Abstract 2340: Development of a CCR8 monoclonal antibody which blocks CCR8 signaling and abolishes the immunosuppressive function of Treg for the treatment of cancer

Abstract Within the tumor microenvironment (TME), regulatory T (Treg) cells are one attractive cell type for targeting as they play a critical role in immunosuppression. Therapeutic strategies that specifically inhibit tumor-infiltrating Tregs while sparing peripheral and normal tissue Tregs are highly desirable. The tumor-associated Tregs express the chemokine receptor CCR8, which plays a role in the induction, expansion, chemotactic migration, and immunosuppression of tumor-associated Tregs. Thus, targeted inhibition of CCR8 is a potential therapeutic strategy against cancer. We have developed a monoclonal antibody antagonist of CCR8, IPG0521, which potently inhibited the receptor-mediated signaling and chemotaxis in Treg cells with single digital nanomolar IC50. RNA sequencing (RNA-seq)analysis indicated that CCL1-induced up-regulation of immunosuppressive genes, including PD-1, CTLA4, IL-10, TIGIT etc., were reversed by IPG0521 in tumor-derived Treg cells. IPG0521 potently inhibited the growth of multiple tumor types in both syngeinic and immune-humanized mouse models, including lung cancer, liver cancer, breast cancer, via inhibiting Treg and activating CD8+ T cells. These data pave the way for the development of IPG0521, which is under IND filing, as a novel therapeutic agent against cancer. Citation Format: Guohuang Fan, Jianfei Wang, Na Wang, Yuanyuan Zhang, Yong Zhang, Binle Tian, Xuebing Jia. Development of a CCR8 monoclonal antibody which blocks CCR8 signaling and abolishes the immunosuppressive function of Treg for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2340.