Bispecific targeting of 4-1BB and CCR8 boosts antitumor immunity via Ti-Treg depletion and CD8+ activation

IF 4.6 2区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Jiefang Xu , Ran Wang , Shipeng Cheng , Sonam Wangmo , Jichao Yang , Fuquan Jin , Xiao Lu , Liyan Ma , Ying Zhu , Haoting Sun , Lunxiu Qin , Zhiyang Ling , Yaguang Zhang , Xiaoyu Sun , Chunyan Yi , Bing Sun
{"title":"Bispecific targeting of 4-1BB and CCR8 boosts antitumor immunity via Ti-Treg depletion and CD8+ activation","authors":"Jiefang Xu ,&nbsp;Ran Wang ,&nbsp;Shipeng Cheng ,&nbsp;Sonam Wangmo ,&nbsp;Jichao Yang ,&nbsp;Fuquan Jin ,&nbsp;Xiao Lu ,&nbsp;Liyan Ma ,&nbsp;Ying Zhu ,&nbsp;Haoting Sun ,&nbsp;Lunxiu Qin ,&nbsp;Zhiyang Ling ,&nbsp;Yaguang Zhang ,&nbsp;Xiaoyu Sun ,&nbsp;Chunyan Yi ,&nbsp;Bing Sun","doi":"10.1016/j.isci.2025.112829","DOIUrl":null,"url":null,"abstract":"<div><div>Immune checkpoint therapy has transformed cancer treatment, yet efficacy and safety challenges persist. Selectively inhibiting tumor-infiltrating regulatory T cells (Ti-Tregs) while enhancing CD8<sup>+</sup> T cell function are complementary strategies in cancer immunotherapy. Here, we engineered a bispecific antibody, FRP303, targeting 4-1BB and CCR8, which are co-expressed on a highly immunosuppressive subset of Ti-Tregs. <em>In vivo,</em> FRP303 outperformed monoclonal antibodies in CT26 and MC38 colorectal tumors and poorly immunogenic B16F10 melanoma. Treatment with FRP303 reduced Ti-Treg frequency, increased CD8<sup>+</sup> T cell infiltration, and elevated antitumor cytokines IFN-γ and TNF-α. Safety assessments showed FRP303 does not disrupt immune homeostasis in peripheral tissues or induce significant hepatotoxicity. Moreover, FRP303 demonstrated strong synergistic effects when combined with a PD-1 antibody. In summary, FRP303 mediated anti-tumor activity through a dual mechanism involving the selective depletion of Ti-Tregs and the enhancement of CD8<sup>+</sup> T cell function, offering a promising strategy for cancer immunotherapy.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"28 7","pages":"Article 112829"},"PeriodicalIF":4.6000,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"iScience","FirstCategoryId":"103","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2589004225010909","RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0

Abstract

Immune checkpoint therapy has transformed cancer treatment, yet efficacy and safety challenges persist. Selectively inhibiting tumor-infiltrating regulatory T cells (Ti-Tregs) while enhancing CD8+ T cell function are complementary strategies in cancer immunotherapy. Here, we engineered a bispecific antibody, FRP303, targeting 4-1BB and CCR8, which are co-expressed on a highly immunosuppressive subset of Ti-Tregs. In vivo, FRP303 outperformed monoclonal antibodies in CT26 and MC38 colorectal tumors and poorly immunogenic B16F10 melanoma. Treatment with FRP303 reduced Ti-Treg frequency, increased CD8+ T cell infiltration, and elevated antitumor cytokines IFN-γ and TNF-α. Safety assessments showed FRP303 does not disrupt immune homeostasis in peripheral tissues or induce significant hepatotoxicity. Moreover, FRP303 demonstrated strong synergistic effects when combined with a PD-1 antibody. In summary, FRP303 mediated anti-tumor activity through a dual mechanism involving the selective depletion of Ti-Tregs and the enhancement of CD8+ T cell function, offering a promising strategy for cancer immunotherapy.

Abstract Image

双特异性靶向4-1BB和CCR8通过Ti-Treg消耗和CD8+激活增强抗肿瘤免疫
免疫检查点疗法已经改变了癌症治疗,但有效性和安全性方面的挑战仍然存在。选择性抑制肿瘤浸润调节性T细胞(Ti-Tregs)同时增强CD8+ T细胞功能是癌症免疫治疗的补充策略。在这里,我们设计了一种双特异性抗体FRP303,靶向4-1BB和CCR8,这两种抗体在高度免疫抑制的Ti-Tregs亚群上共同表达。在体内,FRP303在CT26和MC38结直肠肿瘤以及免疫原性较差的B16F10黑色素瘤中的表现优于单克隆抗体。用FRP303治疗可降低Ti-Treg频率,增加CD8+ T细胞浸润,升高抗肿瘤细胞因子IFN-γ和TNF-α。安全性评估显示,FRP303不会破坏外周组织的免疫稳态或诱导显著的肝毒性。此外,FRP303与PD-1抗体联合时显示出很强的协同效应。综上所述,FRP303通过选择性消耗Ti-Tregs和增强CD8+ T细胞功能的双重机制介导抗肿瘤活性,为癌症免疫治疗提供了一种有前景的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
iScience
iScience Multidisciplinary-Multidisciplinary
CiteScore
7.20
自引率
1.70%
发文量
1972
审稿时长
6 weeks
期刊介绍: Science has many big remaining questions. To address them, we will need to work collaboratively and across disciplines. The goal of iScience is to help fuel that type of interdisciplinary thinking. iScience is a new open-access journal from Cell Press that provides a platform for original research in the life, physical, and earth sciences. The primary criterion for publication in iScience is a significant contribution to a relevant field combined with robust results and underlying methodology. The advances appearing in iScience include both fundamental and applied investigations across this interdisciplinary range of topic areas. To support transparency in scientific investigation, we are happy to consider replication studies and papers that describe negative results. We know you want your work to be published quickly and to be widely visible within your community and beyond. With the strong international reputation of Cell Press behind it, publication in iScience will help your work garner the attention and recognition it merits. Like all Cell Press journals, iScience prioritizes rapid publication. Our editorial team pays special attention to high-quality author service and to efficient, clear-cut decisions based on the information available within the manuscript. iScience taps into the expertise across Cell Press journals and selected partners to inform our editorial decisions and help publish your science in a timely and seamless way.
×
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
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
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 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信