药学学报

Drug	Target	Company	Tumor type	NCT number
Relatlimab	LAG-3	Bristol-Myers Squibb	Melanoma, NSCLC, urothelial bladder cancer, colorectal cancer	NCT03470922, NCT05625399, NCT05002569, NCT05987241, NCT06561386
Fianlimab	LAG-3	Regeneron pharmaceuticals	Melanoma, NSCLC	NCT06246916, NCT05785767, NCT05800015, NCT05608291, NCT05352672
Tebotelimab	LAG-3; PD-1	MacroGenicx	Gastric cancer, squamous cell carcinoma of the head and neck	NCT04129320, NCT04082364
IMP321	Fusion protein	Immutep	Breast cancer, NSCLC	NCT05747794, NCT06726265

Drug	Target	Company	Tumor type	NCT number
Relatlimab	LAG-3	Bristol-Myers Squibb	Melanoma, NSCLC, urothelial bladder cancer, colorectal cancer	NCT03470922, NCT05625399, NCT05002569, NCT05987241, NCT06561386
Fianlimab	LAG-3	Regeneron pharmaceuticals	Melanoma, NSCLC	NCT06246916, NCT05785767, NCT05800015, NCT05608291, NCT05352672
Tebotelimab	LAG-3; PD-1	MacroGenicx	Gastric cancer, squamous cell carcinoma of the head and neck	NCT04129320, NCT04082364
IMP321	Fusion protein	Immutep	Breast cancer, NSCLC	NCT05747794, NCT06726265

LAG-3在肿瘤免疫中的研究及靶向药物研发进展

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弓航 , 赵鑫 , 陈文霞 , 薛妮娜 ^*

药学学报 | 综述 2025,60(5): 1315-1324

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药学学报 | 综述 2025, 60(5): 1315-1324

LAG-3在肿瘤免疫中的研究及靶向药物研发进展

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弓航, 赵鑫, 陈文霞, 薛妮娜^*

作者信息

中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室/创新药物非临床药物代谢及PK/PD研究北京市重点实验室, 北京 100050

通讯作者:

^*薛妮娜, Tel: 86-10-63165207, E-mail: angelnina@imm.ac.cn

Research progress of LAG-3 in tumor immunity and targeted drug development

Hang GONG, Xin ZHAO, Wen-xia CHEN, Ni-na XUE^*

Affiliations

State Key Laboratory of Bioactive Substances and Functions of Natural Medicines/Beijing Key Laboratory of Non-clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

出版时间: 2025-05-12 doi: 10.16438/j.0513-4870.2024-1290

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摘要

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淋巴细胞活化因子-3 (lymphocyte activation gene 3, LAG-3) 是一种重要的T细胞抑制型受体, 在肿瘤免疫逃逸中发挥着重要作用。LAG-3主要表达于活化的T细胞、自然杀伤(natural killer, NK) 细胞、B细胞等, 通过与配体结合, 抑制T细胞的增殖、活化和效应功能。LAG-3已成为继程序性死亡分子-1 (programmed death 1, PD-1)/程序性死亡分子配体-1 (programmed death ligand 1, PD-L1) 和细胞毒T淋巴细胞相关抗原-4 (cytotoxic T lymphocyte-associated antigen 4, CTLA-4) 之后第三个应用于临床的免疫检查点蛋白(immune checkpoint protein, ICP)。目前, 至少有20个靶向LAG-3的药物正在进行临床试验。本文主要综述了LAG-3的结构、表达调控、配体、共表达的ICP以及其在肿瘤免疫治疗中的应用, 并展望了LAG-3研究目前面临的挑战。

关键词

淋巴细胞活化因子-3 / 肿瘤微环境 / 肿瘤免疫 / 免疫检查点抑制剂 / 单克隆抗体

Abstract

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Lymphocyte activation gene 3 (LAG-3) is an important inhibitory receptor on T cells, which plays a crucial role in tumor immune evasion. LAG-3 is primarily expressed on activated T cells, natural killer (NK) cells and B cells, et al. By binding to its ligands, LAG-3 inhibits T cell proliferation, activation, and effector functions. LAG-3 has emerged as the third immune checkpoint protein (ICP) used in clinical practice, following programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Currently, there has been at least 20 LAG-3-targeted drugs undergoing clinical trials. This article mainly reviews the structure, expression regulation, ligands, co-expressed ICP of LAG-3, as well as its application in tumor immunotherapy, and discusses the current challenges of targeting LAG-3 research.

