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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.

项目摘要/摘要