Expansion and targeted maturation of germline HIV-1 bNAb-associated BCRs
种系 HIV-1 bNAb 相关 BCR 的扩增和靶向成熟
基本信息
- 批准号:10540724
- 负责人:
- 金额:$ 190.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-12-06 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffinityAnimal ModelAnimalsAnti-Idiotypic AntibodiesAntibodiesAntibody ResponseAntigensB-Cell Antigen ReceptorB-LymphocytesBindingBypassCellsClone CellsCommunicationDataDevelopmentEngineeringEpidemicFred Hutchinson Cancer Research CenterFrequenciesGenesGoalsGrantGrowthHIV-1HIV-1 vaccineHIV/AIDSHumanImmune systemImmunizationImmunoglobulin IdiotypesImmunoglobulin Somatic HypermutationImmunologyInfectionInstitutionLinkMonoclonal AntibodiesMutateNational Institute of Allergy and Infectious DiseaseParticipantPathway interactionsPolysaccharidesProbabilityProcessProductivityReactionReagentSchemeSecondary ImmunizationSiteSjogren&aposs SyndromeStructure of germinal center of lymph nodeTestingUniversitiesVaccinationVaccine Researchdesignexperimental studyglycosylationhumanized mouseimprovedin vivoneutralizing antibodynonhuman primatenovelpassive antibodiespreventprogramsrecruitresponsestructural biologyvaccination strategy
项目摘要
ABSTRACT
The elicitation of potent and broad HIV-1 neutralizing antibodies (bNAbs) by immunization has been one of the
major goals of HIV-1 vaccine research since the beginning of the HIV/AIDS epidemic. During the past decade,
significant technical and conceptual advances have enabled the isolation and detailed characterization of a
plethora of new bNAbs from HIV-1-infected subjects. The structural characterization of such antibodies,
combined with information on their ontogenies, has vastly improved our understanding of how such antibodies
are generated during natural infection, leading to new hypotheses regarding how to elicit them by
immunization. Our HIVRAD Program grant aims at testing novel reagents and prime-boost immunization
schemes to elicit VRC01-class bNAbs, which are among the most broad and potent HIV-1 neutralizing
antibodies known and display impressive protective potential in animal studies. However, the development of
VRC01-class bNAbs by immunization will necessitate overcoming several obstacles. A successful
immunization scheme will likely require, at a minimum, the availability of novel immunogens to initiate and
guide the bNAb maturation process, the development of strategies that will minimize the expansion of
competing off-target B cells, the development of optimal ‘boost’ Env immunogens to guide the appropriate
antibody maturation, and the supply of sustained T helper responses. Here we propose to test concepts, not
tested previously, that we have developed to directly address these issues. One new strategy we will evaluate
is based on the use of anti-idiotypic monoclonal antibodies (aiMAbs) we generated against germline VRC01-
class BCRs. Our preliminary data suggest that these aiMAbs specifically expand naive B cells that express
germline VRC01-class B cell receptors (BCRs) and that these cells enter the germinal center (GC) reaction
and expand even further upon Env immunization. One obvious advantage is a greater expansion in GC of
desired B cells over ‘off target’ B cells, thus improving our chance to induce the correct set of somatic
hypermutations during the boost immunizations. Thus, immunizations with aiMAbs will be followed by booster
immunizations with an Env specifically designed to engage germline VRC01-class BCRs (426c Core) and then
with Envs expressing key steric blocks for VRC01-class antibodies. In this regard we highlight the fact that
since our initial submission we generated new information which indicates that the 426c Core elicits antibodies
that bypass glycans on the conserved N-linked glycosylation site N276, which are one of the major obstacles
preventing germline VRC01-class antibodies from becoming broadly neutralizing. We will test our proposed
strategy by an iterative approach with well-integrated experiments. The preliminary data we present support
our overall approach.
