Research ArticleAutoimmunity

Depleting plasmacytoid dendritic cells reduces local type I interferon responses and disease activity in patients with cutaneous lupus

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Science Translational Medicine  26 May 2021:
Vol. 13, Issue 595, eabf8442
DOI: 10.1126/scitranslmed.abf8442

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Depleting plasmacytoid dendritic cells

Plasmacytoid dendritic cells (pDCs) are immune cells that secrete large amounts of proinflammatory molecules, an essential function that is known to promote clearance of viral infections. However, persistent activation of pDCs is associated with autoimmune diseases, including cutaneous lupus. In this study, Karnell et al. developed and tested a monoclonal antibody to target pDCs, finding that the antibody, VIB7734, depleted pDCs both in nonhuman primates and in patients with autoimmune disease. VIB7734 treatment reduced symptom severity in individuals with cutaneous lupus, suggesting that depleting pDCs is a feasible and effective strategy for treating patients with autoimmunity.

Abstract

Plasmacytoid dendritic cells (pDCs) not only are specialized in their capacity to secrete large amounts of type I interferon (IFN) but also serve to enable both innate and adaptive immune responses through expression of additional proinflammatory cytokines, chemokines, and costimulatory molecules. Persistent activation of pDCs has been demonstrated in a number of autoimmune diseases. To evaluate the potential benefit of depleting pDCs in autoimmunity, a monoclonal antibody targeting the pDC-specific marker immunoglobulin-like transcript 7 was generated. This antibody, known as VIB7734, which was engineered for enhanced effector function, mediated rapid and potent depletion of pDCs through antibody-dependent cellular cytotoxicity. In cynomolgus monkeys, treatment with VIB7734 reduced pDCs in blood below the lower limit of normal by day 1 after the first dose. In two phase 1 studies in patients with autoimmune diseases, VIB7734 demonstrated an acceptable safety profile, comparable to that of placebo. In individuals with cutaneous lupus, VIB7734 profoundly reduced both circulating and tissue-resident pDCs, with a 97.6% median reduction in skin pDCs at study day 85 in VIB7734-treated participants. Reductions in pDCs in the skin correlated with a decrease in local type I IFN activity as well as improvements in clinical disease activity. Biomarker analysis suggests that responsiveness to pDC depletion therapy may be greater among individuals with high baseline type I IFN activity, supporting a central role for pDCs in type I IFN production in autoimmunity and further development of VIB7734 in IFN-associated diseases.

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