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AAV Vectored Delivery of Broadly Neutralizing Antibodies with Optimal Innate Functionality Against HIV

AAV 载体递送具有针对 HIV 的最佳先天功能的广泛中和抗体

基本信息

批准号：
10762553
负责人：
Alejandro Benjamin Balazs
金额：
$ 79.69万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2023-06-15 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10762553
关键词：
AIDS prevention Address Animal Experiments Animal Model Antibodies Antibody-mediated protection Automobile Driving BLT mice Binding Biological Assay Bone Marrow Cell physiology Cell surface Cells Clinical Trials Data Dependovirus Doctor of Philosophy Effectiveness Effector Cell Engineering Epitopes Exhibits Future Gene Transfer Grant HIV HIV Infections HIV therapy Human Immune Immune system Immunity Immunoglobulin Fragments Immunoglobulin G In Vitro Individual Infection Liver Macrophage Measures Mediating Membrane Fusion Modeling Mutation Natural Immunity Natural Killer Cells Neutralization Tests Neutralizing antibody assay Patients Pattern Phagocytosis Population Prevention Principal Investigator Research Role Serum Side Specificity Surface Technology Testing Thymus Gland Vagina Viral Viremia Work adeno-associated viral vector antibody engineering antibody-dependent cell cytotoxicity antibody-dependent cellular phagocytosis comparative efficacy delivery vehicle humanized mouse immunoengineering immunoprophylaxis in vitro Assay in vivo innate immune function innate immune mechanisms medical schools neutralizing antibody next generation novel prevent professor protective efficacy receptor receptor binding transmission process vaginal transmission vector

项目摘要

Project Summary / Abstract This proposal describes the framework of an R01 grant for Alejandro Balazs, PhD. Dr. Balazs is currently an assistant professor at Harvard Medical School working as a principal investigator at the Ragon Institute of MGH, MIT & Harvard. Dr. Balazs’ research is focused on engineering the immune system via gene transfer as a novel means of creating protection against HIV. Broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) show great promise in HIV prevention and therapy as they potently neutralize a significant breadth of globally circulating HIV strains. A number of animal experiments and clinical trials have demonstrated the ability of bNAbs to confer protection from viral challenge and reduce viremia of established infections. BNAbs can inhibit HIV infection by blocking viral attachment or membrane fusion; however, recent work suggests that the fragment crystallizable (Fc) region of antibodies may also contribute significantly to bNAb-mediated HIV inhibition through interactions with innate immunity. This proposal seeks to use in vitro cell-based assays to determine the extent to which next-generation HIV bNAbs engage effector functions, such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). This proposal will modify the Vectored ImmunoProphylaxis technology pioneered by Dr. Balazs to generate sustained expression of antibodies harboring precise Fc-region mutations previously demonstrated to enhance or abrogate, Fc-receptor interactions. By manipulating the specificity and concentration of these antibodies, this study will define the rules governing Fc-receptor engagement that apply to prevention of HIV acquisition. Furthermore, it seeks to determine the potential for Fc-enhanced antibodies to increase the potency of bNAb protection against HIV transmission. Finally, this proposal will manipulate the immune system of humanized mice as a means of dissecting and precisely quantifying the contribution of specific immune cells to prevention of HIV transmission. Together, this work will reveal optimal epitope targets and innate immune mechanisms to produce next-generation AAV vectors encoding bNAbs with enhanced innate immune function to prevent HIV transmission.

项目概要/摘要该提案描述了 Alejandro Balazs 博士的 R01 资助框架。巴拉兹博士是目前是哈佛医学院的助理教授，在 Ragon 担任首席研究员 MGH、麻省理工学院和哈佛大学研究所。 Balazs 博士的研究重点是通过基因改造免疫系统转移作为预防艾滋病毒的一种新手段。广泛中和抗体 (bNAb) 人类免疫缺陷病毒（HIV）在艾滋病毒预防和治疗方面显示出巨大的前景，因为它们具有强大的作用中和大量全球传播的艾滋病病毒毒株。多项动物实验及临床试验已证明 bNAb 能够提供针对病毒攻击的保护并减少病毒血症既定的感染。 BNAb 可以通过阻断病毒附着或膜融合来抑制 HIV 感染；然而，最近的研究表明抗体的片段可结晶 (Fc) 区域也可能有助于通过与先天免疫的相互作用，对 bNAb 介导的 HIV 抑制具有显着影响。该提案旨在使用体外基于细胞的测定来确定下一代 HIV bNAb 与效应子结合的程度功能，例如抗体依赖性细胞毒性（ADCC）和抗体依赖性细胞毒性吞噬作用（ADCP）。该提案将修改由博士首创的矢量免疫预防技术。 Balazs 能够产生先前含有精确 Fc 区突变的抗体的持续表达被证明可以增强或消除 Fc 受体相互作用。通过操纵特异性和这些抗体的浓度，本研究将定义适用于 Fc 受体结合的规则以预防艾滋病毒感染。此外，它还试图确定 Fc 增强抗体的潜力增强 bNAb 预防 HIV 传播的效力。最后，该提案将操纵人源化小鼠的免疫系统作为解剖和精确量化其贡献的手段特异性免疫细胞可预防艾滋病毒传播。这项工作将共同揭示最佳表位目标和先天免疫机制来产生编码增强型 bNAb 的下一代 AAV 载体先天免疫功能可防止艾滋病毒传播。