Key words

lymphocyte activation gene 3 / tumor microenvironment / tumor immunity / immune checkpoint inhibitor / monoclonal antibody

引用本文

弓航, 赵鑫, 陈文霞, 薛妮娜. LAG-3在肿瘤免疫中的研究及靶向药物研发进展. 药学学报, 2025 , 60 (5) : 1315 -1324 . DOI: 10.16438/j.0513-4870.2024-1290

Hang GONG, Xin ZHAO, Wen-xia CHEN, Ni-na XUE. Research progress of LAG-3 in tumor immunity and targeted drug development[J]. Acta Pharmaceutica Sinica, 2025 , 60 (5) : 1315 -1324 . DOI: 10.16438/j.0513-4870.2024-1290

正文

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近10年来, 免疫检查点抑制剂(immune checkpoint inhibitors, ICIs) 的开发及临床应用彻底改变了肿瘤免疫研究领域。这类药物通过解除肿瘤微环境中的免疫抑制状态, 激活患者T细胞免疫杀伤功能, 从而实现对癌细胞的精准打击^{[1, 2]}。随着靶向免疫检查点蛋白(immune checkpoint protein, ICP) 如程序性死亡分子-1 (programmed death 1, PD-1)/程序性死亡分子配体-1 (programmed death ligand 1, PD-L1) 和细胞毒T淋巴细胞相关抗原-4 (cytotoxic T lymphocyte-associated antigen 4, CTLA-4) 药物陆续上市, 很多肿瘤患者也获得了以往化疗或传统靶向药物无法达到的收益^{[3, 4]}。然而由于肿瘤抵抗、肿瘤微环境中淋巴细胞浸润缺乏等情况, 大多数患者没有表现出长期持久的反应, 仅有大概30%的肿瘤患者呈现出临床效果, 还存在很多患者对PD-1/PD-L1单抗治疗响应不佳或耐药, 从而无法从肿瘤免疫治疗中获益^[5]。因此, 寻找靶向其他ICPs的药物或者探究有效的联合治疗策略改善现有ICIs应答率低或耐药问题, 将为肿瘤患者带来更多获益。

淋巴细胞活化因子-3 (lymphocyte activation gene 3, LAG-3) 是一个与PD-1和CTLA-4并重的T细胞抑制型受体。在慢性病毒感染或癌症等持续抗原刺激下, LAG-3快速表达于活化的T细胞表面, 负性调节T细胞活化信号转导。2022年3月18日, 美国食品药品监督管理局(Food and Drug Administration, FDA) 批准LAG-3抗体relatlimab与PD-1抗体nivolumab联用, 用于治疗12岁以上不可切除或转移性的黑色素瘤患者。至此, LAG-3成为继PD-1/PD-L1和CTLA-4之后第三个应用于临床的ICP。近年来, 越来越多的研究集中在LAG-3的结构解析及其与新配体结合后发挥的抗肿瘤免疫作用, 这为LAG-3靶向药物的研发及应用提供了扎实的理论基础。

1 LAG-3的结构

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1.1 LAG-3的分子结构

LAG-3基因由8个外显子组成, 其染色体位置与第12号染色体远端CD4基因相邻, 且具有与CD4类似的内含子-外显子组织^[6]。LAG-3是一种I型跨膜蛋白, 由525个氨基酸编码组成。LAG-3可分为胞外区、跨膜区和胞内区3个区域。

