Structure-guided neutralizing antibodies developed using EpiVolve technology

使用 EpiVolve 技术开发的结构引导中和抗体

基本信息

批准号：
10698958
负责人：
Xiaofeng Li
金额：
$ 29.61万
依托单位：
ABBRATECH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-05 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10698958
关键词：
2019-nCoV 3-Dimensional ACE2 Affect Affinity Amino Acids Animals Antibodies Antigens Autoantigens B-Lymphocytes Binding Binding Sites Biological Assay COVID-19 pandemic Cells Communicable Diseases Data Development Epitopes Evolution Generations Genetic Polymorphism Hemagglutinin Human Immune Targeting Immune Tolerance Immunization Immunize Immunoglobulin G Immunoglobulin Somatic Hypermutation Immunologic Surveillance Infection Influenza Influenza A virus Life Cycle Stages Measurement Membrane Proteins Methods Modeling Molecular Conformation Mutation Patients Phase Pilot Projects Protein Binding Domain Proteins Proteome Protomer Receptor Cell Rest Sampling Severe Acute Respiratory Syndrome Site Solvents Specificity Structure Surface System Technology Vaccines Validation Variant Virus design empowerment fighting hands-on learning immunogenicity influenzavirus innovation neutralizing antibody novel pandemic virus phase 1 study receptor binding screening stem technology development vaccination strategy

项目摘要

Abstract Current strategies for developing neutralizing Abs are not effective and typically involve screening IgGs from recovered patients. Pandemic viruses evolve for mutations that can shield their epitopes from host immune surveillance system, so a lot of important epitopes will be missed. Even after neutralizing Abs isolated are from human sample, they still need further characterization using epitope binning and determination of specificities to avoid off target effect. A systematic method for exploring the entire protein surface of a virus that can identify all potential sites on the virus which can affect its life cycle would have significant impact and is needed. We propose a structure-guided systematic Ab development pipeline to discover Abs that can fight infectious diseases. We propose using our novel site-directed Ab development technology, ‘EpiVolve’ (short for Epitope Evolution). EpiVolve will be used to develop site-specific Abs to solvent-exposed residues and the adjacent ‘context’ sequences. These Abs will be used for fighting infectious disease. The advantages of EpiVolve are a) overcoming immune tolerance and targeting virus’ human proteome-mimicking epitopes, b) precisely targeting any antigenic epitopes regardless of its immunogenicity, c) taking advantage of B cell expansion and somatic hypermutation to generate IgG clonotypes against one targeted residue, which allows an ability to generate both pan-variants Abs and polymorphism-specific Abs, and d) an ability for generating a neutralizing Ab discovery pipeline. We will model this on SARS-cov-2 virus in Phase I and Influenza A in Phase II. EpiVolve developed site-specific antibodies will target solvent-exposed residues on the protein surface. Structure-guided Ag design will empower the EpiVolve technology in this systematic analysis. For this proposal, we will present the current preliminary data on the pilot EpiVolve study on SARS- cov-2 Receptor Binding Domain (RBD), focused mainly on the host cell receptor ACE2 binding interface. For Phase I studies, we propose to complete the pilot study and extend the study to the whole protein surface of the RBD domain. Characterizing each Ab by its binding affinity and ability to neutralize SARS-cov-2 virus will be included in Phase I studies. For Phase II, we propose to apply the learnings from this Phase I study on another virus model of great importance, the Influenza A virus. Specifically targeting the solvent-accessible residues of the conserved Stem/Stalk region of the Hemagglutinin (HA) protein

抽象的目前中和抗体的开发策略无效，通常涉及从中和抗体中筛选 IgG。恢复的大流行病毒会进化出突变，从而保护其表位免受宿主免疫的影响。监视系统，因此即使在中和分离的抗体后，许多重要的表位也会被遗漏。从人类样本中，他们仍然需要使用表位分类和确定来进一步表征避免脱靶效应的特异性，用于探索病毒整个蛋白质表面的系统方法。能够识别病毒上所有可能影响其生命周期的潜在位点将产生重大影响我们提出了一个以结构为导向的系统性抗体开发流程来发现具有以下特点的抗体。我们建议使用我们新颖的定点抗体开发技术， “EpiVolve”（Epitope Evolution 的缩写）将用于开发针对溶剂暴露的位点特异性抗体。这些抗体将用于对抗传染病。 EpiVolve 的优点是 a) 克服免疫耐受并针对病毒的人类蛋白质组模拟表位，b) 精确靶向任何抗原表位，无论其免疫原性如何，c) 利用优势 B 细胞扩增和体细胞超突变以产生针对某一目标残基的 IgG 克隆型，其允许产生泛变体抗体和多态性特异性抗体的能力，以及 d) 能力用于生成中和抗体发现管道，我们将在第一阶段和第二阶段以 SARS-cov-2 病毒为模型。 EpiVolve 开发的位点特异性抗体将针对 A 型流感病毒的溶剂暴露残基。结构引导的 Ag 设计将为该系统中的 EpiVolve 技术提供支持。对于本提案的分析，我们将提供 EpiVolve 试点研究的当前初步数据。 cov-2受体结合域（RBD），主要集中于宿主细胞受体ACE2结合界面。第一阶段研究，我们建议完成试点研究并将研究扩展到整个蛋白质表面 RBD 结构域通过其结合亲和力和中和 SARS-cov-2 病毒的能力来表征对于第二阶段的研究，我们建议应用第一阶段研究的经验教训。另一种非常重要的病毒模型是甲型流感病毒，专门针对溶剂可及的病毒。血凝素 (HA) 蛋白保守茎/茎区域的残基