LYC001, a high-affinity hierarchical assembly for lymph node-targeted IL-2 immunotherapy: Preclinical validation of potent antitumor immunity and preliminary safety from the first-in-human phase Ia study

High-dose systemic interleukin-2 (IL-2) has demonstrated efficacy in metastatic renal cell carcinoma and melanoma but is severely limited by vascular leak syndrome (VLS) and a short half-life. Current engineering strategies often compromise efficacy for safety. LYC001 is a novel IL-2 formulation engineered via a High-Affinity Hierarchical-Assembly Platform (H 2 P), utilizing PEG 2000 -DSPE to form a stable, non-covalent complex (Kd ≈ 10⁻⁸ M). Leveraging a hydrodynamic diameter of ~15 nm, LYC001 is designed for preferential lymphatic uptake following subcutaneous (SC) administration. This "lymph-targeting" strategy, combined with a "masking effect," aims to bias immune activation towards lymph-resident CD8 + T cells while minimizing systemic toxicity and Treg stimulation. In preclinical studies, LYC001 monotherapy demonstrated robust antitumor activity with tumor growth inhibition (TGI) rates >70% in multiple syngeneic murine tumor models (B16F10, CT26, Renca & AB1). Mechanism studies revealed a superior immune profile of LYC001 with an approximate 10-fold increase in the CD8 + T cell to Treg ratio vs untreated control in murine models. Pharmacodynamic (PD) analysis in non-human primates (NHP) focused on lymphocyte expansion >300%, a historic predictor of survival benefit in IL-2 responders. LYC001 outperformed the marketed control, with 60% of high-dose (400,000 IU/kg) subjects exceeding this efficacy threshold (mean increase 315%) compared to only 20% in the control group. Pharmacokinetics (PK) analysis in NHPs confirmed that SC administration of 200,000 IU/kg LYC001 resulted in a longer T 1/2 (5.71 ± 0.51 h vs 2.27 ± 0.54 h), higher C max (255 ± 60 IU/mL vs 123 ± 33 IU/mL), and greater AUC 0-34h (1283 ± 209 h·IU/mL vs. 841 ± 322 h·IU/mL) compared to marketed products. By minimizing non-target tissue exposure, toxicology studies showed no evidence of VLS, cardiovascular toxicity, injection site reactions, or ADA, validating the safety of LYC001. LYC001-I-01 (CTR20254113) is an ongoing Phase Ia, open-label, single-center dose-escalation study in patients with advanced solid tumors, utilizing an accelerated titration followed by a 3+3 design (12,000 IU/kg to 540,000 IU/kg). Objectives are to evaluate safety, MTD determination, PK, immunogenicity, and preliminary efficacy. The first patient (12,000 IU/kg) was successfully dosed and completed the DLT observation period. The drug was well-tolerated with no dose-limiting toxicities (DLTs) or signs of VLS. Enrollment is ongoing, and updated dose-escalation data will be presented.