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

iScience Pub Date : 2025-06-04 DOI:10.1016/j.isci.2025.112829

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

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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.

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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。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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