1.1.1 胞外区

胞外区具有4个Ig样结构域(D1~D4)。其中, D1结构域包含一个由大约30个氨基酸组成的独特的“额外环”^[7]。这个环在LAG-3与主要组织相容性复合体(major histocompatibility complex, MHC) Ⅱ类的相互作用中起到关键作用^[8]。结构生物学研究^[9]表明, 小鼠LAG-3的D1结构域能够与MHC-Ⅱ的一个保守、跨越α2和β2亚结构域的膜近端区域结合, 这与CD4和MHC-Ⅱ的结合位点重叠, 从而竞争性地抑制CD4-MHC-Ⅱ的相互作用。D2~D4结构域中存在多个N-糖基化位点, 这些位点使得LAG-3能够与一些特定的糖类分子如半乳糖凝集素-3 (galectin-3, Gal-3) 和肝窦内皮细胞凝集素(liver and lymph node sinusoidal endothelial cell C-type lectin, LSECtin) 等结合(图 1)^{[10, 11]}。而且, 该区域发生糖基化可以增加LAG-3在细胞表面的稳定性, 防止其被快速降解或内化。

1.1.2 跨膜区

跨膜区通过外显子Ⅶ编码的长连接肽与D4相连。该连接肽可以被解整合素金属蛋白酶(a disintegrin and metalloprotease, ADAM) 10和ADAM17剪切, 从而以可溶性形式释放LAG-3的胞外区域, 即可溶性LAG-3 (soluble LAG-3, sLAG-3) (图 1)^[12]。研究表明, LAG-3的剪切能够降低其对T细胞活化的抑制作用^[13]。此外, sLAG-3可能成为某些肿瘤的生物标志物, 用于癌症的早期诊断和预后评估^[14-16]。

1.1.3 胞内区

胞内区由潜在的丝氨酸磷酸化位点(S454)、高度保守的KIEELE基序和谷氨酸-脯氨酸(EP) 重复序列组成。S454可能被蛋白激酶C (protein kinase C, PKC) 磷酸化, 进而增强LAG-3与MHC-Ⅱ的结合能力^[17]。KIEELE基序负责传导LAG-3的胞内抑制信号, 有效阻止T细胞进入细胞周期的S期, 抑制T细胞的扩增^[18]。EP基序中带负电的氨基酸降低了免疫突触附近的pH值, 并将Zn²⁺隔离在质膜上, 这破坏了淋巴细胞特异性酪氨酸激酶(lymphocyte-specific protein tyrosine kinase, Lck) 与共受体CD4/CD8之间依赖Zn²⁺的相互作用, 干扰T细胞受体(T cell receptor, TCR) 下游信号的传递, 从而抑制T细胞的活化(图 1)^[19]。此外, EP基序通过与LAG-3相关蛋白(LAG-3-associated protein, LAP) 的结合来抑制TCR/CD3信号通路的激活, 并协助LAG-3在脂筏内与CD3、CD4和CD8共定位^{[20, 21]}。

1.2 LAG-3的空间结构

LAG-3在细胞表面以单体、二聚体和高阶低聚体的形式分布^[12]。LAG-3的二聚体形式是与配体MHC-Ⅱ和纤维蛋白原样蛋白1 (fibrinogen-like protein 1, FGL1) 结合所必需的^[22]。在晶体结构和冷冻电镜结构中, LAG-3通过D2-D2相互作用形成V形二聚体^[23-25]。人源LAG-3的二聚化是由一簇疏水残基(Trp184、Ile186、Phe225和Phe227) 介导的, 这与介导小鼠LAG-3二聚化的残基(Trp180、Ile182和Leu221) 相类似^[23]。由于在二聚体界面形成的角度不同, 人源LAG-3二聚体比小鼠LAG-3二聚体窄得多^[26]。然而, 这些不同的构象是否反映了物种特有的结构特征, 或代表了不同的功能状态, 尚需进一步研究。

