A Novel Attenuated CD122-Biased IL15 Mutein Promotes Strong NK and T Cell–Dependent Antitumor Immunity

Interleukin-15 (IL-15) potentiates NK and T cell immunity and has huge potential for tumor immunotherapy. However, the clinical prospects of IL-15 has been hindered by poor pharmacokinetics and systemic immune-related toxicities. Here we report the development of a novel CD122-biased IL-15 mutein, V0013, generated by the truncating four C-terminal amino acids (I111, N112, T113 and S114) of IL-15. V0013 retains the overall cytokine structure and has intact binding to the critical CD122 receptor subunit, but exhibits significantly reduced overall potency. In vivo, V0013 demonstrates a prolonged half-life, improved safety and sustained pharmacodynamic effects. As a single agent, V0013 effectively promotes NK cell-driven anti-tumor immunity and enhances therapeutic efficacy of antibodies. Further mechanistic studies reveal that the interaction with specific receptor subunits dictates the function and potency of IL-15 mutein. CD122 is essential for IL-15-mediated signaling and prescribes its preference to NK and memory CD8+ T cells. Compared to an IL-15 mutein with similar attenuation but markedly weaker CD122 binding (weak-β IL-15), V0013 more closely resembles WT IL-15 functions, driving superior NK cell proliferation and survival. In a tumor model engrafted with T cells, V0013 selectively enhances memory but not naïve CD8+ T cells in tumor, leading to enhanced tumor inhibition compared to weak-β IL-15. RNAseq analysis further elucidates the critical role of CD122 in IL-15 signaling, and demonstrates that the mutein retaining intact CD122 binding elicits strong anti-tumor immunity. These findings support the therapeutic potential of the attenuated CD122-biased IL-15 mutein therapy for cancer and other diseases.