On November 11, 2025 iLeukon Therapeutics, Inc., a San Diego-based clinical-stage biotechnology company developing next-generation mRNA-based immunotherapies, reported new clinical results from the ongoing first-in-human Phase I trial (NCT05978102) of ILKN421H, presented during a Late-Breaking Clinical Oral Session at the 2025 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting in National Harbor, MD.
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The study evaluates ILKN421H, a lipid-nanoparticle (LNP)-formulated mRNA encoding a non-α HSA–IL-2 variant (IL-2v), as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors, including first-line non-small cell lung cancer (NSCLC). The presentation highlighted ILKN421H’s unique scientific design and distinct pharmacologic advantages that enable potent immune activation with a favorable safety profile.
Key Advantages of ILKN421H in Preclinical Research:
Stem-like CD8+ T Cell Amplification: ILKN421H selectively expands PD1- stem-like CD8⁺ T cells, a subset capable of self-renewal and durable antitumor immunity.
Lymphoid Specific Expression and Reduced Systemic Exposure: ILKN421H mRNA is predominantly expressed in lymphoid organs, such as the spleen and lymph nodes, with <5% expressed in liver and other organs. This targeted biodistribution reduces the systemic exposure of IL–2v while enhancing its immune activity.
Overcoming the Cytokine-Sink Effect and a Remarkable Amplification of CD8+ T and NK cells: Unlike protein-based IL-2 therapies that are rapidly internalized by the targeting cells which terminates the IL-2 signaling towards T cell proliferation, ILKN421H’s sustained mRNA–mediated production bypasses the cytokine-sink effect. This enables robust CD8+ T/NK cell proliferation with 1/100 of systemic IL-2v exposure compared with other protein based counterparts like PEG-IL-2v.
Favorable Safety and Tolerability
Across 45 patients with advanced solid tumors, ILKN421H was well tolerated with no dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) was not reached. There were no Grade 4 adverse events (AEs), no treatment-related deaths, and no serious adverse events (SAEs) occurring in more than one patient. The Grade 3 AEs observed in more than one patient included anemia, decreased neutrophil count, decreased platelet count, fever, and hypokalemia. The safety profile of ILKN421H in combination with pembrolizumab is generally similar to that of pembrolizumab alone. No vascular leak syndrome (VLS) or hypotension were observed. These findings highlight ILKN421H’s favorable safety and tolerability relative to earlier-generation IL-2 therapeutics.
Reliable and Robust PK/PD
Pharmacokinetic data from the Phase I study demonstrated prolonged IL-2v expression with a half-life of approximately 20 hours. Pharmacodynamic study showed marked increase of peripheral CD8⁺ T cells and NK cells, up to 10-fold and 25-fold respectively. No ADA was detected, and no sign of reduced IL-2v expression or pharmacological effect was observed after repeated administration up to 30 cycles (Q3W per cycle).
Clinical Efficacy
In patients with first-line (1L) non-small cell lung cancer (NSCLC) regardless of PD-L1 expression levels (n=20), ILKN421H in combination with pembrolizumab demonstrated promising efficacy, with a confirmed objective response rate (ORR) of 80% (16/20 patients). When analyzed by PD-L1 status, ORR was 87% in PD-L1–positive patients and 60% in PD-L1–negative patients. Median progression-free survival (PFS) has not yet been reached and is projected to exceed 12 months. In the post–immunotherapy (post-IO) NSCLC cohort (n=3), ILKN421H combined with pembrolizumab achieved an ORR of 33.3% (1/3 patients), including one partial response (PR) and one patient with durable stable disease (SD) lasting more than 14 months. Together, these results highlight the clinical promise of ILKN421H in both first-line and post-IO NSCLC, supporting its continued development across treatment settings.
Advancement to Phase II Development
Based on these favorable Phase I results, the FDA has cleared iLeukon’s IND application and Phase II protocol to evaluate ILKN421H in combination with pembrolizumab for both 1L and post-IO treatment of NSCLC. "These Phase I results validate the novel design of ILKN421H and demonstrate its potential to deliver meaningful clinical benefit for patients with cancer," said Haining Huang, Ph.D., Chief Executive Officer of iLeukon Therapeutics. "ILKN421H defines the next evolution of IL-2 therapy by combining mRNA technology with selective immune activation to deliver durable efficacy and a favorable safety profile. We look forward to advancing this program into Phase II evaluation."
(Press release, iLeukon Therapeutics, NOV 11, 2025, View Source [SID1234659765])