Solomon et al. generated a non-IL-2-blocking, Treg-depleting anti-CD25 antibody (anti-CD25NIB) that demonstrated complete tumor rejection and prolonged survival in multiple solid tumor models, in an IL-2-dependent manner. Anti-CD25NIB decreased Tregs and enhanced Teff activation in vivo. In non-immunogenic tumor models, anti-CD25NIB reduced tumor growth in combination with anti-PD-L1 or GVAX. RG6292, an anti-human version of anti-CD25NIB, depleted Tregs and activated Teff cells in patient-derived tumor samples, in tumor-bearing humanized mice (more effectively than ipilimumab), and in cynomolgus monkeys, without severe toxicity.
Contributed by Shishir Pant
ASTRACT: 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.
Author Info: Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK: Isabelle Solomon, Frederick Arce Vargas, Dimitrios Zervas, Chen
Author Info: Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK: Isabelle Solomon, Frederick Arce Vargas, Dimitrios Zervas, Chen Qing, Jake Y. Henry, Ehsan Ghorani, Anna Śledzińska, Mariana Werner Sunderland, Dafne Franz Demane, Joanne Ruth Clancy, Andrew Georgiou, Karl S. Peggs & Sergio A. Quezada
Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development (pRED), Schlieren, Switzerland: Maria Amann, Reto Flury, Claudio Murgia, Johannes Sam & Roger Sutmuller
Tusk Therapeutics Ltd., Stevenage Bioscience Catalyst, Stevenage, UK: Anne Goubier, Josephine Salimu, Pascal Merchiers & Mark Adrian Brown
Department of Cellular Pathology, University College London Hospital, London, UK: Ayse U. Akarca & Teresa Marafioti
Roche Innovation Center Munich, Roche Pharmaceutical Research and Development (pRED), Penzberg, Germany: Jan Eckmann & Hans Koll
Roche Innovation Center Basel, Roche Pharmaceutical Research and Development (pRED), Basel, Switzerland: Bjoern Jacobsen, Estelle Marrer-Berger, Christophe Boetsch, Sara Belli, Lea Leibrock & Joerg Benz
