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

针对苏丹埃博拉病毒的哺乳动物和植物源性抗体疗法

• 批准号: 8694246
• 负责人: John M Dye
• 金额: $ 60.27万
• 依托单位: GENEVA FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8694246
• 关键词: Accounting; Address; Africa; Antibodies; Antibody Therapy; Antigens; Area; Binding; Biological; Bioterrorism; Categories; Cessation of life; Data; Democratic Republic of the Congo; Development; Disease Outbreaks; Dose; Drug Kinetics; Ebola virus; Evaluation; FDA approved; Family; General Population; Goals; Half-Life; Human; Immunotherapeutic agent; Immunotherapy; In Vitro; Lead; Libraries; Military Personnel; Modeling; Monoclonal Antibodies; Mus; National Institute of Allergy and Infectious Disease; Patients; Performance; Plantibodies; Plants; Positioning Attribute; Production; Reporting; Research; Research Design; Selection Criteria; Series; Serum; Source; Specificity; Sudan; Sudan Ebola virus; Supportive care; System; Testing; Therapeutic; Therapeutic Uses; Treatment Protocols; USSR; Vaccines; Virus; Virus Diseases; Work; Zaire Ebola virus; base; biodefense; design; efficacy testing; efficacy trial; hemorrhagic fever virus; immunogenic; in vivo; mortality; mouse model; nonhuman primate; pathogen; protective efficacy; public health relevance; success; therapeutic vaccine

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 This NIAID Category A biodefense pathogen is a potential biological threat agent and unpublished reports indicate that the former Soviet Union attempted to weaponize this family of viruses.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.

描述(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因子，未发表的报告表明，前苏联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)造成的暴发数量最多，占所有与埃博拉病毒有关的死亡人数的94%。由于目前还没有获得批准的埃博拉病毒感染预防性疫苗或治疗药物，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暴露后治疗的一种方法在很大程度上被忽视，主要是因为许多保护非人类灵长类动物(HHP)免受埃博拉病毒攻击的尝试失败了。最近几个独立小组的成功提供了令人信服的证据，表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的单抗鸡尾酒在NHP模型中被证明是有效的。然而，目前缺乏致力于开发基于SUDV特异性抗体的免疫疗法的研究努力。考虑到最近四次埃博拉病毒暴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针对SUDV的基于抗体的免疫疗法来解决SUDV特异性治疗中的空白。利用现有的SUDV特异性单抗和单链抗体文库，我们将从选定的候选单抗和单链抗体中产生鼠-人嵌合单抗，并使用基于植物和哺乳动物的表达系统来生产这些SUDV特异性单抗。在植物和哺乳动物系统中生产SUDV特异性单抗将提供基于去免疫的SUDV特异性抗体免疫疗法的可再生来源，并允许对来自每个表达系统的单抗进行直接性能比较。在进入体内保护效力TRIAS之前，将评估植物和哺乳动物来源的SUDV特异性单抗的体外抗原特异性和病毒中和能力。小鼠的疗效研究将被用来下选择最好的三种SUDV特异性单抗，以推进NHP疗效试验。我们将对我们的SUDV特异性单抗鸡尾酒进行药代动力学评估和暴露后疗效测试，目的是开发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疗法中的一个空白 如果成功，将提供一种有效的应对苏丹病毒的对策，为IND研究奠定基础。