2 LAG-3的表达与调控

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2.1 LAG-3的表达

LAG-3在Naïve T细胞上不表达, 持续的抗原刺激会导致LAG-3在CD4⁺和CD8⁺ T细胞上高表达, 负调控T细胞扩增, T细胞进入衰竭状态^[27]。Annunziato等^[28]发现在活化的CD4⁺ T细胞中, Th0和Th1细胞上存在LAG-3的表达, 而Th2细胞上LAG-3表达极少或不表达。LAG-3也表达于调节性T细胞(regulatory T cells, Tregs) 中, 维持Tregs固有抑制活性^{[29, 30]}。研究发现, LAG-3可以通过抑制STAT5/IL-2信号通路来调节Tregs的信号转导^[31]。此外, Tregs上的LAG-3还可与树突状细胞(dendritic cells, DCs) 上MHC-Ⅱ相互作用, 诱导PLCγ2和p72syk蛋白的磷酸化以及PI3K/Akt、ERK1/2和p38 MAPK信号通路的激活, 进而有助于DCs的成熟^{[32, 33]}。

LAG-3也在自然杀伤(natural killer, NK) 细胞、B细胞和浆细胞样树突状细胞(plasmacytoid dendritic cells, pDCs) 上表达^[34-36]。Miyazaki等^[37]发现敲除小鼠的LAG-3基因后, NK细胞对肿瘤的杀伤作用减弱甚至消失。然而Huard等^[38]发现阻断LAG-3不影响人NK细胞对肿瘤的杀伤功能。LAG-3在活化B细胞中的表达依赖于T细胞的激活, 该过程可能是由T细胞活化所产生的多种可溶性因子共同介导的。Lino等^[39]鉴定出一种特异性表达LAG-3的调节性B细胞(regulatory B cells, Bregs), 它能通过分泌IL-10促进免疫抑制环境。Workman等^[35]首次报道LAG-3也可以在pDCs上表达, 活化的pDCs中LAG-3的mRNA水平显著高于T细胞。Camisaschi等^[40]发现LAG-3阳性pDCs亚群向黑色素瘤迁移, pDCs上LAG-3与肿瘤细胞上MHC-Ⅱ相互作用介导pDCs的Toll样受体(Toll-like receptors, TLR) 非依赖性激活, 诱导白细胞介素6 (interleukin-6, IL-6) 和干扰素α (interferon-alpha, IFN-α) 的产生, 有助于肿瘤免疫抑制微环境的产生和维持。

此外, 研究发现非小细胞肺癌(non-small cell lung cancer, NSCLC) 肿瘤组织和细胞系中也存在LAG-3的表达^[41]。肾癌和黑色素肿瘤样本中LAG-3存在多位点DNA甲基化, 并影响肿瘤内LAG-3的表达水平、免疫细胞浸润及患者总生存期^{[42, 43]}。

2.2 LAG-3表达的调控模式

在未受刺激的T细胞中, LAG-3存储于溶酶体中, 这在维持机体免疫稳态中起着重要作用^[44]。在肿瘤或慢性病毒感染持续抗原刺激下, PKC信号通路被激活, LAG-3的胞质结构域发生构象改变, 从而触发其从溶酶体到细胞膜的转运过程。这种存储与转运机制使得LAG-3能够在需要时迅速被招募到细胞膜上, 从而发挥其免疫调节作用。此外, T淋巴细胞激活后, ADAM10和ADAM17的转录水平显著提高, 对T细胞表面LAG-3的剪切作用进一步增强^{[12, 13]}。

