Abstract
Rituximab, a monoclonal antibody targeting CD20 on B cells, is currently used to treat many subtypes of B cell lymphomas. However, treatment is not curative and response rates are variable. Recombinant interleukin-21 (rIL-21) is a cytokine that enhances immune effector function and affects both primary and transformed B cell differentiation. We hypothesized that the combination of rIL-21 plus rituximab would be a more efficacious treatment for B cell malignancies than rituximab alone. We cultured human and cynomolgus monkey NK cells with rIL-21 and found that their activity was increased and proteins associated with antibody dependent cytotoxicity were up-regulated. Studies in cynomolgus monkeys modeled the effects of rIL-21 on rituximab activity against CD20 B cells. In these studies, rIL-21 activated innate immune effectors, increased ADCC and mobilized B cells into peripheral blood. When rIL-21 was combined with rituximab, deeper and more durable B cell depletion was observed. In another series of experiments, IL-21 was shown to have direct antiproliferative activity against a subset of human lymphoma cell lines, and combination of murine IL-21 with rituximab yielded significant survival benefits over either agent alone in xenogeneic mouse tumor models of disseminated lymphoma. Therefore, our results do suggest that the therapeutic efficacy of rituximab may be improved when used in combination with rIL-21.
Highlights
Interleukin-21 (IL-21) is a class I cytokine produced by CD4+ and NK-T cells that acts directly on B cells, T cells, monocytes, dendritic cells and natural killer (NK) cells
Human and monkey NK cells were cultured with Recombinant interleukin-21 (rIL-21) to examine ADCC, using trastuzumab- or rituximabcoated tumor cells as targets
Human NK cells pretreated for 72 h with rIL-21 mediated a higher percentage of lysis of rituximab-coated DOHH2 lymphoma cells than of media-treated NK cells (Figure 1B). rIL-21 enhanced ADCC for Namalwa cells, which express low levels of CD20, as well as Ramos cells, which highly express CD20 (Figure 1C) [21]
Summary
Interleukin-21 (IL-21) is a class I cytokine produced by CD4+ and NK-T cells that acts directly on B cells, T cells, monocytes, dendritic cells and natural killer (NK) cells. It signals via STAT phosophorylation through a heterodimeric receptor comprised of the IL-21 receptor (IL-21R) and the common gamma chain (cC, CD132) [1], [2]. IL-21 has been reported to promote B cell differentiation and, depending on the stimulation context, may inhibit B cell proliferation. In vitro IL21 treatment of cells from these tumors induced STAT signaling and was associated with growth arrest and tumor cell apoptosis [7], [8]
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