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

Interleukin-15 (IL15) potentiates NK and T cell immunity and has huge potential for tumor immunotherapy. However, the clinical prospects of IL15 has been hindered by poor pharmacokinetics and systemic immune-related toxicities. Here, we report the development of a novel CD122-biased IL15 mutein, V0013, generated by the truncating four C-terminal amino acids (I111, N112, T113, and S114) of IL15. 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 antitumor immunity and enhances therapeutic efficacy of antibodies. Further mechanistic studies reveal that the interaction with specific receptor subunits dictates the function and potency of IL15 mutein. CD122 is essential for IL15-mediated signaling and prescribes its preference to NK and memory CD8+ T cells. Compared with an IL15 mutein with similar attenuation but markedly weaker CD122 binding (weak-β IL15), V0013 more closely resembles WT IL15 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 with weak-β IL15. RNA sequencing analysis further elucidates the critical role of CD122 in IL15 signaling and demonstrates that the mutein retaining intact CD122 binding elicits strong antitumor immunity. These findings support the therapeutic potential of the attenuated CD122-biased IL15 mutein therapy for cancer and other diseases.