Abstract 3143: A novel approach to deplete Treg cells using non-IL-2 blocking anti-CD25-targeting antibodies leads to complete rejection of established tumors

The accumulation of regulatory T cells (Tregs) in the tumor hampers effector anti-tumor activity and correlates with a bad prognosis in several human cancers. Increasing the effector T cell (Teff) to regulatory T cell (Treg) ratio is known to result in improved control of established tumors. Studies demonstrating high levels of CD25 expression on Tregs but not Teff in human tumors have underscored its relevance as a target for Treg depletion. This supported the development of anti-CD25 depleting monoclonal antibodies (mAbs) as a promising monotherapy as well as combination partner in cancer immunotherapies. To date, anti-CD25 antibodies for clinical use have been designed to deplete CD25 positive cells but also to block IL-2 binding and signaling. Since IL-2 is a critical cytokine involved in T cell activation and proliferation, we hypothesized that a depleting antibody targeting CD25 on Treg cells but not blocking IL-2 signaling on Teff cells would induce a more potent anti-tumor response by depleting Tregs whilst still allowing IL-2 to stimulate effector T cells. We therefore compared the functional activity of anti-mouse CD25 depleting mAbs with and without IL-2 blocking activity. After having confirmed their differential impact on IL-2 signaling, we evaluated the therapeutic activity of these mAbs in various syngeneic tumor models. While both the IL-2 blocking and non-IL-2 blocking mAbs showed equivalent Treg-depleting activity, the antibody sparing IL-2 signaling promoted stronger anti-tumor effect than the IL-2 blocking mAb, with complete tumor regression observed in 70-100% of the mice after a single administration of the antibody. Our data demonstrates that targeting CD25 with ADCC enabled antibodies preserving IL-2 signaling is a novel and powerful strategy for rejection of established tumors via depletion of Treg cells and enhanced, cell intrinsic, IL-2-driven effector T cell activation. Citation Format: Isabelle Solomon, Frederick Arce Vargas, Dimitrios Zervas, Chen Qing, Josephine Salimu, Mark Brown, Pascal Merchiers, Aghiles Boughetane, Karl S. Peggs, Anne Goubier, Sergio A. Quezada. A novel approach to deplete Treg cells using non-IL-2 blocking anti-CD25-targeting antibodies leads to complete rejection of established tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3143.