Abstract 574: Depletion of regulatory T cells without interruption of IL-2 signaling by antibody against CD25 for enhancing antitumor immunity

Abstract

Abstract Depleting regulatory T cells from the tumor microenvironment is an attractive strategy for enhancing immunotherapy. Here we developed a humanized antibody against CD25 (H11E11-2V1) with Treg-biased binding. This antibody has a medium affinity to CD25 (KD=8.9nM), weaker than Daclizumab (KD=1.5nM) and RG6292 (KD=4.5nM). Primary T cells activated with CD3 and CD28 beads had increased CD25 expression. H11E11-2V1 bound to Treg (CD4+Foxp3+) with a concentration as low as 0.07nM, similar to RG6292, while it has no detectable binding to activated Teff (CD4+Foxp3-) with a concentration below 2nM (vs. RG6292 below 0.7nM). In addition, H11E11-2V1 did not block IL-2 signaling in NK-92 cells, which expressed CD25 on the cell surface, while Daclizumab blocked the IL-2 signaling. Daclizumab inhibited T cell proliferation (ki67+%) and activation (Granzyme B+%), but not by RG6292 and H11E11-2V1. In vitro cytotoxicity assay indicated that H11E11-2V1 with modified Fc to enhance ADCC specifically depletes Treg from activated primary T cells at a minimal concentration of 0.07nM (vs. RG6292 at 0.14nM) while leaving 90% of Teff intact. In the in vivo MC38 murine tumor model with mice whose CD25 was replaced with human CD25, H11E11-2V1 given by I.P. injection suppressed tumor growth with higher efficiency than RG6292. These results suggested that H11E11-2V1 was an excellent candidate therapeutical antibody against CD25 for cancer therapy. Citation Format: Yuxuan Gao, Feng He, Hao Peng, Kefei Wu, Hui Zhao, Yanpeng Feng, Feng Hao, Guojin Wu, Jinying Ning. Depletion of regulatory T cells without interruption of IL-2 signaling by antibody against CD25 for enhancing antitumor immunity [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 574.