Structure-guided neutralizing antibodies developed using EpiVolve technology

使用 EpiVolve 技术开发的结构引导中和抗体

• 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
• 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

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 当前开发中和ABS的策略无效，通常涉及筛选IgG 康复的患者。突变的大流行病毒演变可以使其表位免于宿主免疫 监视系统，因此会错过许多重要的表位。即使在中和ABS分离后， 从人类样本中，它们仍然需要使用表位式套筒进行进一步的表征和确定 避免目标效应的特异性。一种用于探索病毒整个蛋白质表面的系统方法 可以识别病毒上所有可能影响其生命周期的所有潜在部位将产生重大影响，并且 需要。我们提出了一个结构引导的系统AB开发管道，以发现ABS 可以打击传染病。我们建议使用我们新颖的以网站为导向的AB开发技术， “ epivolve”（表位进化的缩写）。 epivolve将用于开发特定于溶剂的站点特异性ABS 残基和相邻的“上下文”序列。这些ABS将用于抵抗传染病。这 epivolve的优势是a）克服免疫耐受性并瞄准病毒的人类蛋白质组模仿 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细胞膨胀和体细胞超成名，以产生IgG锁骨型针对一个靶向居住 这允许产生同时生成泛变量的ABS和多态性特异性ABS以及D）能力 用于产生中和的AB发现管道。我们将在I期中对SARS-COV-2病毒进行建模，并 第二阶段的流感。 epivolve开发的特定地点特异性抗体将靶向暴露于溶剂的拯救 蛋白质表面。结构引导的AG设计将赋予这种系统的epivolve技术 分析。对于此提案，我们将介绍有关SARS-的试验epivolve研究的当前初步数据 COV-2受体结合结构域（RBD）主要集中在宿主细胞受体ACE2结合界面上。为了 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域。通过其结合亲和力和中和SARS-COV-2病毒的能力来表征每个AB 被包括在I期研究中。对于第二阶段，我们建议在此阶段I研究中应用学习 另一个非常重要的病毒模型，即流感病毒。专门针对溶剂可访问 血凝素（HA）蛋白的构型茎/茎区的残留物