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: 7932815
• 负责人: Adam Lacy-Hulbert
• 金额: $ 77.27万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932815
• 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; 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; 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(申请人提供)：该提案旨在开发一种新的免疫疗法，以预防和治疗丝状病毒家族中危及生命的马尔堡病毒和埃博拉病毒感染，这些病毒可能被操纵为构成严重公共威胁的生物武器。该提议基于这样一个事实，即甘露糖结合凝集素(MBL)是一种广谱的天然免疫分子。这种血清蛋白可识别多种病原体，如细菌、寄生虫和包括丝状病毒在内的病毒。初步数据表明，重组人MBL(RHuMBL)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，使其成为在暴露于丝状病毒之前和/或之后使用的强有力的免疫治疗剂。该项目的一个关键目标是评估临床级别的rHuMBL，该rHuMBL已首次用于第一阶段临床研究，以及第二代MBL的衍生品，其中包含另一种凝集素样蛋白L的一部分。初步研究表明，这些新的凝集素嵌合体与甘露聚糖结合，甘露聚糖与丝状病毒装饰的碳水化合物相同。这项赠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、天然免疫领域研究人员的广泛科学经验、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，在那里已经建立了小鼠和豚鼠丝状病毒感染模型。我们将利用丝状病毒糖蛋白假型HIV颗粒，在体外评价rHuMBL和凝集素嵌合体激活凝集素补体途径和调节吞噬功能的效果。此外，我们将研究这些凝集素在MBL、补体成分3、FICLIN-A(鼠型L-FICROLIN)或其组合缺陷的转基因小鼠中的保护效果，以阐明每种先天免疫分子在天然丝状病毒致死攻击的啮齿动物中的相对作用。这项提议的最终目标是开发一种rHuMBL或其衍生物的配方，可用于预防和/或治疗暴露于丝状病毒的士兵或平民。

项目成果

The mannose-binding lectin: a prototypic pattern recognition molecule.

• DOI: 10.1016/j.coi.2005.11.014
• 发表时间: 2006-03
• 期刊: Current opinion in immunology
• 影响因子: 7
• 作者: Takahashi K;Ip WE;Michelow IC;Ezekowitz RA
• 通讯作者: Ezekowitz RA

Lectin-dependent enhancement of Ebola virus infection via soluble and transmembrane C-type lectin receptors.

• DOI: 10.1371/journal.pone.0060838
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Brudner M;Karpel M;Lear C;Chen L;Yantosca LM;Scully C;Sarraju A;Sokolovska A;Zariffard MR;Eisen DP;Mungall BA;Kotton DN;Omari A;Huang IC;Farzan M;Takahashi K;Stuart L;Stahl GL;Ezekowitz AB;Spear GT;Olinger GG;Schmidt EV;Michelow IC
• 通讯作者: Michelow IC

Complex role of mannose-binding lectin in infectious diseases.

甘露糖结合凝集素在传染病中的复杂作用。

• DOI: 10.1016/j.jpeds.2009.04.039
• 发表时间: 2009
• 期刊: The Journal of pediatrics
• 作者: Michelow,IanC;Yantosca,LouisM;Karpel,Marshall;Schmidt,EmmettV
• 通讯作者: Schmidt,EmmettV