title: A cytotoxic anti-IL-3Rα antibody targets key cells and cytokines implicated in systemic lupus erythematosus.
abstract: To date, the major target of biologic therapeutics in systemic lupus erythematosus (SLE) has been the B cell, which produces pathogenic autoantibodies. Recently, targeting type I IFN, which is elaborated by plasmacytoid dendritic cells (pDCs) in response to endosomal TLR7 and TLR9 stimulation by SLE immune complexes, has shown promising results. pDCs express high levels of the IL-3Rα chain (CD123), suggesting an alternative potential targeting strategy. We have developed an anti-CD123 monoclonal antibody, CSL362, and show here that it affects key cell types and cytokines that contribute to SLE. CSL362 potently depletes pDCs via antibody-dependent cell-mediated cytotoxicity, markedly reducing TLR7, TLR9, and SLE serum-induced IFN-α production and IFN-α-upregulated gene expression. The antibody also inhibits TLR7- and TLR9-induced plasmablast expansion by reducing IFN-α and IL-6 production. These effects are more pronounced than with IFN-α blockade alone, possibly because pDC depletion reduces production of other IFN subtypes, such as type III, as well as non-IFN proinflammatory cytokines, such as IL-6. In addition, CSL362 depletes basophils and inhibits IL-3 signaling. These effects were confirmed in cells derived from a heterogeneous population of SLE donors, various IFN-dependent autoimmune diseases, and healthy controls. We also demonstrate in vivo activity of CSL362 following its s.c. administration to cynomolgus monkeys. This spectrum of effects provides a preclinical rationale for the therapeutic evaluation of CSL362 in SLE.
authors.affiliation: Division of Inflammation, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Rheumatology, The Royal Melbourne Hospital, Parkville, Victoria, Australia.|The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Shereen
authors.initials: S
authors.lastname: Oon
authors.affiliation: CSL Limited, Parkville, Victoria, Australia.
authors.forename: Huy
authors.initials: H
authors.lastname: Huynh
authors.affiliation: CSL Limited, Parkville, Victoria, Australia.
authors.forename: Tsin Yee
authors.initials: TY
authors.lastname: Tai
authors.affiliation: CSL Limited, Parkville, Victoria, Australia.
authors.forename: Milica
authors.initials: M
authors.lastname: Ng
authors.affiliation: CSL Limited, Parkville, Victoria, Australia.
authors.forename: Katherine
authors.initials: K
authors.lastname: Monaghan
authors.affiliation: CSL Limited, Parkville, Victoria, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Biondo
authors.affiliation: CSL Limited, Parkville, Victoria, Australia.
authors.forename: Gino
authors.initials: G
authors.lastname: Vairo
authors.affiliation: CSL Limited, Parkville, Victoria, Australia.
authors.forename: Eugene
authors.initials: E
authors.lastname: Maraskovsky
authors.affiliation: CSL Limited, Parkville, Victoria, Australia.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Nash
authors.affiliation: Division of Inflammation, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Rheumatology, The Royal Melbourne Hospital, Parkville, Victoria, Australia.|The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Wicks
authors.affiliation: CSL Limited, Parkville, Victoria, Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wilson
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D000936:Antigen-Antibody Complex; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000097:blood; D053650:Interleukin-3 Receptor alpha Subunit / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000628:therapy*; D051199:Toll-Like Receptor 7 / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; C115022:IL3RA protein, human; C508600:IL6 protein, human; D016898:Interferon-alpha; D053650:Interleukin-3 Receptor alpha Subunit; D015850:Interleukin-6; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9