抽象的
通过免疫接种产生有效且广泛的 HIV-1 中和抗体 (bNAb) 一直是解决这一问题的方法之一。
自艾滋病毒/艾滋病流行以来,HIV-1 疫苗研究的主要目标。在过去的十年里,
重大的技术和概念进步使得能够隔离和详细表征
来自 HIV-1 感染者的大量新 bNAb。此类抗体的结构特征,
结合其个体发育信息,极大地提高了我们对此类抗体如何发挥作用的理解
是在自然感染过程中产生的,导致了关于如何通过以下方式引发它们的新假设:
免疫接种。我们的 HIVRAD 计划赠款旨在测试新型试剂和初免-加强免疫
引发 VRC01 类 bNAb 的计划,这是最广泛、最有效的 HIV-1 中和药物之一
已知的抗体在动物研究中显示出令人印象深刻的保护潜力。然而,发展
通过免疫接种 VRC01 级 bNAb 需要克服几个障碍。一个成功的
免疫计划可能至少需要有新的免疫原来启动和
指导 bNAb 成熟过程,制定策略,最大限度地减少 BNAb 的扩张
竞争脱靶 B 细胞,开发最佳“增强”Env 免疫原以指导适当的
抗体成熟,以及持续 T 辅助反应的供应。在这里我们建议测试概念,而不是
之前经过测试,我们开发了该方法来直接解决这些问题。我们将评估一项新策略
基于我们针对种系 VRC01 生成的抗独特型单克隆抗体 (aiMAb)
BCR 类。我们的初步数据表明,这些 aiMAb 特异性扩增表达的幼稚 B 细胞
种系 VRC01 类 B 细胞受体 (BCR) 以及这些细胞进入生发中心 (GC) 反应
并进一步扩展环境免疫。一个明显的优势是 GC 的更大扩展
所需的 B 细胞超过“脱靶”B 细胞,从而提高我们诱导正确的体细胞集的机会
加强免疫期间的超突变。因此,使用 aiMAb 免疫后将进行加强免疫
使用专门设计用于接合种系 VRC01 级 BCR(426c 核心)的 Env 进行免疫接种,然后
Envs 表达 VRC01 类抗体的关键空间块。在这方面,我们强调以下事实:
自我们首次提交以来,我们生成了新信息,表明 426c Core 会引发抗体
绕过保守的 N 连接糖基化位点 N276 上的聚糖,这是主要障碍之一
防止种系 VRC01 类抗体变得广泛中和。我们将测试我们的提议
通过迭代方法和良好集成的实验来制定策略。我们提供的初步数据支持
我们的总体方法。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
HIV-1 VRC01 Germline-Targeting Immunogens Select Distinct Epitope-Specific B Cell Receptors.
- DOI:10.1016/j.immuni.2020.09.007
- 发表时间:2020-10-13
- 期刊:
- 影响因子:32.4
- 作者:Lin YR;Parks KR;Weidle C;Naidu AS;Khechaduri A;Riker AO;Takushi B;Chun JH;Borst AJ;Veesler D;Stuart A;Agrawal P;Gray M;Pancera M;Huang PS;Stamatatos L
- 通讯作者:Stamatatos L
Adjuvants influence the maturation of VRC01-like antibodies during immunization.
- DOI:10.1016/j.isci.2022.105473
- 发表时间:2022-11-18
- 期刊:
- 影响因子:5.8
- 作者:Knudsen, Maria L.;Agrawal, Parul;MacCamy, Anna;Parks, K. Rachael;Gray, Matthew D.;Takushi, Brittany N.;Khechaduri, Arineh;Salladay, Kelsey R.;Coler, Rhea N.;LaBranche, Celia C.;Montefiori, David;Stamatatos, Leonidas
- 通讯作者:Stamatatos, Leonidas
Targeting broadly neutralizing antibody precursors: a naïve approach to vaccine design.
针对广泛中和抗体前体:疫苗设计的一种简单方法。
- DOI:10.1097/coh.0000000000000548
- 发表时间:2019
- 期刊:
- 影响因子:4.1
- 作者:McGuire,AndrewT
- 通讯作者:McGuire,AndrewT
Development of a VRC01-class germline targeting immunogen derived from anti-idiotypic antibodies.
靶向抗二动抗体的免疫原的VRC01级种系的开发。
- DOI:10.1016/j.celrep.2021.109084
- 发表时间:2021-05-04
- 期刊:
- 影响因子:8.8
- 作者:Seydoux E;Wan YH;Feng J;Wall A;Aljedani S;Homad LJ;MacCamy AJ;Weidle C;Gray MD;Brumage L;Taylor JJ;Pancera M;Stamatatos L;McGuire AT
- 通讯作者:McGuire AT
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Leonidas Stamatatos其他文献
Leonidas Stamatatos的其他文献
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{{ truncateString('Leonidas Stamatatos', 18)}}的其他基金
Guiding the maturation of anti-CD4-BS bnAbs through sequential heterologous Env immunization
通过序贯异源 Env 免疫指导抗 CD4-BS bnAb 的成熟
- 批准号:
10849963 - 财政年份:2023
- 资助金额:
$ 190.06万 - 项目类别:
Self-amplifying mRNA-based vaccines to elicit VRC01-class bnAbs
基于 mRNA 的自我扩增疫苗可引发 VRC01 级 bnAb
- 批准号:
10589641 - 财政年份:2023
- 资助金额:
$ 190.06万 - 项目类别:
Expansion and targeted maturation of germline HIV-1 bNAb-associated BCRs
种系 HIV-1 bNAb 相关 BCR 的扩增和靶向成熟
- 批准号:
10300438 - 财政年份:2018
- 资助金额:
$ 190.06万 - 项目类别:
Development of prime-boost immunization schemes to elicit VRC01-class bNAbs in polyclonal human BCR backgrounds
开发初免-加强免疫方案以在多克隆人 BCR 背景中引发 VRC01 类 bNAb
- 批准号:
10593446 - 财政年份:2018
- 资助金额:
$ 190.06万 - 项目类别:
Development of prime-boost immunization schemes to elicit VRC01-class bNAbs in polyclonal human BCR backgrounds
开发初免-加强免疫方案以在多克隆人 BCR 背景中引发 VRC01 类 bNAb
- 批准号:
10540729 - 财政年份:2018
- 资助金额:
$ 190.06万 - 项目类别:
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