CSL311, a novel, potent, therapeutic monoclonal antibody for the treatment of diseases mediated by the common β chain of the IL-3, GM-CSF and IL-5 receptors

ABSTRACT

The β common-signaling cytokines interleukin (IL)-3, granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-5 stimulate pro-inflammatory activities of haematopoietic cells via a receptor complex incorporating cytokine-specific α and shared β common (β_c, CD131) receptor. Evidence from animal models and recent clinical trials demonstrate that these cytokines are critical mediators of the pathogenesis of inflammatory airway disease such as asthma. However, no therapeutic agents, other than steroids, that specifically and effectively target inflammation mediated by all 3 of these cytokines exist. We employed phage display technology to identify and optimize a novel, human monoclonal antibody (CSL311) that binds to a unique epitope that is specific to the cytokine-binding site of the human β_c receptor. The binding epitope of CSL311 on the β_c receptor was defined by X-ray crystallography and site-directed mutagenesis. CSL311 has picomolar binding affinity for the human β_c receptor, and at therapeutic concentrations is a highly potent antagonist of the combined activities of IL-3, GM-CSF and IL-5 on primary eosinophil survival in vitro. Importantly, CSL311 inhibited the survival of inflammatory cells present in induced sputum from human allergic asthmatic subjects undergoing allergen bronchoprovocation. Due to its high potency and ability to simultaneously suppress the activity of all 3 β common cytokines, CSL311 may provide a new strategy for the treatment of chronic inflammatory diseases where the human β_c receptor is central to pathogenesis. The coordinates for the β_c/CSL311 Fab complex structure have been deposited with the RCSB Protein Data Bank (PDB 5DWU).

KEYWORDS:

• Affinity maturation
• asthma
• β common receptor
• cytokine
• eosinophil
• GM-CSF
• IL-3
• IL-5
• myeloid
• phage display
• therapeutic antibody

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank CSL Limited Research staff (Recombinant Proteins Group, Antibody Technologies Group, Protein Technologies Group, Analytical Biochemistry Group), Karen Howie (M^cMaster University) and Kay Wycherley (WEHI Antibody Facility). This research was partly undertaken on the MX2 beamline at the Australian Synchrotron, Victoria, Australia and we thank the beamline staff for their assistance. This crystallography work was supported by a grant from the National Health and Medical Research Council of Australia (NHMRC) to M.W.P and A.F.L. and from the Australian Cancer Research Foundation to M.W.P. Funding from the Victorian Government Operational Infrastructure Support Scheme to St Vincent's Institute is acknowledged. U.D. and M.W.P. are NHMRC Postdoctoral and Research Fellows, respectively.