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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.

流感病毒感染可在人类和动物中引起传染性呼吸道疾病，并造成严重的发病率