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:
- 金额:$ 79.69万
- 依托单位:
- 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:
- 关键词:AIDS preventionAddressAnimal ExperimentsAnimal ModelAntibodiesAntibody-mediated protectionAutomobile DrivingBLT miceBindingBiological AssayBone MarrowCell physiologyCell surfaceCellsClinical TrialsDataDependovirusDoctor of PhilosophyEffectivenessEffector CellEngineeringEpitopesExhibitsFutureGene TransferGrantHIVHIV InfectionsHIV therapyHumanImmuneImmune systemImmunityImmunoglobulin FragmentsImmunoglobulin GIn VitroIndividualInfectionLiverMacrophageMeasuresMediatingMembrane FusionModelingMutationNatural ImmunityNatural Killer CellsNeutralization TestsNeutralizing antibody assayPatientsPatternPhagocytosisPopulationPreventionPrincipal InvestigatorResearchRoleSerumSideSpecificitySurfaceTechnologyTestingThymus GlandVaginaViralViremiaWorkadeno-associated viral vectorantibody engineeringantibody-dependent cell cytotoxicityantibody-dependent cellular phagocytosiscomparative efficacydelivery vehiclehumanized mouseimmunoengineeringimmunoprophylaxisin vitro Assayin vivoinnate immune functioninnate immune mechanismsmedical schoolsneutralizing antibodynext generationnovelpreventprofessorprotective efficacyreceptorreceptor bindingtransmission processvaginal transmissionvector
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。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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。
- DOI:10.1016/j.cell.2024.02.011
- 发表时间:2024
- 期刊:
- 影响因子:64.5
- 作者:Nitido,AdamN;Balazs,AlejandroB
- 通讯作者:Balazs,AlejandroB
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Alejandro Benjamin Balazs其他文献
Alejandro Benjamin Balazs的其他文献
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{{ truncateString('Alejandro Benjamin Balazs', 18)}}的其他基金
Development of Vectored ImmunoProphylaxis as a strategy against HIV
开发载体免疫预防作为抗 HIV 策略
- 批准号:
8411105 - 财政年份:2014
- 资助金额:
$ 79.69万 - 项目类别:
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