CSL362 potently and specifically depletes pDCs invitro 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

doi:10.1016/j.isci.2023.107173

CSL362 potently and specifically depletes pDCs invitro and ablates SLE-immune complex-induced IFN responses

iScience. 2023 Jun 20;26(7):107173. doi: 10.1016/j.isci.2023.107173. eCollection 2023 Jul 21.

Authors

Katherine A Monaghan¹, Alberta Hoi^{2

3}, Cristina Gamell¹, Tsin Yee Tai¹, Bryan Linggi⁴, Jarrat Jordan⁴, Matteo Cesaroni⁴, Takahiro Sato⁴, Milica Ng¹, Shereen Oon^{5

6

7}, Jacqueline Benson⁴, Ian Wicks^{5

6

7}, Eric Morand^{2

3}, Nicholas Wilson¹

Affiliations

¹ Research and Development, CSL Limited, Melbourne, VIC 3010, Australia.
² Centre for Inflammatory Disease, School of Clinical Sciences, Monash University, Melbourne, VIC 3168, Australia.
³ Monash Health, Clayton, VIC 3168, Australia.
⁴ Janssen Research and Development LLC, Spring House, PA 19477, USA.
⁵ The Walter and Eliza Hall Institute, Parkville, VIC 3052, Australia.
⁶ The Royal Melbourne Hospital, Parkville, VIC 3050, Australia.
⁷ The University of Melbourne Parkville, Parkville, VIC 3010, Australia.

Abstract

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.

Keywords: Health sciences; Immunology; Pathophysiology.