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Background Interleukin-2 (IL-2) is a cytokine that plays a central role in enhancing anti-tumor immune responses, particularly by promoting the cytotoxic T lymphocyte and NK cell expansion and activation while modulating immunosuppressive regulatory T cell (T reg). HM16390 is a novel, long-acting IL-2 analog engineered with precise binding properties, featuring increased affinity for CD122 and optimal binding to CD25. Compared to several IL-2 analogs, these features promote robust expansion of cytotoxic effector cells while minimizing Treg activation and mitigating peripheral toxicities such as vascular leak syndrome and cytokine release syndrome. Conjugation to a human IgG4 Fc fragment enables subcutaneous (SC) administration once per treatment cycle. In nonclinical studies, HM16390 demonstrated a favorable safety profile, dose-dependent expansion of cytotoxic effector cells, and enhanced tumor infiltration by peripheral tumor-killing T cells, accompanied by reduced Treg within the tumor microenvironment. Additionally, when combined with an anti-programmed cell death protein 1 (anti-PD-1) antibody, HM16390 exhibited additive anti-tumor activity in aggressive tumor mice models. Given the promising nonclinical findings, a first-in-human study of HM16390, as a single agent and in combination with pembrolizumab, is currently in progress.Methods This phase I, open-label, multicenter study evaluates HM16390, as a monotherapy and in combination with pembrolizumab, in patients with advanced or metastatic solid tumor patients who have failed or are intolerant to standard therapy. The study is being conducted simultaneously in the USA and South Korea and comprises three parts: Dose-Escalation, Dose-Ranging and Dose-Expansion. The Dose-Escalation Part in Arm A (monotherapy) will consist of an accelerated titration design (ATD) followed by a Bayesian optimal interval (BOIN) design, while a 3+3 design applies to Arm B (combination with pembrolizumab). The maximum tolerated dose (MTD) and/or recommended doses (RDs) will be determined of HM16390, as a single agent and in combination with pembrolizumab. HM16390 is administered SC every three weeks (Q3W), starting at a MABEL-based dose of 1 μg/kg. Arm B will initiate only after a dose level of HM16390 monotherapy is determined to be safe and tolerable, beginning from the lowest BOIN dose. In this arm, pembrolizumab will be administered at 200mg IV Q3W. The randomized Dose-Ranging Part aims to find optimal dose by evaluating its safety and preliminary efficacy across feasible doses, including backfilled patients. The Dose-Expansion Part is designed to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics in specific indications informed by preclinical and emerging clinical data. ClinicalTrials.gov Identifier: NCT06724016.BackgroundzTrial Registration ClinicalTrials.gov Identifier: NCT06724016.Ethics Approval This study has been approved by the Institutional Review Board at each investigational site.