在临床前人源化小鼠模型中,mRNA-LNP 推动前体向类似于 VRC01 的广谱中和抗体进化

IF 17.6 1区 医学 Q1 IMMUNOLOGY Science Immunology Pub Date : 2024-05-16 DOI:10.1126/sciimmunol.adn0622
Xuesong Wang, Christopher A. Cottrell, Xiaozhen Hu, Rashmi Ray, Maria Bottermann, Paula Maldonado Villavicencio, Yu Yan, Zhenfei Xie, John E. Warner, Jordan Renae Ellis-Pugh, Oleksandr Kalyuzhniy, Alessia Liguori, Jordan R. Willis, Sergey Menis, Sebastian Rämisch, Saman Eskandarzadeh, Michael Kubitz, Ryan Tingle, Nicole Phelps, Bettina Groschel, Sunny Himansu, Andrea Carfi, Kathrin H. Kirsch, Stephanie R. Weldon, Usha Nair, William R. Schief, Facundo D. Batista
{"title":"在临床前人源化小鼠模型中,mRNA-LNP 推动前体向类似于 VRC01 的广谱中和抗体进化","authors":"Xuesong Wang,&nbsp;Christopher A. Cottrell,&nbsp;Xiaozhen Hu,&nbsp;Rashmi Ray,&nbsp;Maria Bottermann,&nbsp;Paula Maldonado Villavicencio,&nbsp;Yu Yan,&nbsp;Zhenfei Xie,&nbsp;John E. Warner,&nbsp;Jordan Renae Ellis-Pugh,&nbsp;Oleksandr Kalyuzhniy,&nbsp;Alessia Liguori,&nbsp;Jordan R. Willis,&nbsp;Sergey Menis,&nbsp;Sebastian Rämisch,&nbsp;Saman Eskandarzadeh,&nbsp;Michael Kubitz,&nbsp;Ryan Tingle,&nbsp;Nicole Phelps,&nbsp;Bettina Groschel,&nbsp;Sunny Himansu,&nbsp;Andrea Carfi,&nbsp;Kathrin H. Kirsch,&nbsp;Stephanie R. Weldon,&nbsp;Usha Nair,&nbsp;William R. Schief,&nbsp;Facundo D. Batista","doi":"10.1126/sciimmunol.adn0622","DOIUrl":null,"url":null,"abstract":"<div >Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) to the CD4-binding site of the HIV envelope (Env) have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle–encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as a soluble self-assembling nanoparticle in mouse models. In a model with three humanized B cell lineages bearing distinct VRC01-precursor B cell receptors (BCRs) with similar affinities for eOD-GT8, all lineages could be simultaneously primed and undergo diversification and affinity maturation without exclusionary competition. Boosts drove precursor B cell participation in germinal centers; the accumulation of somatic hypermutations, including in key VRC01-class positions; and affinity maturation to boost and native-like antigens in two of the three precursor lineages. We have preclinically validated a prime-boost regimen of soluble self-assembling nanoparticles encoded by mRNA-LNP, demonstrating that multiple lineages can be primed, boosted, and diversified along the bnAb pathway.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6000,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adn0622","citationCount":"0","resultStr":"{\"title\":\"mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models\",\"authors\":\"Xuesong Wang,&nbsp;Christopher A. Cottrell,&nbsp;Xiaozhen Hu,&nbsp;Rashmi Ray,&nbsp;Maria Bottermann,&nbsp;Paula Maldonado Villavicencio,&nbsp;Yu Yan,&nbsp;Zhenfei Xie,&nbsp;John E. Warner,&nbsp;Jordan Renae Ellis-Pugh,&nbsp;Oleksandr Kalyuzhniy,&nbsp;Alessia Liguori,&nbsp;Jordan R. Willis,&nbsp;Sergey Menis,&nbsp;Sebastian Rämisch,&nbsp;Saman Eskandarzadeh,&nbsp;Michael Kubitz,&nbsp;Ryan Tingle,&nbsp;Nicole Phelps,&nbsp;Bettina Groschel,&nbsp;Sunny Himansu,&nbsp;Andrea Carfi,&nbsp;Kathrin H. Kirsch,&nbsp;Stephanie R. Weldon,&nbsp;Usha Nair,&nbsp;William R. Schief,&nbsp;Facundo D. Batista\",\"doi\":\"10.1126/sciimmunol.adn0622\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) to the CD4-binding site of the HIV envelope (Env) have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle–encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as a soluble self-assembling nanoparticle in mouse models. In a model with three humanized B cell lineages bearing distinct VRC01-precursor B cell receptors (BCRs) with similar affinities for eOD-GT8, all lineages could be simultaneously primed and undergo diversification and affinity maturation without exclusionary competition. Boosts drove precursor B cell participation in germinal centers; the accumulation of somatic hypermutations, including in key VRC01-class positions; and affinity maturation to boost and native-like antigens in two of the three precursor lineages. We have preclinically validated a prime-boost regimen of soluble self-assembling nanoparticles encoded by mRNA-LNP, demonstrating that multiple lineages can be primed, boosted, and diversified along the bnAb pathway.</div>\",\"PeriodicalId\":21734,\"journal\":{\"name\":\"Science Immunology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":17.6000,\"publicationDate\":\"2024-05-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.science.org/doi/reader/10.1126/sciimmunol.adn0622\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/sciimmunol.adn0622\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Immunology","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/sciimmunol.adn0622","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

