击的多次尝试失败。几个独立团体最近取得的成功提供了令人信服的证据，证明基于抗体的免疫疗法可以成为对抗埃博拉病毒感染的有效对策。事实上，几种针对EBOV的单克隆抗体（mAb）鸡尾酒已被证明在NHP模型中有效。然而，目前缺乏致力于开发sudv特异性抗体免疫疗法的研究。考虑到最近四次埃博拉病毒爆发中有三次的病原体是SUDV，这一点尤其令人担忧。我们的建议旨在通过开发特异性靶向SUDV的基于抗体的免疫疗法来解决SUDV特异性治疗的空白。利用现有的suv特异性单克隆抗体和scFv库，我们将从选择的主要候选单克隆抗体和scFv中生成鼠-人嵌合单克隆抗体，并使用基于植物和哺乳动物的表达系统生产这些suv特异性单克隆抗体。在植物和哺乳动物系统中生产suv特异性单克隆抗体将为去免疫suv特异性抗体免疫疗法提供可再生来源，并允许对来自每种表达系统的单克隆抗体进行直接性能比较。植物和哺乳动物来源的suv特异性单克隆抗体将在进入体内保护功效试验之前评估其体外抗原特异性和病毒中和性。小鼠疗效研究将用于筛选最佳的三种sudv特异性单克隆抗体，以进入NHP疗效试验。我们将完成sudv特异性单抗鸡尾酒的药代动力学评估和暴露后疗效测试，目的是制定最佳剂量和治疗方案，并确定治疗窗口。我们建议的目标是开发一种基于抗体的免疫疗法，用于治疗和管理苏丹病毒感染。这一努力直接解决了目前埃博拉病毒治疗方法的空白

DESCRIPTION (provided by applicant): Ebola viruses pose a significant threat to US military forces and the general population, particularly in areas endemic areas of equatorial Africa. This NIAID Category A biodefense pathogen is a potential biological threat agent and unpublished reports indicate that the former Soviet Union attempted to weaponize this family of viruses. Of all the species of Ebola virus, Zaire virus (EBOV) and Sudan virus (SUDV) have caused the greatest number of outbreaks and account for 94% of all Ebola virus-related deaths. Since there are no approved preventative vaccines or therapeutics for Ebola virus infections, supportive care remains the only option for treating Ebola virus infected patients. Historically, antibody immunotherapy as a post-exposure treatment for Ebola virus infection was largely ignored due primarily to numerous failed attempts to protect non-human primates (NHPs) from Ebola virus challenge. Recent successes by several independent groups have provided convincing evidence that antibody-based immunotherapies can be an effective countermeasure against Ebola virus infection. In fact, several monoclonal antibody (mAb) cocktails targeting EBOV have proven efficacious in NHP models. However, there is currently a lack of research efforts dedicated to developing SUDV-specific antibody-based immunotherapies. This is particularly concerning considering the causative agent of three of the last four Ebola virus outbreaks has been SUDV. Our proposal is designed to address the void in SUDV-specific therapeutics by developing antibody-based immunotherapeutics that target SUDV specifically. Leveraging existing SUDV-specific mAb and scFv libraries, we will generate murine-human chimeric mAbs from select lead-candidate mAbs and scFvs and produce these SUDV-specific mAbs using plant and mammalian-based expression systems. Producing SUDV-specific mAbs in plant and mammalian systems will provide a renewable source of de-immunized SUDV-specific antibody-based immunotherapies and allow a direct performance comparison of mAbs from each expression system. Plant and mammalian-derived SUDV-specific mAbs will be evaluated for in vitro antigen specificity and virus neutralization before entering in vivo protective efficacy trias. Efficacy studies in mice will be used to down-select the best three SUDV-specific mAbs to move forward into NHP efficacy trials. Pharmacokinetic evaluation and post-exposure efficacy testing will be completed for our SUDV-specific mAb cocktail with the intent of developing optimal dosing and treatment regimens and defining the therapeutic window. The objective of our proposal is to develop an antibody-based immunotherapy for the treatment and management of Sudan virus infection. This effort directly addressed a gap in the current Ebola virus therapeutics portfolio and, if successful, will provide an effective countermeasure against Sudan virus that is positioned for IND-enabling studies.