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.

流感病毒感染会导致人类和动物传染性呼吸道疾病，并且发病率很高和全球死亡率。人类未能对流感产生普遍的保护性记忆免疫反应 A，作为血凝素和神经氨酸酶，两种免疫显性甲型流感病毒编码表位，经历抗原转变和漂移，导致甚至以前感染过的人类也可能感染甲型流感病毒株易受.在缺乏通用甲型流感疫苗、预防或治疗剂的情况下，甲型流感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 胞外 (M2e) 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标：它在甲型流感病毒中具有 99% 的保守性血清型，突变率低，对于病毒进入和复制至关重要。然而，只有不到 20% 感染者会产生 M2e 特异性抗体来应对甲型流感感染，这可能是由于 M2e体积小且稀有。因此，我们力求实现我们的长期目标，开发一个通用的预防或治疗甲型流感感染和相关病症的预防剂或治疗剂，通过提供 M2e 特异性 MAb，这是保护性甲型流感特异性免疫反应的重要组成部分目前大多数人类都缺乏。为了实现这一目标，我们产生了七种特异性单克隆抗体 M2e，其中两个完全保护，其中三个部分保护高度甲型流感病毒易感性来自致命挑战的 Balb/c 小鼠。基于这些考虑，我们的中心假设是： M2e 特异性 MAb 可以预防或改善甲型流感感染及相关病理。作为抗体我们假设可以介导多种有助于宿主保护的互补效应器功能 M2e 特异性 MAb 的组合能够干扰 M2 离子通道活性，引发 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。我们期望检验我们的中心假设并通过追求以下三个具体目标来实现本应用程序的目标：目标 1：确定 MAb 结合对 M2e 功能和体外病毒复制的生物学影响；目标 2：发展保护性和体内治疗性 MAb 治疗方案；目标 3：剖析 M2e 特定的个人贡献 MAb 依赖性细胞毒性、吞噬作用和补体激活可保护宿主免受甲型流感病毒侵害感染。为了实现我们的目标，我们组建了由合作科学家组成的专家团队：Beeton 博士，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，具有指定的 M2 专业知识；罗斯博士，雪貂模型专家流感疫苗接种和感染；我本人，Paust 博士，一位免疫学家，拥有详细的知识了解对甲型流感感染的先天和适应性免疫反应。