Non‐IL‐2‐blocking anti‐CD25 antibody inhibits tumor growth by depleting Tregs and has synergistic effects with anti‐CTLA‐4 therapy

• Published in: International journal of cancer 2024-04, Vol.154 (7), p.1285-1297
• Main Authors: Peng, Yujia, Fu, Yuyin, Liu, Hong, Zhao, Shengyan, Deng, Han, Jiang, Xiaohua, Lai, Qinhuai, Lu, Ying, Guo, Cuiyu, Zhang, Guangbing, Luo, Yong, Wang, Yuxi, Gou, Lantu, Yang, Jinliang
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antibodies; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antitumor activity; CD25; CD25 antigen; Effector cells; Gene expression; Graft rejection; Immunoregulation; Immunosuppressive Agents; Immunotherapy; Interleukin-2 Receptor alpha Subunit - metabolism; Lymphocytes T; Mice; Monoclonal antibodies; Neoplasms - drug therapy; Neoplasms - metabolism; non‐IL‐2‐blocking antibody; T-Lymphocytes, Regulatory; Tregs; tumor immune microenvironment; tumor immunotherapy; Tumor Microenvironment; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.34823

CD25, also known as the interleukin‐2 receptor α chain (IL‐2Rα), is highly expressed on regulatory T cells (Tregs), but relatively lower on effector T cells (Teffs). This makes it a potential target for Treg depletion, which can be used in tumor immunotherapy. However, marketed anti‐CD25 antibodies (Basiliximab and Daclizumab) were originally developed as immunosuppressive drugs to prevent graft rejection, because these antibodies can block IL‐2 binding to CD25 on Teffs, which in turn destroys the function of Teffs. Recent studies have shown that non‐IL‐2‐blocking anti‐CD25 antibodies have displayed exciting antitumor effects. Here, we screened out a non‐IL‐2‐blocking anti‐CD25 monoclonal antibody (mAb) 7B7 by hybridoma technology, and confirmed its antitumor activity via depleting Tregs in a CD25 humanized mouse model. Subsequently, we verified that the humanized 7B7, named as h7B7‐15S, has comparable activities to 7B7, and that its Treg depletion is further increased when combined with anti‐CTLA‐4, leading to enhanced remodeling of the tumor immune microenvironment. Moreover, our findings reveal that the Fab form of h7B7‐15S has the ability to deplete Tregs, independent of the Fc region. Taken together, our studies expand the application of anti‐CD25 in tumor immunotherapy and provide insight into the underlying mechanism. What's new? CD25, a component of the interleukin‐2 receptor, mediates T‐cell proliferation and is expressed in high levels on regulatory T cells (Tregs). CD25 is therefore a promising target for Treg depletion and tumor immunotherapy, particularly with non‐IL‐2‐blocking anti‐CD25 antibody. The present study examined the antitumor effect of a non‐IL‐2‐blocking anti‐CD25 monoclonal antibody in a humanized mouse model. Experiments show that non‐IL‐2‐blocking anti‐CD25 antibody can reduce tumor‐associated macrophages and myeloid‐derived suppressor cells within the tumor microenvironment. Treg depletion increased when non‐IL‐2‐blocking anti‐CD25 antibody was combined with anti‐CTLA‐4. The findings cast light on mechanisms underlying anti‐CD25 tumor immunotherapy and broaden its potential applications.