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

• Published in: Molecular therapy
• Main Authors: Wei, Xin, Zhao, Linlin, Yang, Fang, Yang, Yajing, Zhang, Huixiang, Du, Kaixin, Tian, Xinxin, Fan, Ruihua, Si, Guangxu, Wang, Kailun, Li, Yulu, Wei, Zhizhong, He, Miaomiao, Sui, Jianhua
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.09.2024
• Subjects: bispecific antibody; bsAb; CD25; intratumoral regulatory T cells; TIGIT; Treg depletion; Treg depletion; bispecific antibody; intratumoral regulatory T cells; CD25; bsAb; TIGIT
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2024.09.010

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. [Display omitted] Sui and colleagues developed bispecific antibodies (bsAbs) targeting CD25 and TIGIT by leveraging the abundance of immune-suppressive CD25+ TIGIT+ double-positive regulatory T cells (Tregs) in tumor microenvironment. Experiments with mouse models showed that the bsAbs safely enhances intratumoral Tregs depletion and tumor suppression and outperforms the parental monoclonal antibodies.