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: 8484340
• 负责人: Erica Ollmann Saphire
• 金额: $ 63.04万
• 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/8484340
• 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; Hemorrhagic Shock; 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; 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; screening; 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）：Marburg病毒类别引起严重的出血热。该病毒被苏联的气溶胶分布武器化，非洲最近的自然暴发已达到约90％的杀伤力。尚无针对马堡病毒的治疗方法。抗体可以立即提供免疫力：暴露于48小时后，针对相关埃博拉病毒的某些抗体具有保护性，并且抗体是暴露后疫苗接种/预防的关键组成部分，例如狂犬病。但是，很少有针对Marburg病毒的单克隆抗体，我们可以从中开发紧急治疗，甚至可以改善抗原捕获诊断。我们提出了针对马尔堡病毒的广泛的单克隆抗体（mAb）的开发，并在体外和体内对这些mAB和寡克隆组合进行彻底评估。这项工作将为马堡病毒上的不同表位提供广泛的mAb，可以解释这种免疫反应的这种景观中哪些表位导致最有效的体外中和和体内保护，并且哪些MABS在协同方面发挥了作用，以实现针对Marburg病毒序列范围的最高保护。附加的产品开发计划描述了我们的两个公司合作伙伴将如何结合生产和开发这些免疫治疗药作为有形产品的力量。该建议的独特优势是使用三维结构信息来构架和解释功能分析。令人困惑的是，对于有效体外的抗体，在体内并不总是有用的抗体，反之亦然，在体内具有保护性的抗体，不能中和体外。因此，我们可以直接研究抗体和抗原复合物的第三种方法将提供更多的见解，以调和体外和体内结果并指导未来的研究。这里已经确定和提出的结构将为最有效的表位建立3D地图，并提出基本规则，说明为什么某些抗体比其他抗体更好。该提案的另一个主要优点是财团成员在高通量抗体开发和体外分析中的独特而广泛的专业知识，以及用于生理相关的BSL4评估的活体内动物模型的新型活性动物模型的开发和使用。创新的FMAT，SAXS和微观微流体技术以及我们新开发的Marburg病毒模型，结合了初始的，启动MABS的启动小组减轻风险，并确保该提案的成功。我们在这里的努力将导致一套针对MARV GP的完整特征化抗体。其中，我们将仔细选择最有希望的候选人，以进行高级发展，以实现有效的马堡病毒感染后暴露后治疗。