A cytotoxic anti-IL-3Ralpha antibody targets key cells and cytokines implicated in systemic lupus erythematosus

Oon, S; Huynh, H; Tai, TY; Ng, M; Monaghan, K; Biondo, M; Vairo, G; Maraskovsky, E; Nash, AD; Wicks, IP; Wilson, NJ

Author(s): Oon, S; Huynh, H; Tai, TY; Ng, M; Monaghan, K; Biondo, M; Vairo, G; Maraskovsky, E; Nash, AD; Wicks, IP; Wilson, NJ;
Details: Publication Year 2016-05-05,Volume 1,Issue #6,Page e86131
Journal Title: JCI Insight
Publication Type: Journal Article
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-3Ralpha 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-alpha production and IFN-alpha-upregulated gene expression. The antibody also inhibits TLR7- and TLR9-induced plasmablast expansion by reducing IFN-alpha and IL-6 production. These effects are more pronounced than with IFN-alpha 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.
Publisher: ASCI
Research Division(s): Inflammation
PubMed ID: 27699260
Link To PubMed Central Version: https://www.ncbi,nlm,nih,gov/pmc/articles/PMC5033899/
Publisher's Version: https://doi.org/10.1172/jci.insight.86131
NHMRC Grants: NHMRC/1023407, NHMRC/1016647, NHMRC/1039026,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2016-10-19 11:52:32

Last Modified: 2018-09-21 08:51:15