Preassociation of IL-15 with IL-15Rα-IgG1-Fc Enhances Its Activity on Proliferation of NK and CD8+/CD44high T Cells and Its Antitumor Action

Abstract

In the induction of an immune response, IL-15Rα on APCs transpresents IL-15 to NK and CD8+/CD44high T cells that express the IL-2/15Rβ and γc subunits only. In this study, we show data mimicking this transpresentation by using IL-15 preassociated with a chimeric protein that is comprised of the extracellular domain of murine IL-15Rα and the Fc portion of human IgG1. When tested in vitro, IL-15Rα-IgG1-Fc strongly increased the IL-15-mediated proliferation of murine NK and CD8+/CD44high T cells. The effect of IL-15Rα-IgG1-Fc was dependent on the presence of both IgG1-Fc and IL-15Rα. When injected into mice, IL-15Rα-IgG1-Fc enhanced the capacity of IL-15 to expand the number of NK and CD8+/CD44high T cells. The effect on cell numbers in vivo also depended on Fc receptor binding because reduced expansion was observed in FcRγ−/− mice. NK cells cultured in IL-15/IL-15Rα-IgG1-Fc complex gained cytotoxic activity toward a number of NK-sensitive targets. When mice bearing the NK-sensitive syngeneic tumor B16 were treated, the presence of IL-15Rα-IgG1-Fc increased the antitumor activity of IL-15. Thus, a preassociation with IL-15Rα-IgG1-Fc enhances the activities of IL-15 in vivo and in vitro that may be useful in the treatment of tumors.

An Antibody Fusion Protein for Cancer Immunotherapy Mimicking IL-15 trans-Presentation at the Tumor Site

“…Treatment of mice with IL-15xIL15RaFc complexes enhanced the proliferation of CD8 þ memory T cells and NK cells in vivo. Furthermore, tumor burden could be reduced and survival extended in a systemic B16 melanoma mouse model (24,25). Similar results were obtained by an IL-15/IL-15Ra domain fusion protein (26,27).…”

“…Binding of soluble IL-15Ra to soluble IL-15 led to competition with cell surface receptors inhibiting IL-15-mediated function (14). Later, complex formation of recombinant soluble IL-15 and IL-15Ra-Fc molecules was reported to enhance the bioactivity of IL-15, inducing proliferation of NK cells and memory T cells in vitro and in vivo (23,25). Structural studies identified the "sushi" region in the IL-15Ra as the main responsible element for IL-15 binding (31).…”

Safety (toxicity), pharmacokinetics, immunogenicity, and impact on elements of the normal immune system of recombinant human IL-15 in rhesus macaques

“…[6][7][8][9][10] Attempts to treat tumor models in mice by administration of IL-15 have proven effective. [28][29][30][31][32][33][34][35] Whereas wild-type C57Bl/6 mice died by 40 days after IV injection of MC38 colon carcinoma cells, IL-15 transgenic mice did not develop metastases and survived. 28 Furthermore, therapy with IL-15 prolonged survival of mice that received syngeneic CT26, MC38 colon carcinoma cells, or B16 melanoma cells.…”

“…28 Furthermore, therapy with IL-15 prolonged survival of mice that received syngeneic CT26, MC38 colon carcinoma cells, or B16 melanoma cells. 28,33 Klebanoff et al demonstrated that IL-15 enhanced the in vivo activity of tumor-reactive CD8 ϩ T cells in the T-cell receptortransgenic mouse (Pmel-1), in which CD8 T cells recognize an epitope derived from the melanoma antigen GP100. 31 In other studies, synergy between IL-21 and IL-15 in regulating CD8 ϩ T-cell expansion and function yielded cures of established large B16 melanomas.…”

The tumor immunosuppressive microenvironment impairs the therapy of anti-HER2/neu antibody

“…It is reported that the complex of IL-15Rα and IL-15 is a strong stimulator for the responses of NK cells and CD8 + T cells (Dubois et al, 2008;Epardaud et al, 2008;Han et al, 2011). We prepared IL-15R/IL-15 fusion protein by fusing IL-15 receptor α sushi domain with IL-15 (Mortier et al, 2006).…”