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Mechanisms of Protection of Universal Therapeutic Antibodies to Influenza A

甲型流感通用治疗抗体的保护机制

基本信息

批准号：
10078587
负责人：
Silke Paust
金额：
$ 77.37万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10078587
关键词：
Adamantane Animal Model Animals Antibodies Antibody Binding Sites Antibody Therapy Antiviral Agents Avian Influenza A Virus B-Lymphocytes Binding Binding Sites Biological Cell Line Cells Clinical Complement Complement Activation Data Development Disease Dose Effectiveness Epitopes Escape Mutant Extracellular Domain Fc Receptor Ferrets Goals Health Hemagglutinin Human IgG1 Immune Immune response Immunoglobulin Class Switching Immunologic Memory Immunologics Immunologist In Vitro Inbred BALB C Mice Individual Infection Infection prevention Influenza Influenza A Virus, H1N1 Subtype Influenza A virus Influenza vaccination Ion Channel Mediating Modeling Monoclonal Antibodies Morbidity - disease rate Mus Mutant Strains Mice Mutation Neuraminidase Orthomyxoviridae Pathogenicity Pathology Peptides Phagocytosis Proteins Scientist Serotyping Specific qualifier value Spleen Testing Therapeutic Therapeutic Agents Therapeutic Intervention Therapeutic Monoclonal Antibodies Therapeutic antibodies Time Treatment Protocols Vaccinated Vaccination Vaccines Viral Virion Virus Virus Diseases Virus Replication Virus Shedding Zoonoses adaptive immune response antibody-dependent cell cytotoxicity base dosage extracellular human model in vivo influenza infection influenzavirus inhibitor/antagonist lead candidate mortality mouse model mutant nanoGold neutralizing monoclonal antibodies overexpression pandemic influenza prevent prophylactic respiratory response viral resistance

项目摘要

Influenza virus infection causes contagious respiratory illness in humans and animals, and significant morbidity and mortality worldwide. Humans fail to make a universally protective memory immune response to influenza A, as Hemagglutinin and Neuraminidase, the two immune-dominant influenza A virus-encoded epitopes, undergo antigenic shift and drift, resulting in influenza A strains to which even previously infected humans are susceptible to. In the absence of a universal influenza A vaccine, prophylactic or therapeutic agent, influenza A will remain a significant threat to human health. To generate such agents, we developed a panel of Matrix Protein 2 extracellular (M2e)-specific monoclonal antibodies (MAbs). The extracellular domain of the M2-ion channel is an ideal antigenic target for a universal therapeutic agent: It is 99% conserved across influenza A serotypes, has a low mutation rate, and is essential for viral entry and replication. However, less than 20% of infected individuals generate M2e-specific antibodies in response to influenza A infection, perhaps due to M2e's small size and rarity. Thus, we seek to accomplish our long-term goal, to develop a universal prophylactic or therapeutic agent to prevent or treat influenza A infection and associated pathologies, by provision of M2e-specific MAbs, an essential component of a protective influenza A-specific immune response currently lacking in most humans. To achieve this goal, we generated seven monoclonal antibodies specific to M2e, two of which completely protect, and three of which partially protect highly influenza A virus susceptible Balb/c mice from lethal challenge. Based on these considerations, it is our central hypothesis that a cocktail of M2e-specific MAbs can prevent or ameliorate influenza A infection and associated pathology. As antibodies can mediate a variety of complementary effector functions that contribute to host protection, we hypothesize that a combination of M2e-specific MAbs capable of interference with M2-ion channel activity, elicitation of ADCC, phagocytosis and complement activation will be most effective at reducing influenza A virus replication and associated pathology, while preventing immune escape. We expect to test our central hypothesis and to achieve the objective of this application by pursuing the following three specific aims: Aim 1: to identify biological effects of MAb binding on M2e-function and viral replication in vitro; Aim 2: to develop protective and therapeutic MAb treatment regimens in vivo; and Aim 3: to dissect the individual contributions of M2e-specific MAb-dependent cytotoxicity, phagocytosis and complement activation to host protection from influenza A virus infection. To achieve our aims, we have assembled and expert team of collaborating scientists: Dr. Beeton, an expert in the ion channel function; Dr. Tompkins, an expert in animal models of human and zoonotic influenza infection, vaccination, and therapeutics, with specified M2 expertise; Dr. Ross, an expert in the ferret model of influenza vaccination and infection; and, myself, Dr. Paust, an expert immunologist with a detailed understanding of the innate and adaptive immune response to Influenza A infection.

流感病毒感染引起人和动物的传染性呼吸道疾病，和死亡率。人类未能对流感做出普遍保护性记忆免疫反应 A，作为血凝素和神经氨酸酶，两种免疫显性的甲型流感病毒编码表位，经历抗原性转变和漂移，导致甚至先前感染人类的甲型流感病毒株，易受影响的在缺乏通用甲型流感疫苗、预防剂或治疗剂的情况下，仍将对人类健康构成重大威胁。为了生成这样的代理，我们开发了一个矩阵面板，蛋白2细胞外（M2 e）特异性单克隆抗体（MAb）。M2-离子的胞外结构域通道是通用治疗剂的理想抗原靶点：它在甲型流感病毒中具有99%的保守性血清型，具有低突变率，并且对于病毒进入和复制是必需的。然而，只有不到20%的感染个体产生M2 e特异性抗体以响应甲型流感感染，这可能是由于 M2 E的体积小，稀有。因此，我们寻求实现我们的长期目标，发展一个普遍的预防或治疗甲型流感感染和相关病理的预防剂或治疗剂，提供M2 e特异性单克隆抗体，这是保护性甲型流感特异性免疫应答的重要组成部分这是目前大多数人所缺乏的。为了实现这一目标，我们产生了七种特异性单克隆抗体， M2 e，其中两种完全保护，其中三种部分保护高度易感的甲型流感病毒致死攻毒的Balb/c小鼠。基于这些考虑，我们的中心假设是， M2 e特异性MAb可以预防或改善甲型流感感染和相关病理。如抗体可以介导多种互补效应子功能，有助于宿主保护，我们假设能够干扰M2-离子通道活性、诱导M2-离子通道活性的M2 e-特异性单克隆抗体的组合， ADCC、吞噬作用和补体激活将最有效地减少甲型流感病毒复制和相关的病理学，同时防止免疫逃逸。我们希望测试我们的中心假设，通过追求以下三个具体目标来实现本申请的目标：目标1： MAb结合对体外M2 e功能和病毒复制的生物学效应;目的2：开发保护性和目的3：分析M2 e特异性单克隆抗体治疗方案的个体贡献，单克隆抗体依赖的细胞毒性、吞噬作用和补体激活对宿主免受甲型流感病毒的保护感染为了实现我们的目标，我们组建了一个由合作科学家组成的专家团队：离子通道功能专家;汤普金斯博士，人类和人畜共患流感动物模型专家感染，疫苗接种和治疗，与指定的M2专业知识;罗斯博士，在雪貂模型的专家，流感疫苗接种和感染;还有，我自己，Paust博士，一位免疫专家，了解对甲型流感感染的先天性和适应性免疫反应。