@article{26a1e4cd4970405589fbe95bbcc3187e,
title = "Dual Mechanism of Interleukin-3 Receptor Blockade by an Anti-Cancer Antibody",
abstract = "Interleukin-3 (IL-3) is an activated Tcell product that bridges innate and adaptive immunity and contributes to several immunopathologies. Here, we report the crystal structure of the IL-3 receptor α chain (IL3Rα) in complex with the anti-leukemia antibody CSL362 that reveals the N-terminal domain (NTD), a domain also present in the granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-5, and IL-13 receptors, adopting unique {"}open{"} and classical {"}closed{"} conformations. Although extensive mutational analyses of the NTD epitope of CSL362 show minor overlap with the IL-3 binding site, CSL362 only inhibits IL-3 binding to the closed conformation, indicating alternative mechanisms for blocking IL-3 signaling. Significantly, whereas {"}open-like{"} IL3Rα mutants can simultaneously bind IL-3 and CSL362, CSL362 still prevents the assembly of a higher-order IL-3 receptor-signaling complex. The discovery of open forms of cytokine receptors provides the framework for development of potent antibodies that can achieve a {"}double hit{"} cytokine receptor blockade.",
author = "Broughton, \{Sophie E.\} and Hercus, \{Timothy R.\} and Hardy, \{Matthew P.\} and McClure, \{Barbara J.\} and Nero, \{Tracy L.\} and Mara Dottore and Huy Huynh and Hal Braley and Barry, \{Emma F.\} and Kan, \{Winnie L.\} and Urmi Dhagat and Pierre Scotney and Dallas Hartman and Busfield, \{Samantha J.\} and Owczarek, \{Catherine M.\} and Nash, \{Andrew D.\} and Wilson, \{Nicholas J.\} and Parker, \{Michael W.\} and Lopez, \{Angel F.\}",
note = "Funding Information: This research was partly undertaken on the MX2 beamline at the Australian Synchrotron, Victoria, and we thank the beamline staff for their assistance. We acknowledge the technical assistance of the CSL Research Department, Ms. Anna Sapa for help with protein production, and Dr. Mike Gorman for his crystallography advice. This work was also supported by grants from the National Health and Medical Research Council (NHMRC) of Australia to T.R.H., M.W.P., and A.F.L.; Cancer Australia and the Leukaemia Foundation of Australia to A.F.L.; and the Australian Cancer Research Foundation to M.W.P. and to A.F.L. Funding from the Victorian Government Operational Infrastructure Support Scheme to St. Vincent{\textquoteright}s Institute is acknowledged. U.D. and M.W.P. are NHMRC Postdoctoral and Research Fellows, respectively, and S.E.B. is a Postdoctoral Fellow supported by the Leukaemia Foundation of Australia. M.W.P. and A.F.L. are consultants for CSL Limited, which is developing CSL362, and currently receive or have previously received research support from CSL Limited. M.P.H., H.H., H.B., P.S., D.H., S.J.B., C.M.O., A.D.N., and N.J.W. are employees of CSL Limited. ",
year = "2014",
month = jul,
day = "24",
doi = "10.1016/j.celrep.2014.06.038",
language = "English",
volume = "8",
pages = "410--419",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Elsevier BV",
number = "2",
}