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Background ILKN421H is an LNP mRNA encoding an IL2Rβγ selective IL-2v derivative fused with Human Serum Album. Preclinically, the novel LNP mRNA Il-2v showed unique features: 1. it expresses IL2v mRNA predominantly in spleen and lymph nodes; 2. it provided extended expression of a not-alpha IL2v, which stimulated significant and sustained expansion of stem-like CD8 T cells and NK cells that is not seen in other protein-based IL-2v. We believe the significant amplification of stem-like CD8 T and NK cells provides passive immunotherapy without direct immune activation, similar to that of PD1 CPI, and this novel MoA of ILKN421H may better unlock the antitumor potential of IL-2 while mitigating its unwanted toxicities.Methods This first-in-human, phase I/IIa, open label, dose escalation and expansion study evaluates the safety, tolerability, and initial efficacy of ILKN421H with or without pembrolizumab in patients with advanced solid tumors. The design includes two portions of the study: Parts A, ILKN421H monotherapy in which participants receive intravenous ILKN421H once every 3 weeks (Q3W) and Part B in which participants receive ILKN421H in combination with pembrolizumab (200 mg on day 1), both intravenous Q3W. Both portions consist of 3+3 escalation cohorts to evaluate dose-limiting-toxicity (DLT). If response signal for certain indication is observed in a given dose cohort, additional 6-12 patients will be enrolled for the indication to further evaluate safety and efficacy.Results A total of 45 participants were enrolled so far. In Part A, 9 patients in three dose cohorts received ILKN421H. All patients demonstrated high and prolonged plasma level of IL-2, and remarkable elevation of CD8 T cells (up to 5 folds) and NK cells (up to 25 folds). No dose-limiting toxicities (DLT) were observed. In Part B, 36 patients in three dose cohorts were enrolled, 20 of which are 1L advanced NSCLC. All patients showed robustly increased CD8 T cells and NK cells, and well tolerated safety profile (TESAE=33%). At the cut-off date (9.1, 2025), of the 20 efficacy evaluable 1L NSCLC patients regardless of the PDL1 expression levels, 16 were evaluated to be PR (ORR=80%), and 50% PFS was not reached.Conclusions ILKN421H was generally well tolerated at the current dose level, which already demonstrated prolonged plasma IL-2v expression, and robust stem-like CD8 T cells and NK cells proliferation in human participants. Initial signs of antitumor efficacy were seen in combination with pembrolizumab in 1L NSCLC regardless of PDL1 expression levels.Trial Registration NCT05978102