LAG-3的表达调节对其功能至关重要。研究表明, IFN-γ、IL-2、IL-7、IL-12等细胞因子可以诱导T细胞上LAG-3的表达。其中, IL-12被认为是最有效的诱导剂, 能够激活T细胞并触发一系列信号传导事件, 最终导致LAG-3的表达上调^[45]。IL-27可以促进LAG-3在Tregs上的表达^[30]。IL-10和IL-12促进NK细胞上LAG-3的表达^[38]。自然杀伤细胞受体家族C亚家族成员2 (natural killer cell receptor family C member 2, NKG2C) 激动剂和IL-15相互作用能够诱导NKG2C⁺ NK细胞上LAG-3的高表达, 并导致NK细胞功能障碍, IFN-γ分泌减少^[46]。IL-6能够诱导LAG-3在B细胞上的表达^[47]。IL-3和CpG DNA等可以刺激黑色素瘤中pDCs细胞上LAG-3的表达^[40]。此外, 转录因子早期生长反应蛋白2 (early growth response protein 2, EGR2) 被认为是CD4⁺CD25^- Tregs中LAG-3表达的关键调节因子, CD4⁺CD25^-LAG-3⁺ Tregs通过分泌IL-10和TGF-β3诱导免疫抑制环境^{[48, 49]}。但是, 这些细胞因子等如何调节LAG-3的表达还不清楚。

3 LAG-3的配体

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3.1 MHC-Ⅱ

MHC-Ⅱ是LAG-3的典型配体, 主要表达在树突状细胞、巨噬细胞、B细胞和肿瘤细胞等抗原呈递细胞(antigen-presenting cells, APCs) 表面^[50]。LAG-3和CD4的胞外区具有高度的结构和氨基酸序列同源性, 因此最初人们认为LAG-3通过竞争性地阻断CD4和MHC-Ⅱ之间的相互作用而导致T细胞功能障碍^[51]。随着研究的不断深入, Maruhashi等^[52]发现LAG-3受体不是广泛地与MHC-Ⅱ结合, 而是选择性地与抗原肽-MHC-Ⅱ (peptide-MHC-Ⅱ, pMHC-Ⅱ) 形成稳定的复合物。LAG-3不直接干扰CD4和MHC-Ⅱ或TCR和MHC-Ⅱ之间的相互作用, 而是通过其胞内区抑制基序转导抑制信号, 优先抑制对pMHC-Ⅱ有反应的T细胞^[53]。LAG-3和pMHC-Ⅱ之间的这种相互作用可以使T细胞进入静息状态, 抑制T细胞的杀伤能力。通过阻断LAG-3与pMHC-Ⅱ的相互作用恢复T细胞的功能已经成为肿瘤免疫治疗的一种新策略。

3.2 FGL1

FGL1主要由肝细胞分泌, 参与肝脏的代谢功能^[54]。FGL1属于纤维蛋白原家族, 由一个介导寡聚化的N端卷曲结构域和一个C端纤维蛋白原样结构域组成。FGL1通过其C末端结构域与LAG-3胞外区D1和D2相互作用, 这种相互作用不依赖于MHC-Ⅱ的结合^[55]。通过基因敲除或使用单克隆抗体阻断LAG3-FGL1的相互作用可增强肿瘤免疫反应, 抑制小鼠黑色素瘤和结肠癌的生长。然而, Maruhashi等^[56]的研究指出FGL1的结合对于LAG-3发挥抑制T细胞活化的功能并非必需的。缺乏FGL1结合能力的LAG-3突变体仍能有效抑制T细胞活化, 而缺乏pMHC-Ⅱ结合能力的LAG-3突变体则不能。这提示pMHC-Ⅱ作为LAG-3的经典配体, 在介导LAG-3的抑制功能上可能更为关键。此外, 肿瘤细胞也能合成和释放FGL1^[57]。肿瘤细胞FGL1的表达水平与患者预后及T细胞功能密切相关。肝癌、肺癌、胃癌等实体肿瘤中FGL1表达上调, 患者预后不良^[58-60]。采用氧卡地平阻断IL-6诱导的JAK2/STAT3信号通路可以抑制FGL1的表达, 从而改善CD8⁺ T细胞的功能, 增强LAG-3抗体治疗肝癌的敏感性^[61]。

