Evolutionary lead optimization for immunotherapy of Marburg & Ebola viruses

马尔堡病毒免疫疗法的进化先导优化

• 批准号: 7677956
• 负责人: EMMETT Vance SCHMIDT
• 金额: $ 91.46万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7677956
• 关键词: Academic Medical Centers; Address; Aerosols; Affect; Affinity; Alveolar Macrophages; Animal Model; Antiviral Agents; Applications Grants; Avidity; Back; Bacteria; Binding; Biological; Biological Assay; Biological Products; Biological Warfare; Biotechnology; Bioterrorism; C-Type Lectins; Calcium; Carbohydrates; Categories; Cavia; Cell Nucleus; Cells; Characteristics; Chimera organism; Chimeric Proteins; Clinical; Clinical Research; Clinical Trials; Collagen; Collectins; Communicable Diseases; Complement; Complement 3; Containment of Biohazards; Data; Dendritic Cells; Disease; Dose; Drug Formulations; Drug Kinetics; Ebola virus; Electron Microscopy; Embryo; Epidemic; Equipment; Evolution; Exposure to; FDA approved; Family; Fibrinogen; Filovirus; Flow Cytometry; Fluorescence; Frankfurt-Marburg Syndrome Virus; Freeze Drying; General Hospitals; Generations; Genes; Genetic Engineering; Glycoproteins; Goals; Gram-Negative Bacteria; HIV; Half-Life; Herpesvirus 1; Host Defense; Human; Hybrids; Immune; Immune system; Immunoglobulins; Immunology; Immunotherapeutic agent; Immunotherapy; In Vitro; Industry; Infection; Infection prevention; Infectious Agent; Inflammatory; Intercellular Adhesion Molecules; Investigation; Kidney; Knock-out; Knockout Mice; Laboratories; Lead; Lectin; Length; Leukocytes; Life; Ligand Binding; Lipopolysaccharides; Mannans; Mannose; Mannose Binding Lectin; Mannose-Binding Lectins; Massachusetts; Measures; Mediating; Medical Research; Microbiology; Modeling; Molecular; Mononuclear; Mus; Natural Immunity; Opsonin; Organism; Outcome Measure; Panic; Parasites; Pattern; Pattern recognition receptor; Peptidoglycan; Phagocytes; Phagocytosis; Phase; Phase I Clinical Trials; Plants; Plasma; Plasmids; Play; Principal Investigator; Process; Production; Property; Protein Binding; Proteins; Pulmonary Surfactant-Associated Proteins; Recombinants; Relative (related person); Research Infrastructure; Research Institute; Research Personnel; Resources; Rodent; Role; Route; Serine Protease; Serum; Serum Proteins; Signal Transduction; Soldier; Specificity; Structure; Subfamily lentivirinae; Surface; Tail; Techniques; Temperature; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toll-like receptors; United States; Vaccines; Viral; Viral Hemorrhagic Fevers; Viral Load result; Virulence; Virulent; Virus; Virus Diseases; Virus Receptors; Virus-like particle; Wild Type Mouse; Work; antimicrobial; complement pathway; conglutinin; cost; cystic fibrosis patients; cytokine; developmental immunology; experience; ficolin; ficolin-A; ficolin-beta; improved; in vitro Assay; influenzavirus; intraperitoneal; lipoteichoic acid; monocyte; mortality; neutrophil; novel; particle; pathogen; prevent; product development; programs; protective efficacy; receptor; research study; response; social; subcutaneous; uptake; viral RNA; weapons

DESCRIPTION (provided by applicant): This proposal is aimed at developing a novel immunotherapeutic that will prevent and treat life-threatening infections with Marburg and Ebola viruses of the filovirus family that might be manipulated as bioweapons posing grave public threats. The proposal builds on the fact that the mannose-binding lectin (MBL) is a broad-spectrum molecule of innate immunity. This serum protein recognizes a wide range of pathogens, such as bacteria, parasites and viruses including filoviruses. Preliminary data indicate that recombinant human MBL (rHuMBL) recognizes the envelope glycoproteins of Ebola and Marburg viruses. This observation, together with the role of MBL in first line host defense, makes it a strong candidate as an immunotherapeutic agent for use before and/or after exposure to filoviruses. A key goal of this project is to evaluate clinical grade rHuMBL that has been used in Phase 1 clinical studies in the first instance, and second generation derivatives of MBL that incorporate a part of L-ficolin, another lectin-like protein. Preliminary studies demonstrated that these novel lectin chimeras bind mannan, the same carbohydrate that adorns filoviruses. This grant proposal will leverage the infrastructure of the Laboratory of Developmental Immunology at Massachusetts General Hospital, the extensive scientific experience of the investigators in the field of innate immunity, the product development expertise of Natlmmune, a Danish biotechnology company that developed therapeutic rHuMBL, and the highly specialized resources of the United States Army Medical Research Institute for Infectious Diseases where mouse and guinea pig models of filovirus infection have been established. We will evaluate the efficacy of rHuMBL and lectin chimeras to activate the lectin complement pathway and to modulate phagocytic function in vitro using HIV particles pseudotyped with filovirus glycoproteins. Furthermore, we will investigate the protective efficacy of these lectins in strains of genetically modified mice deficient in MBL, complement component 3, ficolin-A (murine form of L-ficolin) or combinations thereof to elucidate the relative roles of each innate immune molecule in rodents fatally challenged with native filoviruses. The ultimate goal of this proposal is to develop a formulation of rHuMBL or a derivative thereof that could be used prophylactically and/or therapeutically by soldiers or civilians exposed to filoviruses.

描述（由申请人提供）：该提案旨在开发一种新型免疫疗法，用于预防和治疗危及生命的丝状病毒家族马尔堡病毒和埃博拉病毒感染，这些病毒可能被操纵为生物武器，对公众构成严重威胁。该提案基于甘露糖结合凝集素（MBL）是一种广谱先天免疫分子这一事实。这种血清蛋白可识别多种病原体，例如细菌、寄生虫和病毒（包括丝状病毒）。初步数据表明，重组人 MBL (rHuMBL) 可识别埃博拉病毒和马尔堡病毒的包膜糖蛋白。这一观察结果，加上 MBL 在一线宿主防御中的作用，使其成为在接触丝状病毒之前和/或之后使用的免疫治疗剂的有力候选者。该项目的一个关键目标是首先评估已用于一期临床研究的临床级rHuMBL，以及包含L-ficolin（另一种凝集素样蛋白）一部分的MBL第二代衍生物。初步研究表明，这些新型凝集素嵌合体与甘露聚糖结合，甘露聚糖与丝状病毒的碳水化合物相同。该拨款提案将利用马萨诸塞州总医院发育免疫学实验室的基础设施、研究人员在先天免疫领域的丰富科学经验、开发治疗性 rHuMBL 的丹麦生物技术公司 Natlmmune 的产品开发专业知识，以及美国陆军传染病医学研究所的高度专业化资源，其中小鼠和豚鼠的丝状病毒模型 感染已成立。我们将评估 rHuMBL 和凝集素嵌合体激活凝集素补体途径并使用丝状病毒糖蛋白假型化的 HIV 颗粒体外调节吞噬功能的功效。此外，我们将研究这些凝集素在缺乏 MBL、补体成分 3、ficolin-A（小鼠形式的 L-ficolin）或其组合的转基因小鼠品系中的保护功效，以阐明每种先天免疫分子在遭受天然丝状病毒致命攻击的啮齿类动物中的相对作用。该提案的最终目标是开发一种 rHuMBL 或其衍生物的制剂，可供暴露于丝状病毒的士兵或平民预防和/或治疗。