Abstract
ObjectiveIn the last few years, anti-CD20 antibody rituximab profoundly changed the therapeutic landscape of granulomatosis with polyangiitis (GPA). Here, we investigated whether natural killer (NK) cells may play a role in rituximab’s mechanism of action in GPA.MethodsB cell depletion, NK cell degranulation, and the expression of CD69 and CD16 on NK cells were measured in a series of in vitro experiments using peripheral blood mononuclear cells (PBMCs). In vivo activation of NK cells was investigated in patients receiving rituximab infusions. Cells were analyzed by seven-color flow cytometry.ResultsNK cells from GPA patients were activated by immobilized rituximab. Also soluble rituximab activated NK cells, provided that B cells were present. NK cells degranulated and expressed the activation marker CD69 while CD16 expression was decreased. This activation of NK cells by soluble rituximab was accompanied by a reduction of B cells. The next-generation anti-CD20 antibody obinutuzumab showed stronger effects compared to rituximab on both the reduction of B cells and the activation of NK cells. Finally, we found that rituximab led to the activation of NK cells in vivo, provided that B cells were not depleted due to prior rituximab infusions.ConclusionB cell-bound rituximab activates NK cells in GPA. While NK cells therefore participate in rituximab’s mechanism of action in humans, their potential may be more efficiently exploited, e.g., by Fc engineering of therapeutic antibodies.
Highlights
Granulomatosis with polyangiitis (GPA) is a nonmalignant, life-threatening systemic inflammatory disease [1]
We further show that obinutuzumab, a type 2 anti-CD20 antibody with similar affinity to CD20 but enhanced affinity to CD16 [25] is more potent in activating GPA natural killer (NK) cells than rituximab
We first examined whether CD16 was functional on NK cells from GPA patients: Peripheral blood mononuclear cell (PBMC) were cultured overnight on plates coated with an anti-CD16 antibody, which has a high affinity for CD16 and is known to activate NK cells
Summary
Granulomatosis with polyangiitis (GPA) is a nonmalignant, life-threatening systemic inflammatory disease [1]. Rituximab has been licensed for both induction and maintenance therapy [2,3,4,5], profoundly changing the therapeutic landscape of GPA. Despite this important progress, the response to rituximab treatment is not ideal. Biomarkers predicting a good response do not exist, and further questions regarding rituximab treatment in GPA and other inflammatory diseases remain [6, 7]. As a fundamental step to clarify these obscurities, a deeper understanding of rituximab’s mechanism of action in GPA is needed
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