3.3 凝集素

Gal-3和LSECtin这两种凝集素是近年来发现的能与LAG-3结合的新型配体。它们都具有碳水化合物识别域(carbohydrate-recognition), 能与LAG-3结构中的糖基化位点相结合。Gal-3主要由肿瘤细胞及肿瘤相关基质细胞分泌^[62]。LAG-3与Gal-3相互作用能够抑制CD8⁺ T细胞IFN-γ的释放^[11]。靶向LAG-3-Gal-3相互作用能够增强子宫内膜癌、多发性骨髓瘤和外阴鳞状瘤的抗肿瘤应答^[63-65]。此外, Gal-3也直接参与肿瘤转移和免疫应答等多种生物过程, 通过下调APCs的抗原呈递能力和pDCs的扩增抑制CD8⁺ T细胞的活化^{[66, 67]}。

LSECtin属于C型凝集素家族, 是一种在肝脏和淋巴结高度表达的Ⅱ型跨膜蛋白^[68]。近年来发现, LSECtin也在肿瘤细胞表面表达。通过生物信息学工具筛选、表面等离子共振、免疫共沉淀等技术发现, LSECtin能与LAG-3相互作用。在临床前黑色素瘤模型中, LSECtin与LAG-3相互作用能够抑制效应T细胞分泌IFN-γ, 促进肿瘤免疫逃逸, 而使用LAG-3抗体可以逆转上述作用^[10]。此外, LSECtin可通过下调细胞周期激酶(包括CDK2、CDK4和CDK6) 直接抑制T细胞的增殖。

4 与LAG-3共表达的ICP

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越来越多的研究表明, LAG-3和PD-1可以在肿瘤浸润淋巴细胞上广泛共表达, 并在CD4⁺和CD8⁺ T细胞上发挥协同作用。Matsuzaki等^[69]报道卵巢癌中约80%的浸润性CD8⁺LAG-3⁺ T淋巴细胞表达PD-1, 在体外和小鼠模型中同时阻断LAG-3和PD-1可以提高抗原特异性T淋巴细胞的抗肿瘤活性。最新的研究表明, 在小鼠黑色素瘤模型中, 与LAG-3或PD-1单独缺失相比, CD8⁺ T细胞上LAG-3和PD-1共缺失会促进肿瘤清除, 小鼠生存期延长。LAG-3单独缺失导致T细胞持续杀伤能力降低, 在与PD-1抗体联用时, 会诱导干细胞样记忆性CD8⁺ T细胞的增殖。而LAG-3和PD-1共缺失诱导CD8⁺ T细胞效应功能增加, 促进INF-γ的释放, 同时能够激活NK细胞受体的表达^{[70, 71]}。此外, LAG-3和PD-1共同调节转录因子TOX的表达, TOX能够促使CD8⁺ T细胞效应功能逐渐丧失、代谢失调以及增殖潜力受损^{[71, 72]}。这为LAG-3和PD-1联用疗效增强提供了理论支持。

5 LAG-3靶向药物在肿瘤免疫治疗中的应用

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LAG-3靶向药物主要包括单克隆抗体、双特异性抗体和融合蛋白等。目前至少有20种LAG-3药物进入临床试验, 涉及的癌种包括黑色素瘤、肺癌、乳腺癌、肾癌、结直肠癌等实体肿瘤, 以及血液肿瘤(表 1)^[73]。

5.1 LAG-3单克隆抗体

大多数LAG-3单克隆抗体是通过杂交瘤技术先获得小鼠单克隆抗体, 再将其进行人源化得到的。临床上大部分LAG-3单克隆抗体通过阻断LAG-3与pMHC-Ⅱ的结合来恢复T细胞效应功能^[26]。目前, 进展较快的relatlimab已获批上市, fianlimab正在进行Ⅲ期临床试验。

