6YIO

CRYSTAL STRUCTURE OF FAB RG6292 IN COMPLEX WITH CD25 ECD

Summary for 6YIO

• Entry DOI: 10.2210/pdb6yio/pdb
• Descriptor: Interleukin-2 receptor subunit alpha, FAB FRAGMENT HEAVY CHAIN, FAB FRGAMENT LIGHT CHAIN, ... (4 entities in total)
• Functional Keywords: antibody, cd25 ecd, fab rg6292, il2ra, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 70263.51

Authors

Benz, J.,Koll, H.,Leibrock, L. (deposition date: 2020-04-01, release date: 2020-11-11, Last modification date: 2024-11-13)

Primary citation

Solomon, I.,Amann, M.,Goubier, A.,Vargas, F.A.,Zervas, D.,Qing, C.,Henry, J.Y.,Ghorani, E.,Akarca, A.U.,Marafioti, T.,Sledzinska, A.,Sunderland, M.W.,Demane, D.F.,Clancy, J.R.,Georgiou, A.,Salimu, J.,Merchiers, P.,Brown, M.A.,Flury, R.,Eckmann, J.,Murgia, C.,Sam, J.,Jacobsen, B.,Marrer-Berger, E.,Boetsch, C.,Belli, S.,Leibrock, L.,Benz, J.,Koll, H.,Sutmuller, R.,Peggs, K.S.,Quezada, S.A.
CD25-T reg -depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity.
Nat Cancer, 1:1153-1166, 2020

PubMed 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.

PubMed: 33644766
DOI: 10.1038/s43018-020-00133-0

Experimental method

X-RAY DIFFRACTION (1.83 Å)