The ßc family of cytokines (GM-CSF, IL-3 and IL-5) are largely products of activated T cells and regulate the survival, proliferation, differentiation and functional activation of hematopoietic cells following infection or bleeding. They are variously able to target myeloid hematopoietic stem and progenitor cells as well as mature neutrophils, eosinophils, macrophages and mast cells. Recent evidence suggests that this family of cytokines plays a role in other biological systems and importantly also in cancer, through the development and metastasis of solid tumours. Intriguingly, CD123, the IL-3 receptor alpha subunit (IL3Rα) is overexpressed by stem cells and primary blast cells of patients with acute myelogenous leukaemia (AML) and this correlates with poor prognosis leading to the development of multiple strategies that target CD123.

We have now solved the structure of soluble IL3Rα, in complex with a Fab fragment of CSL362, a humanised monoclonal antibody that binds IL3Rα, blocks IL-3 function and is optimised for NK cell-mediated killing of leukaemic cells (Broughton et al, 2014). CSL362 is currently in a Phase 1 clinical trial for the treatment of patients with AML (Clinical Trials Gov. Identifier: NCT01632852). The three domain IL3Rα structure unexpectedly revealed two alternative conformations, an open and a closed form based on the orientation of the N-terminal domain (NTD). The open conformation has not previously been reported for other Type I cytokine receptors with a similar domain structure, IL5Rα, IL13Rα1 and IL13Rα2. The IL3Rα structure will be presented together with data that supports a mechanism of IL-3 recognition and receptor signalling that may be applicable to other members of the Type I cytokine receptor superfamily. An unexpected dual mechanism of IL-3 antagonism utilised by CSL362 that involves direct antagonism of IL-3 binding as well as blockade of IL-3 receptor assembly, will also be presented.

Broughton et al, 2014 Cell Reports in press.