Plasmacytoid dendritic cells as a treatment target

In the 1970s, Hooks et al . at the National Institutes of Health noted the presence of interferon in the blood of approximately 70% of patients with active systemic lupus erythematosus (SLE). They concluded that interferon may play a role in the pathogenesis of SLE.(1) Additional evidence linking interferon and SLE emerged in the form of isolated case reports.(2) With the introduction of the interferon gene signature in the early 2000s, interferon science evolved to even greater heights.(3 4) The burning clinical question was whether the interferon pathway could be inhibited and whether this would impact lupus disease activity. With the success of the anifrolumab development programme, additional strategies to subdue interferon pathway activation were explored.(5-7) The plasmacytoid dendritic cell (pDC), a mass producer of type I and III interferons, was a very compelling target. Abundant in the skin as well as other organs in patients with SLE, development programs evolved with litifilimab and daxdilimab. The former monoclonal antibody binds blood cell dendritic antigen 2 (BDCA2), a protein selectively expressed on pDCs.(8) BDCA2 ligation results in the suppression of type I and III interferon production as well as other proinflammatory cytokines and chemokines. Building upon the successes of the phase 2 programme,(9 10) litifilimab is currently in phase III studies of both SLE and cutaneous lupus. Daxdilimab, a cytolytic antibody that targets Immunoglobulin-like transcript 7 (ILT7), is also in development for the treatment of SLE.(11) Strategies to dampen SLE disease activity are incredibly eclectic, and the interferon pathway is no exception. Regardless of which approach rises to the top, the future is bright for our patients with SLE.