Article
作者: Flury, Reto ; Georgiou, Andrew ; Śledzińska, Anna ; Quezada, Sergio A ; Eckmann, Jan ; Benz, Joerg ; Merchiers, Pascal ; Salimu, Josephine ; Henry, Jake Y ; Brown, Mark Adrian ; Sutmuller, Roger ; Werner Sunderland, Mariana ; Marafioti, Teresa ; Goubier, Anne ; Jacobsen, Bjoern ; Peggs, Karl S ; Qing, Chen ; Akarca, Ayse U ; Franz Demane, Dafne ; Boetsch, Christophe ; Zervas, Dimitrios ; Amann, Maria ; Solomon, Isabelle ; Koll, Hans ; Belli, Sara ; Clancy, Joanne Ruth ; Murgia, Claudio ; Ghorani, Ehsan ; Sam, Johannes ; Leibrock, Lea ; Marrer-Berger, Estelle ; Arce Vargas, Frederick
Intratumoral regulatory T cell (Treg) abundance associates with diminished anti-tumor immunity and poor prognosis in human cancers. Recent work demonstrates that CD25, the high affinity receptor subunit for IL-2, is a selective target for Treg depletion in mouse and human malignancies; however, anti-human CD25 antibodies have failed to deliver clinical responses against solid tumors due to bystander IL-2 receptor signaling blockade on effector T cells, which limits their anti-tumor activity. Here we demonstrate potent single-agent activity of anti-CD25 antibodies optimized to deplete Tregs whilst preserving IL-2-STAT5 signaling on effector T cells, and demonstrate synergy with immune checkpoint blockade in vivo. Pre-clinical evaluation of an anti-human CD25 (RG6292) antibody with equivalent features demonstrates, in both non-human primates and humanized mouse models, efficient Treg depletion with no overt immune-related toxicities. Our data supports the clinical development of RG6292 and evaluation of novel combination therapies incorporating non-IL-2 blocking anti-CD25 antibodies in clinical studies.