Journal Article
. 2021 Mar; 1(12):1153-1166.
doi: 10.1038/s43018-020-00133-0.

CD25-Treg-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity

Isabelle Solomon 1 Maria Amann 2 Anne Goubier 3 Frederick Arce Vargas 1 Dimitrios Zervas 1 Chen Qing 1 Jake Y Henry 1 Ehsan Ghorani 1 Ayse U Akarca 4 Teresa Marafioti 4 Anna Śledzińska 1 Mariana Werner Sunderland 1 Dafne Franz Demane 1 Joanne Ruth Clancy 1 Andrew Georgiou 1 Josephine Salimu 3 Pascal Merchiers 3 Mark Adrian Brown 3 Reto Flury 5 Jan Eckmann 6 Claudio Murgia 5 Johannes Sam 5 Bjoern Jacobsen 7 Estelle Marrer-Berger 7 Christophe Boetsch 7 Sara Belli 7 Lea Leibrock 7 Joerg Benz 7 Hans Koll 6 Roger Sutmuller 5 Karl S Peggs 8 Sergio A Quezada 9 
Affiliations
  • PMID: 33644766
  •     51 References
  •     19 citations

Abstract

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.

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