5.1.1 Relatlimab

Relatlimab是一种免疫球蛋白G4 (IgG4), 作为一种有效的LAG-3拮抗剂, 可同时阻断LAG-3与pMHC-Ⅱ和FGL1的相互作用, 增强TCR信号传导和细胞因子分泌, 从而活化T细胞^[74]。Opdualag是由百时美施贵宝(Bristol Myers Squibb, BMS) 开发的一种新型LAG-3抗体(relatimab) 和PD-1抗体(nivolumab) 组合治疗方案。在Ⅱ/Ⅲ期临床试验中, Opdualag用于未经治疗的转移性或不可切除的黑色素瘤患者(NCT03470922)^[75]。与nivolumab单药治疗相比, 联用组无进展生存期(progression-free survival, PFS) 增加了1倍以上(10.1个月vs 4.6个月, P = 0.006), 12个月PFS分别为47.7%和36.0%。虽然联用组3级或4级治疗相关不良事件(treatment-related adverse event, TRAE) 的发生率更高(18.9% vs 9.7%), 但没有出现新的安全性问题, 临床不良反应可控。2022年3月, FDA批准其用于不可切除或转移性黑色素瘤的治疗。2024年欧洲肿瘤内科学会(European Society for Medical Oncology, ESMO) 大会上, BMS公布了Opdualag联合化疗作为转移性NSCLC一线疗法Ⅱ期临床试验(NCT04623775) 的具体数据。在PD-L1表达率≥ 1%非鳞状NSCLC的患者中, Opdualag+化疗组的客观反应率(objective response rate, ORR) 为58%, 中位PFS为11.6个月, 而对照(PD-1抗体Keytruda+化疗) 组ORR和中位PFS仅分别为39.6%和6.9个月。基于这次数据, BMS已经启动一项Ⅲ期临床试验(NCT06561386) 以评估Opdualag联合化疗在PD-L1表达率1%~49%的非鳞状NSCLC患者中的疗效。BMS还计划明年启动另一项针对PD-L1表达率≥ 50%非鳞状NSCLC患者的Ⅲ期临床试验。此外, BMS还正在进行Opdualag辅助治疗切除后黑色素瘤和尿路上皮性膀胱癌的Ⅲ期临床试验(NCT05002569、NCT05987241)。此外, BMS还开发了该复方的皮下注射制剂, 正在开展对比静脉注射制剂的Ⅲ期研究(NCT05625399)。

5.1.2 Fianlimab

Fianlimab (REGN3767) 是由再生元和赛诺菲联合开发的一种人IgG4抗体。Burova等^[76]利用人源化PD-1/LAG-3敲入小鼠模型, 评估了fianlimab单药或与PD-1抗体cemiplimab联合使用对小鼠体内肿瘤生长的影响。与单独治疗相比, 联合治疗显著提高了抗肿瘤疗效, 并促进了肿瘤微环境中T细胞的活化。在前期的Ⅰ期临床试验(NCT03005782) 中, fianlimab和cemiplimab联用在晚期黑色素瘤显示出良好的临床疗效和安全性^{[77, 78]}。在既往未接受PD-1抗体治疗的晚期黑色素瘤患者, 联合疗法ORR为61.2%, 中位PFS为13.3个月。在接受PD-1抗体辅助治疗的13例晚期黑色素瘤患者中, ORR为61.5%, 中位PFS为12个月。治疗中3级及以上TRAE的发生率为22%, 除了肾上腺皮质功能减退的发生率增加外, 没有观察到新的不良反应。目前, fianlimab联合cemiplimab在黑色素瘤患者手术切除后预防或延缓复发、未经治疗的不可切除的局部晚期或转移性黑色素瘤患者的Ⅲ期临床试验正在进行当中(NCT05608291、NCT05352672)。此外, fianlimab联合cemiplimab在PD-L1表达率≥ 50%的晚期NSCLC患者中的Ⅱ/Ⅲ期研究(NCT05785767) 也正在进行中。

5.2 LAG-3双特异性抗体

LAG-3双特异性抗体通常同时靶向LAG-3和其他ICPs如PD-1/PD-L1等。通过阻断两个信号通路, 维持或恢复耗竭T细胞的功能, 协同增强T细胞的抗肿瘤活性。以下主要介绍分别同时靶向LAG-3和PD-1、PD-L1的代表性抗体tebotelimab和FS-118。

