학술논문
CD25-Treg -depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity
Document Type
Original Paper
Author
Solomon, Isabelle; Amann, Maria; Goubier, Anne; Arce Vargas, Frederick; Zervas, Dimitrios; Qing, Chen; Henry, Jake Y.; Ghorani, Ehsan; Akarca, Ayse U.; Marafioti, Teresa; Śledzińska, Anna; Werner Sunderland, Mariana; Franz Demane, Dafne; Clancy, Joanne Ruth; Georgiou, Andrew; Salimu, Josephine; Merchiers, Pascal; Brown, Mark Adrian; Flury, Reto; Eckmann, Jan; Murgia, Claudio; Sam, Johannes; Jacobsen, Bjoern; Marrer-Berger, Estelle; Boetsch, Christophe; Belli, Sara; Leibrock, Lea; Benz, Joerg; Koll, Hans; Sutmuller, Roger; Peggs, Karl S.; Quezada, Sergio A.
Source
Nature Cancer. 1(12):1153-1166
Subject
Language
English
ISSN
2662-1347
Abstract
Intratumoral regulatory T (Treg ) cell abundance associates with diminished antitumor immunity and poor prognosis in human cancers. Recent work demonstrates that CD25, the high-affinity receptor subunit for interleukin (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 antitumor activity. Here we demonstrate potent single-agent activity of anti-CD25 antibodies optimized to deplete Treg cells, while preserving IL-2-STAT5 signaling on effector T cells and show synergy with immune checkpoint blockade in vivo. Pre-clinical evaluation of an anti-human CD25 (RG6292) antibody with equivalent features demonstrates, in both nonhuman primates and humanized mouse models, efficient Treg cell depletion with no overt immune-related toxicities. Our data support the clinical development of RG6292 and evaluation of new combination therapies incorporating non-IL-2-blocking anti-CD25 antibodies in clinical studies.
Quezada and colleagues develop improved anti-CD25 antibodies that preserve IL-2 signaling and enhance single-agent antitumor immunity and immunotherapy through specific and efficient Treg cell depletion.
Quezada and colleagues develop improved anti-CD25 antibodies that preserve IL-2 signaling and enhance single-agent antitumor immunity and immunotherapy through specific and efficient T