A CD25×TIGIT bispecific antibody induces anti-tumor activity through selective intratumoral Treg cell depletion.

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-09-07 DOI:10.1016/j.ymthe.2024.09.010
Xin Wei, Linlin Zhao, Fang Yang, Yajing Yang, Huixiang Zhang, Kaixin Du, Xinxin Tian, Ruihua Fan, Guangxu Si, Kailun Wang, Yulu Li, Zhizhong Wei, Miaomiao He, Jianhua Sui
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引用次数: 0

Abstract

Intratumoral regulatory T cells (Tregs) express high levels of CD25 and TIGIT, which are also recognized as markers of effector T cell (Teff) activation. Targeting these molecules each alone with monoclonal antibodies (mAbs) poses a risk of concurrently depleting both Teffs and peripheral Tregs, thereby compromising the effectiveness and selectivity of intratumoral Treg depletion. Here, leveraging the increased abundance of CD25+ TIGIT+ double-positive Tregs in the solid tumor microenvironment (but not in peripheral tissues), we explore the feasibility of using a CD25×TIGIT bispecific antibody (bsAb) to selectively deplete intratumoral Tregs. We initially constructed a bsAb co-targeting mouse CD25 and TIGIT, NSWm7210, and found that NSWm7210 conferred enhanced intratumoral Treg depletion, Teff activation, and tumor suppression as compared to the parental monotherapies in mouse models. We subsequently constructed a bsAb co-targeting human CD25 and TIGIT (NSWh7216), which preferentially eliminated CD25+ TIGIT+ double-positive cells over single-positive cells in vitro. NSWh7216 exhibited enhanced anti-tumor activity without toxicity of peripheral Tregs in CD25 humanized mice compared to the parental monotherapies. Our study illustrates the use of CD25×TIGIT bsAbs as effective agents against solid tumors based on selective depletion of intratumoral Tregs.

CD25×TIGIT 双特异性抗体通过选择性消耗瘤内 Treg 细胞诱导抗肿瘤活性。
瘤内调节性 T 细胞(Tregs)表达高水平的 CD25 和 TIGIT,它们也被认为是效应 T 细胞(Teff)激活的标志物。用单克隆抗体(mAbs)单独靶向这些分子有可能同时消耗掉Teffs和外周Tregs,从而影响瘤内Treg消耗的有效性和选择性。在这里,我们利用实体瘤微环境中(而非外周组织中)CD25+ TIGIT+双阳性Tregs数量增加的特点,探索了使用CD25×TIGIT双特异性抗体(bsAb)选择性消耗瘤内Tregs的可行性。我们最初构建了一种共同靶向小鼠 CD25 和 TIGIT 的 bsAb(NSWm7210),并发现在小鼠模型中,与亲代单药相比,NSWm7210 能增强瘤内 Treg 的清除、Teff 的激活和肿瘤的抑制。我们随后构建了一种共同靶向人类 CD25 和 TIGIT 的 bsAb(NSWh7216),它在体外优先消除 CD25+ TIGIT+ 双阳性细胞,而不是单阳性细胞。与亲代单药相比,NSWh7216在CD25人源化小鼠中表现出更强的抗肿瘤活性,且不会对外周集落细胞产生毒性。我们的研究表明,CD25×TIGIT bsAbs 是基于选择性消耗瘤内 Tregs 的有效抗实体瘤药物。
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来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
期刊介绍: Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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