Analysis of immunotherapeutics to native Marburg virus epitopes

针对天然马尔堡病毒表位的免疫治疗分析

• 批准号: 7939958
• 负责人: Erica Ollmann Saphire
• 金额: $ 53.52万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939958
• 关键词: Advanced Development; Aerosols; Affinity; Africa; Angola; Animal Model; Antibodies; Antigen-Antibody Complex; Antigens; Binding; Biological; Categories; Cavia; Complex; Democratic Republic of the Congo; Development; Development Plans; Diagnostic; Disease Outbreaks; Ebola virus; Emergency Situation; Emergency treatment; Ensure; Epitope Mapping; Epitopes; Evaluation; Filovirus; Foundations; Frankfurt-Marburg Syndrome Virus; Future; Glycoproteins; Goals; Hand; Hour; Human; Hybridomas; Immune response; Immunity; Immunization; Immunologic Surveillance; Immunotherapeutic agent; In Vitro; Individual; Infection; Lead; Life; Maps; Microfluidics; Modeling; Monoclonal Antibodies; Mucins; Mus; Outcome; Preparation; Prophylactic treatment; Protein Biochemistry; Proteins; Rabies; Risk; Roentgen Rays; Screening procedure; Shock; Site; Solutions; Sorting - Cell Movement; Structure; Sudan; Surface; System; Techniques; Technology; Testing; Therapeutic antibodies; USSR; Vaccination; Vaccines; Viral; Viral Hemorrhagic Fevers; Virus; Virus Diseases; Work; X-Ray Crystallography; antigen binding; group competition; improved; in vitro activity; in vivo; innovation; insight; member; mouse model; neutralizing antibody; nonhuman primate; novel; pathogen; pathogen exposure; product development; success

DESCRIPTION (provided by applicant): The Category A Marburg virus causes a severe hemorrhagic fever. The virus was weaponized by the Soviet Union for aerosol distribution and recent natural outbreaks in Africa have achieved ~90% lethality. No treatments against Marburg virus are yet available for human use. Antibodies could provide immediate immunity: some antibodies against the related Ebola virus are protective even 48 hours after exposure, and antibodies are a key component of post-exposure vaccination/prophylaxis for viruses such as rabies. However, very few monoclonal antibodies against Marburg virus exist from which we can develop emergency treatments or even improved antigen-capture diagnostics. We propose development of an extensive panel of monoclonal antibodies (mAbs) against Marburg virus, and thorough evaluation of these mAbs alone and in oligoclonal combinations, in vitro and in vivo. This work will provide a broad array of mAbs against different epitopes on Marburg virus, will explain which epitopes among this landscape of immune responses lead to the most effective in vitro neutralization and in vivo protection, and which mAbs function synergistically to achieve highest protection against the range of Marburg virus sequences. An appended product development plan delineates how our two corporate partners will combine forces to manufacture and develop these immunotherapeutics as tangible products. A unique strength of this proposal is the use of three-dimensional structural information to frame and interpret the functional analysis. Perplexingly, for the filoviruses, antibodies that are effective in vitro are not always useful in vivo, and vice versa, antibodies that are protective in vivo, do not neutralize in vitro. Hence, a third approach, in which we can directly look at the antibody and antigen complexes, will provide additional insight to reconcile in vitro and in vivo results and guide future studies. The structures already determined and proposed here will establish 3D maps to the most effective epitopes and propose ground rules for why some antibodies work better than others. Another chief advantage of this proposal is the unique and extensive expertise of the consortium members in high-throughput antibody development and in vitro analysis, as well as development and use of novel animal models of live, in vivo Marburg virus for physiologically relevant BSL4 evaluation. Innovative FMAT, SAXS, and microscale microfluidic techniques and our newly developed Marburg virus models, combined with an initial in-hand, starting panel of mAbs mitigate risk and ensure the success of this proposal. Our efforts here will result in a complete set of well-characterized antibodies against MARV GP. Of these, we will carefully select the most promising candidates for advanced development towards our ultimate goal of an efficacious post-exposure treatment for Marburg virus infection.

描述（由申请人提供）：A 类马尔堡病毒会引起严重的出血热。该病毒被苏联武器化，用于气溶胶传播，最近在非洲的自然爆发已达到约 90% 的致死率。目前还没有针对马尔堡病毒的治疗方法可供人类使用。抗体可以提供即时免疫力：一些针对相关埃博拉病毒的抗体甚至在暴露后 48 小时内仍具有保护作用，而抗体是狂犬病等病毒暴露后疫苗接种/预防的关键组成部分。然而，针对马尔堡病毒的单克隆抗体非常少，我们可以从中开发紧急治疗方法，甚至改进抗原捕获诊断。我们建议开发一系列针对马尔堡病毒的单克隆抗体 (mAb)，并在体外和体内对这些单克隆抗体单独和寡克隆组合进行彻底评估。这项工作将提供针对马尔堡病毒不同表位的广泛单克隆抗体，将解释免疫反应景观中的哪些表位导致最有效的体外中和和体内保护，以及哪些单克隆抗体协同发挥作用以实现对马尔堡病毒的最高保护。马尔堡病毒序列范围。随附的产品开发计划描述了我们的两家企业合作伙伴将如何联合力量来制造和开发这些有形产品的免疫治疗药物。该提案的独特优势是使用三维结构信息来构建和解释功能分析。令人困惑的是，对于丝状病毒来说，在体外有效的抗体在体内并不总是有用，反之亦然，在体内具有保护性的抗体在体外不会被中和。因此，第三种方法，我们可以直接观察抗体和抗原复合物，将为协调体外和体内结果并指导未来的研究提供额外的见解。这里已经确定和提出的结构将建立最有效表位的 3D 图谱，并提出为什么某些抗体比其他抗体效果更好的基本规则。该提案的另一个主要优势是联盟成员在高通量抗体开发和体外分析以及开发和使用活体马尔堡病毒新型动物模型进行生理相关 BSL4 评估方面拥有独特且广泛的专业知识。创新的 FMAT、SAXS 和微型微流体技术以及我们新开发的马尔堡病毒模型，与初始的现有单克隆抗体组合相结合，可降低风险并确保该提案的成功。我们在这里的努力将产生一整套特性良好的 MARV GP 抗体。其中，我们将仔细选择最有希望的候选药物进行高级开发，以实现对马尔堡病毒感染进行有效的暴露后治疗的最终目标。