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Adjuvant, mimicry and booster requirements for shepherding the development of neutralizing antibodies to the high-mannose patch on HIV-1

促进 HIV-1 高甘露糖贴片中和抗体开发的佐剂、模拟和加强剂要求

基本信息

批准号：
10689097
负责人：
Ralph Alphonso Pantophlet
金额：
$ 54万
依托单位：
SIMON FRASER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10689097
关键词：
Address Adjuvant Affinity Antibodies Antibody Response Antibody titer measurement Antigen Mimicry Avidity B-Lymphocytes Bacterial Polysaccharides Binding Carrier Proteins Cells Clinical Development Discrimination Epitopes Family Formulation Frequencies Future Glycoconjugates Glycosides HIV HIV Envelope Protein gp120 HIV vaccine HIV-1 Human Immune Tolerance Immune system Immunization Immunize Immunologics Individual Infection Investigation Lead Lipid A Mannose Mus Nature Oligosaccharides Polysaccharides Progress Reports Proteins Publishing Rat Transgene Recombinants Reporting Research Site Specificity Structure Surface TLR4 gene TLR7 gene Time Transgenic Mice Vaccine Design Work analog arm cross reacting material 197 cross reactivity design glycomimetics glycosylation immunogenicity insight interest mimetics mimicry mouse model neutralizing antibody preclinical study receptor sugar

项目摘要

PROJECT SUMMARY The HIV-1 envelope spike (Env) bears a cluster of oligomannose-type glycans that is a target for broadly neutralizing antibodies (bnAbs). However, while nAbs to this cluster, dubbed the high-mannose patch (HMP), are known to develop in at least some HIV-infected individuals, past attempts to elicit similar antibodies by immunization have been largely unsuccessful. Most previous approaches have involved presenting clusters of natural or synthetic high-mannose glycans on the surface of carrier proteins. The difficulty in eliciting high-mannose-targeting nAbs by immunization is believed to relate, at least in part, to the ‘self’ nature of the targeted glycans; naïve B cells bearing Ig receptors of the desired fine specificity or affinity might be anergic or at relatively low frequency due to tolerance mechanisms. The approach that we are pursuing is based on the scientific premise that antigenic mimicry of mammalian host structures can stimulate cross-reactive antibodies if such mimics are presented in the proper ‘foreign’ milieu. Our overarching hypothesis is that, upon immunization, an antigenic mimic of mammalian oligomannose will more readily elicit antibodies that bind the HMP than native or synthetic oligomannose. In our progress report, we show that a CRM197-conjugate of our lead oligomannose mimetic, the design of which is inspired by a bacterial polysaccharide with resemblance to mammalian oligomannose, is bound with high avidity by various HMP-specific bnAbs as well as their germline precursors. Furthermore, human antibody transgenic mice immunized with this neoglycoconjugate yield antibodies that bind recombinant HIV-1 SOSIP trimers, albeit only when the conjugate is formulated in the TLR4-stimulating Th1-adjuvant GLA-SE; not when formulated in Th2- or mixed Th1/2-adjuvants. Based on our findings so far, we propose in this renewal application to extend our investigations. A first step (Aim 1) will be to probe the relevance of Th1 stimulation further, by assessing immunogenicity of our lead glycoconjugate when formulated with other Th1-directing adjuvants. These additional adjuvants will not be agonistic for TLR4, thus helping to reveal whether stimulating TLR4 is relevant. We will assess also (Aim 2) the significance of antigenic mimicry for triggering high mannose-specific antibodies, by comparing the immunogenicity of our lead mimetic to synthetic oligomannose. We will evaluate also whether incorporating an archetypical component of gram-negative bacterial LPS –Kdo and lipid A—into our lead glycoside is immunologically beneficial. Our third step (Aim 3) will be to investigate whether injecting glycoconjugate-primed transgenic mice at specific time points with select SOSIP trimers boosts nAb titers. We expect our findings to help sharpen our strategy and critically inform the pursuit of future preclinical studies. Results from this research could inform other HIV vaccine design strategies also.

项目总结 HIV-1包膜尖峰(Env)含有一簇低聚糖链，是广泛靶标中和抗体(BNAbs)。然而，虽然NAB到这个集群，被称为高甘露糖贴片 (HMP)，已知至少在一些艾滋病毒感染者中会发生，过去曾试图引起类似的通过免疫的抗体在很大程度上是不成功的。以前的大多数方法都涉及到在载体蛋白表面呈现一簇簇天然或合成的高甘露糖多聚糖。这个通过免疫诱导高甘露糖靶向NAB的困难被认为至少部分地与靶向多糖的‘自身’性质；幼稚的B细胞携带所需的良好特异性的Ig受体或者，由于耐受机制，亲和力可能是无能的或频率相对较低。我们正在追求的方法是基于这样一个科学前提，即抗原模拟哺乳动物的宿主结构可以刺激交叉反应抗体，如果这种模拟出现在适当的“异域”环境。我们的主要假设是，在免疫后，抗原性模仿哺乳动物的寡聚甘露糖比天然的或合成的更容易产生结合HMP的抗体寡头注解。在我们进度报告中，我们显示了我们的低聚铅的CRM197结合物模仿，其设计灵感来自于一种与哺乳动物相似的细菌多糖寡核苷酸与多种HMP特异性bNAb及其种系结合具有高亲和力先驱物。此外，用该新糖偶联物免疫的人抗体转基因小鼠结合重组HIV-1 SOSIP三聚体的抗体，尽管仅当结合物在 TLR4刺激Th1佐剂GLA-SE；在Th2佐剂或混合Th1/2佐剂中不使用。根据我们到目前为止的调查结果，我们在这次续签申请中建议延长我们的调查期限。第一次步骤(目标1)将通过评估Th1刺激的免疫原性进一步探讨Th1刺激的相关性我们的先导糖结合物与其他Th1导向佐剂一起配制时。这些额外的佐剂将不是TLR4的激动剂，因此有助于揭示刺激TLR4是否相关。我们将评估此外(目标2)抗原模拟对于触发高甘露糖特异性抗体的意义，通过比较我们的铅模拟物和合成低聚甘露糖的免疫原性。我们也将进行评估是否将革兰氏阴性细菌的典型成分内毒素-KDO和脂类A- 我们的铅苷对免疫有益。我们的第三步(目标3)将是调查在特定时间点注射糖结合蛋白引发的转基因小鼠，并选择SOSIP三聚体增强作用 NAB效价。我们期待我们的发现有助于我们的战略，并为未来的追求提供关键的信息临床前研究。这项研究的结果也可以为其他艾滋病毒疫苗设计策略提供参考。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Synthetic Neoglycoconjugates of Hepta- and Nonamannoside Ligands for Eliciting Oligomannose-Specific HIV-1-Neutralizing Antibodies.

DOI：
10.1002/cbic.202200061
发表时间：
2022-04-05
期刊：
CHEMBIOCHEM
影响因子：
3.2
作者：
Cattin, Matteo;Bruxelle, Jean-Francois;Ng, Kurtis;Blaukopf, Markus;Pantophlet, Ralph;Kosma, Paul
通讯作者：
Kosma, Paul

A glycoside analog of mammalian oligomannose formulated with a TLR4-stimulating adjuvant elicits HIV-1 cross-reactive antibodies.