CSL362 potently and specifically depletes pDCs in vitro and ablates SLE-immune complex-induced IFN responses
Katherine A. Monaghan,
Alberta Hoi,
Cristina Gamell,
Tsin Yee Tai,
Bryan Linggi,
Jarrat Jordan,
Matteo Cesaroni,
Takahiro Sato,
Milica Ng,
Shereen Oon,
Jacqueline Benson,
Ian Wicks,
Eric Morand,
Nicholas Wilson
Affiliations
Katherine A. Monaghan
Research and Development, CSL Limited, Melbourne, VIC 3010, Australia; Corresponding author
Alberta Hoi
Centre for Inflammatory Disease, School of Clinical Sciences, Monash University, Melbourne, VIC 3168, Australia; Monash Health, Clayton, VIC 3168, Australia
Cristina Gamell
Research and Development, CSL Limited, Melbourne, VIC 3010, Australia
Tsin Yee Tai
Research and Development, CSL Limited, Melbourne, VIC 3010, Australia
Bryan Linggi
Janssen Research and Development LLC, Spring House, PA 19477, USA
Jarrat Jordan
Janssen Research and Development LLC, Spring House, PA 19477, USA
Matteo Cesaroni
Janssen Research and Development LLC, Spring House, PA 19477, USA
Takahiro Sato
Janssen Research and Development LLC, Spring House, PA 19477, USA
Milica Ng
Research and Development, CSL Limited, Melbourne, VIC 3010, Australia
Shereen Oon
The Walter and Eliza Hall Institute, Parkville, VIC 3052, Australia; The Royal Melbourne Hospital, Parkville, VIC 3050, Australia; The University of Melbourne Parkville, Parkville, VIC 3010, Australia
Jacqueline Benson
Janssen Research and Development LLC, Spring House, PA 19477, USA
Ian Wicks
The Walter and Eliza Hall Institute, Parkville, VIC 3052, Australia; The Royal Melbourne Hospital, Parkville, VIC 3050, Australia; The University of Melbourne Parkville, Parkville, VIC 3010, Australia
Eric Morand
Centre for Inflammatory Disease, School of Clinical Sciences, Monash University, Melbourne, VIC 3168, Australia; Monash Health, Clayton, VIC 3168, Australia
Nicholas Wilson
Research and Development, CSL Limited, Melbourne, VIC 3010, Australia
Summary: Systemic lupus erythematosus (SLE) is an autoimmune disease with significant morbidity and mortality. Type I interferon (IFN) drives SLE pathology and plasmacytoid dendritic cells (pDCs) are potent producers of IFN; however, the specific effects of pDC depletion have not been demonstrated. We show CD123 was highly expressed on pDCs and the anti-CD123 antibody CSL362 potently depleted pDCs in vitro. CSL362 pre-treatment abrogated the induction of IFNα and IFN-induced gene transcription following stimulation with SLE patient-derived serum or immune complexes. RNA transcripts induced in pDCs by ex vivo stimulation with TLR ligands were reflected in gene expression profiles of SLE blood, and correlated with disease severity. TLR ligand-induced protein production by SLE patient peripheral mononuclear cells was abrogated by CSL362 pre-treatment including proteins over expressed in SLE patient serum. These findings implicate pDCs as key drivers in the cellular activation and production of soluble factors seen in SLE.
