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.

项目摘要 /摘要该提案描述了Alejandro Balazs博士的R01赠款的框架。 Balazs博士是目前是哈佛医学院的助理教授，担任Ragon的首席研究员 MGH学院，麻省理工学院和哈佛大学。 Balazs博士的研究重点是通过基因进行工程Immuno系统工程转移是一种新的保护艾滋病毒的方法。广泛中和抗体（BNAB）人类免疫缺陷病毒（HIV）在预防HIV和治疗方面表现出巨大的希望中和大量的全球循环艾滋病毒菌株。许多动物实验和临床试验证明了BNAB赋予病毒挑战保护并减少病毒血症的能力已建立的感染。 BNAB可以通过阻断病毒附着或膜融合来抑制HIV感染；但是，最近的工作表明抗体的碎片可结晶（FC）区域也可能有助于通过与先天免疫相互作用，可以显着对BNAB介导的HIV抑制作用。该提议试图使用基于体外细胞的测定方法来确定下一代HIV BNABS吸引效应器的程度功能，例如抗体依赖性细胞细胞毒性（ADCC）和抗体依赖性细胞吞噬作用（ADCP）。该提案将修改博士开创的矢量免疫保障技术。 Balazs以前产生具有精确FC区突变的抗体的持续表达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，本研究将定义有关适用FC受体参与的规则预防艾滋病毒收购。此外，它试图确定FC增强抗体的潜力增加BNAB保护抗HIV传播的效力。最后，该提议将操纵人性化小鼠的免疫系统是解剖和精确量化的一种手段特异性免疫细胞可预防HIV传播。这项工作将揭示最佳的表位目标和先天的免疫力学生产下一代AAV矢量，编码BNAB，以增强先天免疫功能以防止HIV传播。