PO.CT01.01 · 临床试验
LYC001，一种用于淋巴结靶向IL-2免疫治疗的高亲和力分级组装体：强效抗肿瘤免疫的临床前验证及首次人体Ia期研究的初步安全性
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
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摘要 Abstract
中文摘要
高剂量全身性白细胞介素-2（IL-2）在转移性肾细胞癌和黑色素瘤中已显示出疗效，但其应用因血管渗漏综合征（VLS）和短半衰期而受到严重限制。目前的工程化策略往往为了安全性而牺牲疗效。LYC001是一种新型IL-2制剂，通过高亲和力分级组装平台（H2P）进行工程化设计，利用PEG2000-DSPE形成稳定的非共价复合物（Kd ≈ 10⁻⁸ M）。LYC001的流体动力学直径约为15 nm，设计用于在皮下（SC）给药后优先经淋巴摄取。这种"淋巴靶向"策略与"掩蔽效应"相结合，旨在使免疫激活偏向淋巴驻留的CD8+ T细胞，同时最大限度地减少全身毒性和Treg刺激。在临床前研究中，LYC001单药治疗展现出强劲的抗肿瘤活性，在多种同基因小鼠肿瘤模型（B16F10、CT26、Renca和AB1）中的肿瘤生长抑制（TGI）率>70%。机制研究揭示LYC001具有更优的免疫特征，在小鼠模型中CD8+ T细胞与Treg的比值较未治疗对照增加约10倍。在非人灵长类动物（NHP）中的药效动力学（PD）分析聚焦于淋巴细胞扩增>300%，这是IL-2应答者生存获益的一项历史性预测指标。LYC001优于已上市对照药，高剂量组（400,000 IU/kg）中有60%的受试者超过该疗效阈值（平均增幅315%），而对照组仅为20%。NHP的药代动力学（PK）分析证实，皮下给予200,000 IU/kg的LYC001后，与已上市产品相比，具有更长的T1/2（5.71 ± 0.51 h对2.27 ± 0.54 h）、更高的Cmax（255 ± 60 IU/mL对123 ± 33 IU/mL）以及更大的AUC0-34h（1283 ± 209 h·IU/mL对841 ± 322 h·IU/mL）。通过最大限度减少非靶组织暴露，毒理学研究显示无VLS、心血管毒性、注射部位反应或ADA的证据，验证了LYC001的安全性。LYC001-I-01（CTR20254113）是一项正在进行的Ia期、开放标签、单中心剂量递增研究，纳入晚期实体瘤患者，采用加速滴定后接3+3设计（12,000 IU/kg至540,000 IU/kg）。研究目标为评估安全性、确定MTD、PK、免疫原性及初步疗效。首例患者（12,000 IU/kg）已成功给药并完成DLT观察期。该药耐受性良好，未出现剂量限制性毒性（DLT）或VLS体征。入组正在进行中，将呈现更新的剂量递增数据。
查看英文原文 English abstract
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.
利益披露 Disclosure
S. Wang, None..
D. Liu, None..
Y. Han, None.
M. Li,
LiangYuan Bioscience, LLC Employment.
W. Zeng,
LiangYuan Bioscience, LLC Employment.
W. Liang,
LiangYuan Bioscience, LLC Employment.
N. Li, None.