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A cytotoxic anti-IL-3Rα antibody targets key cells and cytokines implicated in systemic lupus erythematosus
Shereen Oon, … , Ian P. Wicks, Nicholas J. Wilson
Shereen Oon, … , Ian P. Wicks, Nicholas J. Wilson
Published May 5, 2016
Citation Information: JCI Insight. 2016;1(6):e86131. https://doi.org/10.1172/jci.insight.86131.
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Technical Advance Immunology Therapeutics

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

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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

Shereen Oon, Huy Huynh, Tsin Yee Tai, Milica Ng, Katherine Monaghan, Mark Biondo, Gino Vairo, Eugene Maraskovsky, Andrew D. Nash, Ian P. Wicks, Nicholas J. Wilson

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Figure 1

CSL362 depletes CD123hi plasmacytoid dendritic cells and basophils and activates NK cells.

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CSL362 depletes CD123hi plasmacytoid dendritic cells and basophils and a...
(A) CD123 expression on peripheral blood cells in SLE donors (n = 34) and healthy (n = 34) and autoimmune (n = 20) controls, as determined by flow cytometry using Quantibrite-PE beads. The number of CD123 molecules per cell is shown for each donor. (B) Representative flow cytometric analysis from SLE donors of viable plasmacytoid dendritic cells (pDCs) (Sytox Blue–, Lin1–, HLA-DR+, BDCA2++) and basophils (Sytox Blue–, Lin1–, CCR3+) after 24-hour culture with media alone (no treatment), CSL362, Fab′CSL362, or isotype control. Percentage of viable (C) pDCs and (D) basophils, as determined by flow cytometry, after 24-hour culture with 0.01 μM CSL362, Fab′CSL362, or isotype control compared with media alone in SLE (n = 30), healthy (n = 25), and autoimmune donors (n = 18). (E) Fold change of percentage viable CD107a+ NK cells, as determined by flow cytometry, after 18- to 21-hour culture with 0.01 μM CSL362, Fab′CSL362, or 2 isotype controls compared with media alone for SLE (n = 12), healthy (n = 12), and autoimmune (n = 11) donors. Isotype control contains the same modified Fc region as CSL362, isotype control 2 contains an unmodified IgG1-Fc. Data are expressed as mean ± SEM, *P < 0.05 (Mann Whitney test).
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