title: 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 (βc, 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 βc receptor. The binding epitope of CSL311 on the βc receptor was defined by X-ray crystallography and site-directed mutagenesis. CSL311 has picomolar binding affinity for the human βc 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 βc receptor is central to pathogenesis. The coordinates for the βc/CSL311 Fab complex structure have been deposited with the RCSB Protein Data Bank (PDB 5DWU).
authors.affiliation: a Research and Development, CSL Limited; Bio21 Molecular Science and Biotechnology Institute , Parkville Victoria , 3010 , Australia.
authors.forename: Con
authors.initials: C
authors.lastname: Panousis
authors.affiliation: b Australian Cancer Research Foundation Rational Drug Discovery Center, St. Vincent's Institute of Medical Research , Fitzroy , Victoria , 3065 , Australia.
authors.forename: Urmi
authors.initials: U
authors.lastname: Dhagat
authors.affiliation: a Research and Development, CSL Limited; Bio21 Molecular Science and Biotechnology Institute , Parkville Victoria , 3010 , Australia.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Edwards
authors.affiliation: a Research and Development, CSL Limited; Bio21 Molecular Science and Biotechnology Institute , Parkville Victoria , 3010 , Australia.
authors.forename: Veronika
authors.initials: V
authors.lastname: Rayzman
authors.affiliation: a Research and Development, CSL Limited; Bio21 Molecular Science and Biotechnology Institute , Parkville Victoria , 3010 , Australia.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Hardy
authors.affiliation: a Research and Development, CSL Limited; Bio21 Molecular Science and Biotechnology Institute , Parkville Victoria , 3010 , Australia.
authors.forename: Hal
authors.initials: H
authors.lastname: Braley
authors.affiliation: c McMaster University , Hamilton , Ontario L8N 3Z5 , Canada.
authors.forename: Gail M
authors.initials: GM
authors.lastname: Gauvreau
authors.affiliation: d Division of Human Immunology, the Center for Cancer Biology, SA Pathology and the University of South Australia, Frome Road, Adelaide, South Australia 5000 and the University of South Australia , Adelaide , South Australia 5001 , Australia.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hercus
authors.affiliation: c McMaster University , Hamilton , Ontario L8N 3Z5 , Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Smith
authors.affiliation: c McMaster University , Hamilton , Ontario L8N 3Z5 , Canada.
authors.forename: Roma
authors.initials: R
authors.lastname: Sehmi
authors.affiliation: a Research and Development, CSL Limited; Bio21 Molecular Science and Biotechnology Institute , Parkville Victoria , 3010 , Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: McMillan
authors.affiliation: d Division of Human Immunology, the Center for Cancer Biology, SA Pathology and the University of South Australia, Frome Road, Adelaide, South Australia 5000 and the University of South Australia , Adelaide , South Australia 5001 , Australia.
authors.forename: Mara
authors.initials: M
authors.lastname: Dottore
authors.affiliation: d Division of Human Immunology, the Center for Cancer Biology, SA Pathology and the University of South Australia, Frome Road, Adelaide, South Australia 5000 and the University of South Australia , Adelaide , South Australia 5001 , Australia.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: McClure
authors.affiliation: a Research and Development, CSL Limited; Bio21 Molecular Science and Biotechnology Institute , Parkville Victoria , 3010 , Australia.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Fabri
authors.affiliation: a Research and Development, CSL Limited; Bio21 Molecular Science and Biotechnology Institute , Parkville Victoria , 3010 , Australia.
authors.forename: Gino
authors.initials: G
authors.lastname: Vairo
authors.affiliation: d Division of Human Immunology, the Center for Cancer Biology, SA Pathology and the University of South Australia, Frome Road, Adelaide, South Australia 5000 and the University of South Australia , Adelaide , South Australia 5001 , Australia.
authors.forename: Angel F
authors.initials: AF
authors.lastname: Lopez
authors.affiliation: b Australian Cancer Research Foundation Rational Drug Discovery Center, St. Vincent's Institute of Medical Research , Fitzroy , Victoria , 3065 , Australia.|e Department of Biochemistry and Molecular Biology , Bio21 Molecular Science and Biotechnology Institute, University of Melbourne , Parkville , Victoria 3010 , Australia.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Parker
authors.affiliation: a Research and Development, CSL Limited; Bio21 Molecular Science and Biotechnology Institute , Parkville Victoria , 3010 , Australia.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Nash
authors.affiliation: a Research and Development, CSL Limited; Bio21 Molecular Science and Biotechnology Institute , Parkville Victoria , 3010 , Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wilson
authors.affiliation: a Research and Development, CSL Limited; Bio21 Molecular Science and Biotechnology Institute , Parkville Victoria , 3010 , Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wilson
authors.affiliation: a Research and Development, CSL Limited; Bio21 Molecular Science and Biotechnology Institute , Parkville Victoria , 3010 , Australia.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Owczarek
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D000936:Antigen-Antibody Complex / Q000737:chemistry / Q000276:immunology; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D018360:Crystallography, X-Ray; D053648:Cytokine Receptor Common beta Subunit / Q000737:chemistry / Q000276:immunology; D004804:Eosinophils / Q000276:immunology / Q000473:pathology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000276:immunology; D006801:Humans; D007377:Interleukin-3 / Q000037:antagonists & inhibitors / Q000276:immunology; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000276:immunology; D051379:Mice
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000936:Antigen-Antibody Complex; C115876:CSF2RB protein, human; D053648:Cytokine Receptor Common beta Subunit; D000939:Epitopes; C508596:IL3 protein, human; C508599:IL5 protein, human; D007377:Interleukin-3; D015848:Interleukin-5; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Affinity maturation; GM-CSF; IL-3; IL-5; asthma; cytokine; eosinophil; myeloid; phage display; therapeutic antibody; β common receptor