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 疫苗和针对人免疫缺陷病毒1（HIV-1）的抗体干预已做出 巨大的进步，但尚未准备好供广泛的临床使用。一种防止新感染的疫苗 通过阻止传播来结束HIV-1大流行，这为结束HIV-1大流行提供了重大提升。 HIV-1融合肽（FP） 由于疫苗 抗原可以有效地启动和扩展针对FP的B细胞反应。但是，HIV-1遗传多样性 FP和FP位点已知抗体的有限效力和中和宽度的进度减慢了 FP定向干预措施。更好地了解抗FP抗体如何获得精致的中和 针对HIV-1的效力和广度将促进疫苗和治疗性开发。这个项目将 探索抗FP抗体的关键突变途径，为新的分子和功能见解提供 针对HIV-1 FP的更好的抗体和疫苗溶液。 该项目的目标1将应用精确的突变扫描和定向进化来工程师精致 针对HIV-1 FP的抗体的中和效力。我们将实施一个新的基于单细胞的液滴 我们实验室建立的筛选平台直接基于中和识别抗体变体 功能。 AIM 1将增强抗FP抗体宽度和效力，超出当前一流的例子，并通过 研究这些抗体，我们将了解有关有效保护的结构和分子要求的更多信息 在FP。对于AIM 2，我们将探索可以增加交叉反应性和广度的亲和力突变景观 反对FP，并将这些数据与AIM 1中的中和概况进行比较，以了解 增强亲和力和中和增强突变。最后，在AIM 3中，我们将探讨抗体的变量 区域突变还可以影响FC效应的功能，以及HIV-1 FC效应蛋白参与如何共同 与对不同HIV-1病毒株的给定突变的亲和力和中和相关。来自AIM的数据 3将加速我们对BNAB FC效应子募集机制的理解，并与 Fab介导的中和效力的改善。 该项目阐明了中和效力，抗原亲和力与效应子之间的关键关系 针对FP位点的抗体中的功能。我们的多平台方法可实现最全面的 迄今为止抗FP抗体的功能研究，具有遗传，生物物理和 导致精致的抗HIV-1活性的功能特征。产生的新bnab和知识获得了 该项目将提供关键的信息和资源，以开发全球相关的疫苗和 针对HIV-1 FP的治疗剂。