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

• 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
• 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

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。 目前是哈佛医学院的助理教授，在 Ragon 担任首席研究员 麻省总医院、麻省理工学院和哈佛大学研究所的 Balazs 博士的研究重点是通过基因改造免疫系统。 转移作为产生针对 HIV 的广泛中和抗体（bNAb）的新方法。 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毒株 大量动物实验和临床。 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 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 抑制产生显着影响。 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 该提案将修改由 Dr. 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 被证明可以通过操纵特异性和消除 Fc 受体相互作用。 这些抗体的浓度，本研究将定义适用于 Fc 受体结合的规则 此外，它还试图确定 Fc 增强抗体的潜力。 最后，该提案将操纵 bNAb 预防 HIV 传播的效力。 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 总之，这项工作将揭示最佳表位靶标。 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。

项目成果

mRNA-based monkeypox virus vaccine prevents disease in non-human primates.

基于 mRNA 的猴痘病毒疫苗可预防非人类灵长类动物的疾病。

• 发表时间: 2024-03-14
• 影响因子: 64.5
• 作者: Nitido, Adam N;Balazs, Alejandro B
• 通讯作者: Balazs, Alejandro B

Ongoing evolution of SARS-CoV-2 drives escape from mRNA vaccine-induced humoral immunity.

SARS-CoV-2 的持续进化促使其逃避 mRNA 疫苗诱导的体液免疫。

• 发表时间: 2024-03-07
• 作者: Roederer, Alex L;Cao, Yi;Denis, Kerri St;Sheehan, Maegan L;Li, Chia Jung;Lam, Evan C;Gregory, David J;Poznansky, Mark C;Iafrate, A John;Canaday, David H;Gravenstein, Stefan;Garcia;Balazs, Alejandro B
• 通讯作者: Balazs, Alejandro B