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.
摘要
通过免疫诱导有效和广泛的HIV-1中和抗体(BNAbs)一直是
自艾滋病毒/艾滋病流行开始以来,艾滋病毒-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描述一个
来自HIV-1感染者的过多新的bNAb。这种抗体的结构特征,
结合它们个体发育的信息,极大地提高了我们对这些抗体如何
是在自然感染期间产生的,这导致了关于如何通过
免疫接种。我们的HIVRAD计划赠款旨在测试新试剂和主要加强免疫
诱导VRC01类bNAb的方案,这是最广泛和最有效的HIV-1中和方案之一
抗体已知,并在动物研究中显示出令人印象深刻的保护潜力。然而,中国的发展
通过免疫接种VRC01类bNAbs需要克服几个障碍。一位成功的
免疫接种计划可能至少需要提供新的免疫原来启动和
指导bNAb成熟进程,制定将扩张降至最低的战略
竞争脱靶的B细胞,开发最佳的Boost环境免疫原来引导适当的
抗体成熟,并提供持续的T辅助反应。在这里,我们建议测试概念,而不是
以前测试过的,我们已经开发出来直接解决这些问题。我们将评估一项新战略
是基于使用我们针对生殖系VRC01产生的抗独特型单抗(AiMAbs)-
BCR类。我们的初步数据表明,这些aiMAb特异性地扩增表达
胚系VRC01-类B细胞受体(BCR)和这些细胞进入生发中心(GC)反应
并在环境免疫后进一步扩大。一个明显的优势是GC的更大扩展
想要的B细胞超过目标外的B细胞,从而提高了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,在使用aiMAb进行免疫后,将使用加强剂。
使用专门设计用于接合种系VRC01类BCR(426c核心)的Env进行免疫,然后
通过EVS表达VRC01类抗体的关键立体区块。在这方面,我们强调以下事实:
自从我们第一次提交以来,我们产生了新的信息,表明426c核心引发抗体
绕过保守的N-连接糖基化位点N276上的多糖,这是主要障碍之一
防止种系VRC01类抗体变得广泛中和。我们将测试我们提议的
战略通过迭代的方法和良好的综合实验。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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Leonidas Stamatatos其他文献
Leonidas Stamatatos的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
- 批准号:
23H01982 - 财政年份:2023
- 资助金额:
$ 190.06万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
- 批准号:
23KJ0116 - 财政年份:2023
- 资助金额:
$ 190.06万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
- 批准号:
10682794 - 财政年份:2023
- 资助金额:
$ 190.06万 - 项目类别:
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
- 批准号:
10598276 - 财政年份:2023
- 资助金额:
$ 190.06万 - 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233343 - 财政年份:2023
- 资助金额:
$ 190.06万 - 项目类别:
Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233342 - 财政年份:2023
- 资助金额:
$ 190.06万 - 项目类别:
Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
- 批准号:
479363 - 财政年份:2023
- 资助金额:
$ 190.06万 - 项目类别:
Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
- 批准号:
10681989 - 财政年份:2023
- 资助金额:
$ 190.06万 - 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
- 批准号:
2237240 - 财政年份:2023
- 资助金额:
$ 190.06万 - 项目类别:
Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
- 批准号:
2305592 - 财政年份:2023
- 资助金额:
$ 190.06万 - 项目类别:
Continuing Grant