Effect of in vivo Hydroxychloroquine and ex vivo Anti-BDCA2 mAb Treatment on pDC IFNα Production From Patients Affected With Cutaneous Lupus Erythematosus.

Objective: Plasmacytoid dendritic cells (pDCs) are a major source of Type-I Interferon (IFN-I), a key driver in cutaneous lupus erythematosus (CLE). Currently evaluated in Phase II clinical trial, 24F4A (BIIB059) is an antibody targeting BDCA2, an inhibitory receptor expressed on pDCs. Given that Hydroxychloroquine (HCQ), a widely-used CLE therapy, and 24F4A are both able to inhibit pDC-derived IFN-I production; this study aimed to determine whether 24F4A would show an additional inhibitory effect on pDC response after ex vivo or in vivo treatment with HCQ. Methods: The effect of 24F4A on pDC-derived IFNα was measured from peripheral blood mononuclear cells (PBMC) either from healthy donors in presence or absence of HCQ or from CLE patients clinically exposed to various levels of HCQ. TLR7, TLR7/8, and TLR9 agonists (ssRNA, R848, and CpG-A) were used for pDC stimulation. Results: PDCs were the only producers of IFNα in response to CpG-A, R848, and ssRNA stimulation in PBMC cultures. CLE patients with higher levels of blood HCQ showed lower ex vivo pDC responses to CpG-A, but not R848 or ssRNA. In contrast, 24F4A reduced the amount of IFNα produced by pDCs from CLE patients in response to all TLR agonists, irrespective of the blood HCQ level. Conclusion: Our findings reveal that clinically-relevant HCQ concentrations partially inhibit the pDC response to TLR9 and weakly affect the response to TLR7/8 stimulation. 24F4A robustly inhibits pDC responses even in the presence of HCQ, highlighting its unique potential to disrupt pDC disease relevant biology, which could provide additional therapeutic benefit for CLE patients.

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