6yio

From Proteopedia

CRYSTAL STRUCTURE OF FAB RG6292 IN COMPLEX WITH CD25 ECD

PDB ID 6yio

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Structural highlights

6yio is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.83Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

IL2RA_HUMAN Genetic variations in IL2RA are associated with susceptibility to diabetes mellitus insulin-dependent type 10 (IDDM10) [MIM:601942. A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.^[1]

Function

IL2RA_HUMAN Receptor for interleukin-2.

Publication Abstract from PubMed

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.

CD25-T(reg)-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity.,Solomon I, Amann M, Goubier A, Arce Vargas F, Zervas D, Qing C, Henry JY, Ghorani E, Akarca AU, Marafioti T, Sledzinska A, Werner Sunderland M, Franz Demane D, Clancy JR, Georgiou A, Salimu J, Merchiers P, Brown MA, 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 KS, Quezada SA Nat Cancer. 2020 Dec;1(12):1153-1166. doi: 10.1038/s43018-020-00133-0. Epub 2020 , Nov 9. PMID:33644766^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lowe CE, Cooper JD, Brusko T, Walker NM, Smyth DJ, Bailey R, Bourget K, Plagnol V, Field S, Atkinson M, Clayton DG, Wicker LS, Todd JA. Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat Genet. 2007 Sep;39(9):1074-82. Epub 2007 Aug 5. PMID:17676041 doi:10.1038/ng2102
↑ Solomon I, Amann M, Goubier A, Arce Vargas F, Zervas D, Qing C, Henry JY, Ghorani E, Akarca AU, Marafioti T, Śledzińska A, Werner Sunderland M, Franz Demane D, Clancy JR, Georgiou A, Salimu J, Merchiers P, Brown MA, 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 KS, Quezada SA. CD25-T(reg)-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity. Nat Cancer. 2020 Dec;1(12):1153-1166. PMID:33644766 doi:10.1038/s43018-020-00133-0