Cross-Protective Monoclonal Antibodies for treatment of pandemic Flu

用于治疗大流行性流感的交叉保护性单克隆抗体

基本信息

批准号：
8394814
负责人：
Christopher H Clegg
金额：
$ 30万
依托单位：
TRIA BIOSCIENCE CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8394814
关键词：
Adjuvant Adverse effects Affinity Animal Model Animals Antibodies Antibody Diversity Antibody Formation Antibody Repertoire Antigens Antiviral Agents B-Lymphocytes Binding Bioinformatics Biological Assay Case Fatality Rates Cells Cessation of life Collaborations Communicable Diseases DNA Sequence Data Databases Emerging Communicable Diseases Epitopes Fab Immunoglobulins Ferrets Flu virus Generations Genes Goals Human Immunity Immunization Immunoglobulin G Immunoglobulins Infection Influenza Influenza A Virus, H5N1 Subtype International Lead Length Lung diseases Methodology Methods Modeling Monoclonal Antibodies Mus Outcome Passive Immunotherapy Pharmaceutical Preparations Phase Prevention Probability Proteins Protocols documentation Public Health Regulation Resistance Risk Screening procedure Small Business Innovation Research Grant Staging Structure-Activity Relationship Surveys Technology Therapeutic Therapeutic Monoclonal Antibodies Therapeutic antibodies Transfection Treatment Efficacy Vaccinated Vaccines Viral Virus Work World Health Organization alternative treatment base biodefense chimeric antibody design drug candidate drug discovery immunogenic improved in vitro Assay in vivo innovation interest mortality neutralizing antibody novel strategies novel therapeutics pandemic influenza prophylactic rapid technique response synthetic biology tool vaccine development

项目摘要

DESCRIPTION (provided by applicant): Influenza is a highly contagious respiratory disease that causes substantial mortality world-wide. There is great international concern that the Avian Influenza virus H5N1 will acquire the ability to transmit between humans and cause a global catastrophe. Consequently, the World Health Organization and the US National Strategy for Pandemic Influenza have delineated goals for stockpiling drugs that can protect against influenza infection. However, currently available H5N1 vaccines are poorly immunogenic and fail to induce broad cross-protective antibody responses to drifted viruses. Therefore, there is an urgent need for alternative treatments that provide potent and broadly cross-protective host immunity that can rapidly neutralize and control dissemination of H5N1 virus in humans. This Phase I SBIR proposal outlines a novel strategy that will simplify and accelerate monoclonal antibody (MAb) drug discovery for Flu. Our methodologies are designed to (1) augment induction of cross-reactive neutralizing antibodies in vivo and (2) permit rational selection of anti-hemagluttinin immunoglobulin (Ig) variable domains for building therapeutic monoclonal antibodies. Our novel approach combines an immunization protocol that dramatically increases antibody diversity in mice with DNA sequencing tools that provide a deep survey of the resulting Ig variable domain repertoire. We propose the following aims: (1) Select and characterize heterosubtypic neutralizing anti-H5 antibodies, and (2) Identify a lead antibody that is cross-protective in animal models of influenza infection. This Phase I SBIR proposal will establish proof of concept that cross-reactive anti-HA MAbs can be selected from immunized animals using a "sequence-first" screening strategy and that they are effective in advanced animal models of H5N1 infection. Successful completion of this project will result in a small set of "therapeutic" chimeric antibodies and will provide a strong rationale for conducting the necessary IND-enabling studies in a subsequent Phase II proposal. Clinically, these antibodies will impact the treatment and prevention of pandemic flu. Scientifically, the availability of these antibodies will clarify HA structure-function relationships, lead to the identification of new epitopes for vaccine development, and guide the regulation of adaptive B cell responses, possibly in humans. We also believe that the concepts, methods and technologies described in this proposal will be broadly applicable for developing therapeutic antibodies to a variety of infectious diseases. PUBLIC HEALTH RELEVANCE: H5N1 viruses have caused over 400 human deaths with a 60% case fatality rate. There is a clear need for improved therapeutics to neutralize and control the spread of H5N1 virus in humans. Our goal is to produce novel therapeutic antibodies that can be used to treat people prior to pandemic flu exposure or during the early stages of infection, thereby reducing the risk of H5N1 infection for millions of people throughout the world.

描述（由申请人提供）：流感是一种高度传染性呼吸道疾病，在世界范围内造成大量死亡。国际社会高度关注禽流感病毒H5N1将获得人际传播能力并引发全球性灾难。因此，世界卫生组织和美国大流行性流感国家战略制定了储存可预防流感感染的药物的目标。然而，目前可用的 H5N1 疫苗免疫原性较差，无法诱导针对漂移病毒的广泛交叉保护性抗体反应。因此，有一个迫切需要替代疗法提供有效且广泛的交叉保护性宿主免疫力，能够快速中和和控制 H5N1 病毒在人类中的传播。该 I 期 SBIR 提案概述了一种新策略，该策略将简化和加速流感单克隆抗体 (MAb) 药物的发现。我们的方法旨在 (1) 增强体内交叉反应中和抗体的诱导，以及 (2) 允许合理选择抗血凝素免疫球蛋白 (Ig) 可变结构域以构建治疗性单克隆抗体。我们的新颖方法结合了可显着增加小鼠抗体多样性的免疫方案与 DNA 测序工具，可对所得 Ig 可变域库进行深入研究。我们提出以下目标：(1) 选择并表征异亚型中和抗 H5 抗体，(2) 鉴定在流感感染动物模型中具有交叉保护作用的先导抗体。该 I 期 SBIR 提案将建立概念证明，即可以使用“序列优先”筛选策略从免疫动物中选择交叉反应性抗 HA MAb，并且它们在 H5N1 感染的高级动物模型中有效。该项目的成功完成将产生一小组“治疗性”嵌合抗体，并将提供强有力的理由在随后的第二阶段提案中进行必要的 IND 支持研究。临床上，这些抗体将影响大流行性流感的治疗和预防。从科学角度来看，这些抗体的可用性将阐明 HA 结构与功能的关系，从而识别用于疫苗开发的新表位，并指导可能在人类中的适应性 B 细胞反应的调节。我们还相信，该提案中描述的概念、方法和技术将广泛适用于开发针对多种传染病的治疗性抗体。公共卫生相关性：H5N1 病毒已导致 400 多人死亡，病死率为 60%。显然需要改进的治疗方法来中和和控制 H5N1 病毒在人类中的传播。我们的目标是生产新型治疗性抗体，可用于在大流行性流感暴露之前或感染早期阶段对人们进行治疗，从而降低全世界数百万人感染 H5N1 的风险。