Potent broadly neutralizing antibody development against the HIV-1 fusion peptide epitope

针对 HIV-1 融合肽表位的强效广泛中和抗体的开发

• 批准号: 10838825
• 负责人: Brandon James DeKosky
• 金额: $ 74.21万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10838825
• 关键词: Acceleration; Address; Affinity; Antibodies; Antibody Response; Antibody Therapy; Antigens; Apical; B-Lymphocytes; Binding; Binding Sites; Biophysics; Cells; Clinical; Complement 1q; Data; Development; Directed Molecular Evolution; Drug Design; Engineering; Epitopes; Exposure to; Fab domain; Genetic; Genetic Variation; Goals; HIV; HIV Antigens; HIV-1; Immune; Immunoglobulin Somatic Hypermutation; Immunosuppression; Individual; Infection; Infection prevention; Interruption; Intervention; Knowledge; Laboratories; Learning; Libraries; Maps; Mediating; Membrane; Mining; Molecular; Monoclonal Antibodies; Mutation; Outcome; Pathway interactions; Peptide Vaccines; Peptide antibodies; Peptides; Performance; Pharmaceutical Preparations; Prevention; Proteins; Protocols documentation; Resources; Site; Techniques; Technology; Therapeutic; Vaccination; Vaccine Antigen; Vaccine Design; Vaccines; Variant; Viral; Yeasts; antibody engineering; antibody libraries; antibody test; antiretroviral therapy; chronic infection; clinically relevant; cost; cross reactivity; global health; improved; innovation; insight; invention; mutation screening; neutralizing antibody; non-Native; pandemic disease; peptide vaccination; prevent; recruit; response; screening; synergism; therapeutic development; transmission blocking; transmission process; vaccine development; vaccine strategy; viral rebound

Project Summary/Abstract Vaccines and antibody interventions against human immunodeficiency virus-1 (HIV-1) have made tremendous progress, but are not yet ready for broad clinical use. A vaccine that prevents new infections could provide a major boost to ending the HIV-1 pandemic by blocking transmissions. The HIV-1 fusion peptide (FP) has shown promise as a broadly neutralizing antibody (bNAb)-directed vaccine target site because vaccine antigens can effectively prime and expand B cell responses targeting FP. However, HIV-1 genetic diversity at FP and the limited potency & neutralization breadth of known antibodies at the FP site has slowed progress for FP-directed interventions. A better understanding of how anti-FP antibodies can attain exquisite neutralization potency and breadth against HIV-1 will enable improved vaccines and therapeutic development. This project will explore critical mutational pathways for anti-FP antibodies, providing new molecular and functional insights for better antibody & vaccine solutions against HIV-1 FP. Aim 1 of the project will apply precision mutational scanning and directed evolution to engineer exquisite neutralization potency for antibodies targeting HIV-1 FP. We will implement a new single-cell droplet-based screening platform established by our laboratory to directly identify antibody variants based on neutralization function. Aim 1 will enhance anti-FP antibody breadth & potency beyond current best-in-class examples, and by studying these antibodies we will learn more about the structural & molecular requirements for potent protection at FP. For Aim 2, we will explore the affinity mutational landscapes that can increase cross-reactivity and breadth against FP, and compare those data with neutralization profiles in Aim 1 to understand the connections between affinity-enhancing and neutralization-enhancing mutations. Finally, in Aim 3 we will explore how antibody variable region mutations can also influence Fc-effector function, and how HIV-1 Fc effector protein engagement co- correlates with affinity and neutralization of a given mutation against diverse HIV-1 viral isolates. Data from Aim 3 will accelerate our understanding of bNAb Fc effector recruitment mechanisms, and synergize with parallel improvements in Fab-mediated neutralization potency. This project elucidates the critical relationships between neutralization potency, antigen affinity, and effector function in antibodies targeting the FP site. Our multi-platform approach enables the most comprehensive functional study of anti-FP antibodies to date, with layered characterization of the genetic, biophysical, and functional features that lead to exquisite anti-HIV-1 activity. The new bNAbs generated and knowledge gained by this project will provide critical information and resources to develop globally relevant vaccines and therapeutics against HIV-1 FP.

项目摘要/摘要 针对人类免疫缺陷病毒-1(HIV-1)的疫苗和抗体干预已取得进展 取得了巨大的进步，但还没有准备好广泛应用于临床。一种预防新感染的疫苗可能会 通过阻断传播，对结束艾滋病毒-1大流行起到重大推动作用。HIV-1融合多肽(FP) 已经显示出作为广泛中和抗体(BNAb)导向的疫苗靶点的希望，因为疫苗 抗原可以有效地激发和扩大针对FP的B细胞反应。然而，HIV-1基因多样性在 FP和FP部位已知抗体的有限效力和中和广度减缓了Fp的进展 以计划生育为导向的干预。更好地理解抗FP抗体如何达到精妙的中和效果 针对HIV-1的效力和广度将使改进疫苗和治疗开发成为可能。这个项目将 探索抗FP抗体的关键突变途径，提供新的分子和功能见解 更好的HIV-1 FP抗体和疫苗解决方案。 该项目的目标1将应用精确突变扫描和定向进化来工程精致 针对HIV-1 FP的抗体的中和效力。我们将实现一种新的基于单细胞液滴的 本实验室建立的基于中和直接鉴定抗体变异体的筛选平台 功能。目标1将增强抗FP抗体的广度和效力，超越目前同类最好的例子，并通过 研究这些抗体，我们将更多地了解有效保护的结构和分子要求。 在FP。对于目标2，我们将探索可以增加交叉反应和广度的亲和力突变场景 与FP进行比较，并将这些数据与目标1中的中和分布进行比较，以了解 亲和力增强和中和增强突变。最后，在目标3中，我们将探索抗体如何变化 区域突变也可以影响Fc-效应器的功能，以及HIV-1 Fc效应器蛋白如何参与 与针对不同HIV-1病毒分离株的给定突变的亲和力和中和性相关。来自AIM的数据 3将加深我们对bNAb Fc效应器招募机制的理解，并与并行 提高Fab介导的中和效力。 这个项目阐明了中和效力、抗原亲和力和效应器之间的关键关系。 在针对FP部位的抗体中起作用。我们的多平台方法实现了最全面的 迄今抗FP抗体的功能研究，包括遗传、生物物理和 导致精致的抗HIV-1活性的功能特征。生成新的bNAbs并获得知识 该项目将提供关键信息和资源，以开发全球相关疫苗和 针对HIV-1 FP的治疗。