IL-15 is a cytokine involved in the regulation of the innate immune system. It stimulates the proliferation and activation of natural killer (NK) cells and memory CD8⁺ T cells. And also it promotes the secretion of a variety of cytokines. Moreover, IL-15 enhances the antibody-dependent cytotoxicity (ADCC) of antibodies. Specifically, in ADCC, the Fc-antibody targets tumor cells and also binds to CD16 receptors on the surface of NK cells. Degranulation of NK cells and target tumor cell lysis occurred under receptor cross-linking. Therefore, NK can not only resist viral infection but also control the development and progression of tumors. NK cells have two main subpopulations, CD56^dim, and CD56^bright. They will inhibit the metastasis and migration of primary tumor cells. They are mediated by activated IL-15 to perform cytotoxic effects on tumor cells. Here, we will introduce a selective and potent agonist of IL-15, the Nanrilkefusp alfa.

Nanrilkefusp alfa consists of IL-15Rα Sushi+ Domain potently activates the IL-15 pathway.

In general, Nanrilkefusp alfa couples with IL-15 via the sushi⁺ domain to effectively activate IL-15. Nanrilkefusp alfa (0.01-10 nM; 7 d) expands the amplification of NK cell isoforms from human PBMC and activates NK cells. Moreover, it (0.1, 1, and 10 nM; 3 d and 7 d) induces the expression of cytotoxic receptors NKp30, DNAM-1 and NKG2D on NK cells. Therefore, it (1 nM; 20 h) further induces cytotoxicity and tumor cell-killing activity of NK cells. However, Nanrilkefusp alfa also has strong anti-metastasis activity and anti-tumor efficacy in vivo. Nanrilkefusp alfa (2 mg/kg; s.c.; 4 consecutive days over 2 weeks) reduces NK cell and CD8⁺ T cell-dependent tumor growth metastatic kidney cancer Renca mouse model. This process is accompanied by the activation of toxic genes in TC-1 tumors (same in vitro results). Nanrilkefusp alfa (1 mg/kg; i.p.; 4 consecutive days over 2 weeks) also shows synergistic tumor inhibition with anti-PD-1 antibodies in an established mouse TRAMP-C2 tumor model. It increases the number of CD8⁺ T cells and NK cells but does not increase T-regulatory cells (Tregs). In summary, Nanrilkefusp alfa contains the IL-15Rα Sushi⁺ domain, which effectively activates the IL-15 pathway. It promotes the proliferation and activation of immune cells, and has anti-metastasis and cell activity against tumor cells.