胚系靶向(GT)蛋白免疫原可诱导针对艾滋病病毒包膜(Env)CD4结合位点的VRC01级广谱中和抗体(bnAbs),已在临床试验中显示出良好的前景。在这里,我们在小鼠模型中对编码 eOD-GT8 60mer 的脂质纳米颗粒封装核苷 mRNA(mRNA-LNP)作为可溶性自组装纳米颗粒进行了临床前验证。在具有三个人源化 B 细胞系的模型中,这些细胞系都带有不同的 VRC01 前体 B 细胞受体(BCR),它们对 eOD-GT8 具有相似的亲和力。增殖推动了前体 B 细胞参与生殖中心;体细胞高突变的积累,包括在关键的 VRC01 类位置;以及三个前体系中两个系对增殖抗原和类原生抗原的亲和性成熟。我们在临床前验证了由 mRNA-LNP 编码的可溶性自组装纳米粒子的启动-启动方案,证明了多系细胞可沿着 bnAb 途径启动、启动和多样化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

摘要图片

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models
Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) to the CD4-binding site of the HIV envelope (Env) have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle–encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as a soluble self-assembling nanoparticle in mouse models. In a model with three humanized B cell lineages bearing distinct VRC01-precursor B cell receptors (BCRs) with similar affinities for eOD-GT8, all lineages could be simultaneously primed and undergo diversification and affinity maturation without exclusionary competition. Boosts drove precursor B cell participation in germinal centers; the accumulation of somatic hypermutations, including in key VRC01-class positions; and affinity maturation to boost and native-like antigens in two of the three precursor lineages. We have preclinically validated a prime-boost regimen of soluble self-assembling nanoparticles encoded by mRNA-LNP, demonstrating that multiple lineages can be primed, boosted, and diversified along the bnAb pathway.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Science Immunology
Science Immunology Immunology and Microbiology-Immunology
CiteScore
32.90
自引率
2.00%
发文量
183
期刊介绍: Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.
期刊最新文献
Macrophage LRRK2 hyperactivity impairs autophagy and induces Paneth cell dysfunction A B cell screen against endogenous retroviruses identifies glycan-reactive IgM that recognizes a broad array of enveloped viruses Monocytes and their doppelgängers: An immunological crossroads The pore-forming apolipoprotein APOL7C drives phagosomal rupture and antigen cross-presentation by dendritic cells TAM-ing the beast with IL-34 blockade
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1