PO.IM02.06 · 免疫学

靶向LILRB1/HLA-G轴的LILRB1抗体：支持首次人体试验的临床前疗效、药代动力学与安全性

LILRB1 antibody targeting the LILRB1/HLA-G axis: Preclinical efficacy, pharmacokinetics, and safety supporting first-in-human trials

编号 5561 展板 4 时间 4/21 02:00–05:00 区域 Section 7 主讲 Han Byoul Kim, PhD

分会场 Oncogenic Pathways and Cancer Immunity

查看 PDF 下载 PDF 🔒 查看 / 下载完整 PDF 需登录并开通下载套餐 · 查看套餐 / 开通 AACR 官方页面

作者与单位 Authors & Affiliations

Han Byoul Kim, Seok-Joo Kim, Younghoon Kim, Junhaeng Cho, Minsoon Kim, JungA Kim, Suji Hong, Heehang Kim, Shin-Young Kang, Kyungna Ko, Jun-Gyu Park, Hyungjin Cho, Jeeyeon Roh, Young Dok Son, Wooseok Ko

LG Chem, Seoul, Korea, Republic of

摘要 Abstract

中文摘要

背景：LILRB1是一种表达于T细胞、B细胞、NK细胞和单核细胞上的抑制性受体。它与HLA I类分子结合，对HLA-G的亲和力最高。这种相互作用传递抑制性信号，使肿瘤细胞得以逃避免疫监视，损害NK细胞、T细胞和巨噬细胞功能。破坏LILRB1/HLA-G轴是恢复抗肿瘤免疫的一种有前景的策略。此外，LILRB1可能独立于PD-1调节T细胞功能，提示其具有克服对PD-1抑制剂耐药的潜力。方法：通过表面等离子体共振和流式细胞术评估LG-LILRB1抗体的结合亲和力和特异性。竞争性结合实验证实了对LILRB1/HLA-G相互作用的阻断。使用流式细胞术和蛋白质印迹法评估免疫细胞功能的恢复。在人LILRB1转基因小鼠中检测抗肿瘤疗效。在食蟹猴中研究药代动力学和毒代动力学，并通过符合GLP的毒理学和免疫毒性研究评估安全性。结果：LG-LILRB1抗体对LILRB1表现出高亲和力、选择性结合，并对HLA-G呈剂量依赖性阻断。功能实验显示T细胞增殖、NK细胞细胞毒性和巨噬细胞吞噬作用增强。在体内，LG-LILRB1抗体显著抑制了荷HLA-G表达肿瘤的转基因小鼠中的肿瘤生长（最高达88.8%）。药效学分析显示CD8⁺ T细胞和NK细胞的浸润与活化增加。与PD-L1阻断联合产生协同抗肿瘤效应。在猴中，LG-LILRB1抗体表现出剂量成比例的暴露和较长的半衰期（>12天）。在为期4周的GLP毒性研究中未观察到与治疗相关的不良发现。结论：LG-LILRB1抗体是一种首创（first-in-class）的LILRB1阻断剂，通过破坏LILRB1/HLA-G轴恢复了抗肿瘤免疫。它增强了免疫细胞功能，并在临床前模型中显示出强效疗效。良好的药代动力学和安全性支持其临床开发。与PD-L1阻断联合进一步改善了疗效。这些发现支持LG-LILRB1抗体作为一种有前景的癌症免疫治疗候选药物，目前一项1a期试验正在进行中（NCT06332755）。

查看英文原文 English abstract

Background: LILRB1 is an inhibitory receptor expressed on T cells, B cells, NK cells, and monocytes. It binds to HLA class I molecules, with the highest affinity for HLA-G. This interaction delivers inhibitory signals that allow tumor cells to evade immune surveillance, impairing NK cell, T cell, and macrophage function. Disrupting the LILRB1/HLA-G axis is a promising strategy for restoring anti-tumor immunity. Additionally, LILRB1 may regulate T cell function independently of PD-1, suggesting potential to overcome resistance to PD-1 inhibitors. Methods: Binding affinity and specificity of LG-LILRB1 antibody were assessed via surface plasmon resonance and flow cytometry. Competitive binding assays confirmed blockade of LILRB1/HLA-G interaction. Restoration of immune cell function was evaluated using flow cytometry and western blotting. Anti-tumor efficacy was tested in human LILRB1 transgenic mice. Pharmacokinetics and toxicokinetics were studied in cynomolgus monkeys, and safety was assessed through GLP-compliant toxicology and immunotoxicity studies. Results: LG-LILRB1 antibody showed high-affinity, selective binding to LILRB1 and dose-dependent blockade of HLA-G. Functional assays revealed enhanced T cell proliferation, NK cell cytotoxicity, and macrophage phagocytosis. In vivo, LG-LILRB1 antibody significantly inhibited tumor growth (up to 88.8%) in transgenic mice bearing HLA-G-expressing tumors. Pharmacodynamic analysis showed increased infiltration and activation of CD8⁺ T cells and NK cells. Combination with PD-L1 blockade yielded synergistic anti-tumor effects. In monkeys, LG-LILRB1 antibody exhibited dose-proportional exposure and a long half-life (>12 days). No treatment-related adverse findings were observed in 4-week GLP toxicity studies. Conclusions: LG-LILRB1 antibody, a first-in-class LILRB1 blocker, restored anti-tumor immunity by disrupting the LILRB1/HLA-G axis. It enhanced immune cell function and showed strong efficacy in preclinical models. Favorable pharmacokinetics and safety support its clinical development. Combination with PD-L1 blockade further improved outcomes. These findings support LG-LILRB1 antibody as a promising candidate for cancer immunotherapy, with a Phase 1a trial currently ongoing (NCT06332755).

利益披露 Disclosure

H. Kim, None.. S. Kim, None.. Y. Kim, None.. J. Cho, None.. M. Kim, None.. J. Kim, None.. S. Hong, None.. H. Kim, None.. S. Kang, None.. K. Ko, None.. J. Park, None.. H. Cho, None.. J. Roh, None.. Y. Son, None.. W. Ko, None.

← 返回 AACR 2026 检索