5.2.1 Tebotelimab

Tebotelimab (MGD013) 是由MacroGenics开发的靶向LAG-3和PD-1的双特异性抗体。Tebotelimab可以特异性结合LAG-3和PD-1, 同时阻断PD-1和LAG-3信号通路, 抑制PD-1/PD-L1、PD-1/PD-L2和LAG-3/MHC-Ⅱ的相互作用^[79]。在tebotelimab的首次人体Ⅰ期临床研究中, 研究人员评估了tebotelimab在既往接受治疗并发生疾病进展的晚期实体瘤和恶性血液瘤患者中的疗效和安全性(NCT03219268)^[80]。结果显示, 在可评估疗效的患者中, 59%的患者在剂量递增期间达到疾病稳定(stable disease, SD) 或更好, 3级以上TRAE的发生率为23.3%。Tebotelimab治疗后, 血清IFN-γ水平明显升高。此外, 在弥漫性大B细胞淋巴瘤患者血液中, 循环CD3⁺CD8⁺ T细胞亚群增加, 血清穿孔素和颗粒酶B水平升高^[81]。目前, 有两项关于tebotelimab的Ⅲ期临床试验正在进行中。第一项试验评估enoblituzumab (B7-H3单抗) 与tebotelimab联用治疗头颈部鳞状细胞癌的疗效(NCT04129320)。第二项试验旨在探究margetuximab (HER2单抗) 联合tebotelimab和化疗治疗转移性或局部晚期HER2阳性胃癌或胃食管结合部癌的效果(NCT04082364)。

5.2.2 FS-118

FS-118是由F-star Therapeutics开发的靶向LAG-3和PD-L1的四价双特异性IgG1抗体。FS-118能同时高亲和力地结合LAG-3和PD-L1。与单克隆抗体组合相比, FS-118能够相当或更好地阻断LAG-3和PD-L1介导的免疫抑制, 增强T细胞活性^{[82, 83]}。在FS-118 (NCT03440437) 的首次临床试验中, 43例PD-1/PD-L1耐药晚期恶性肿瘤患者接受了FS-118单药治疗^[84]。在治疗期间, FS-118耐受性良好, 没有发生与治疗相关的严重不良事件。在接受FS-118治疗的患者血液中观察到sLAG-3的持续升高和外周效应细胞的增加。同时, 治疗期间没有观察到剂量限制性毒性, 也没有达到最大耐受剂量。总体疾病控制率(disease control rate, DCR) 为46.5%, 在接受1 mg·kg^-1或更高剂量的患者中DCR为54.8%。

5.3 LAG-3融合蛋白

IMP321 (Eftilagimod α) 是由LAG-3胞外区与人IgG1 Fc区偶联组成的可溶性二聚体^[85], 是目前唯一进入临床试验的LAG-3融合蛋白。IMP321通过与APCs上的MHC-Ⅱ相互作用激活APCs, 介导CD8⁺ T细胞活化, 并与未成熟DCs上表达的MHC-Ⅱ结合, 诱导DCs的快速成熟, 增强抗原对CD8⁺ T细胞的交叉呈递^{[86, 87]}。在动物模型中, 反复注射IMP321可获得强烈且持续的细胞毒性T细胞反应。此外, IMP321显著增加了共刺激分子的表达以及IL-12和TNF-α的分泌。

在Legat等^[88]进行的Ⅰ/Ⅱa期临床试验中(NCT01308294), 16名转移性黑色素瘤患者注射了包括肿瘤抗原肽、Montanide ISA-51和IMP321的疫苗, IMP321作为APCs激活剂, 降低了Tregs的免疫抑制作用, 从而使抗原向CD8⁺ T细胞呈递。IMP321在所有16例患者中都诱导了特异性CD4⁺ T细胞反应, 在13例患者中诱导了特异性CD8⁺ T细胞反应, 且具有良好的安全性。此外, IMP321和Keytruda联用已经在多个实体瘤中显示出潜在的疗效和安全性。在转移性黑色素瘤患者的Ⅰ期临床试验中(NCT02676869), 联用耐受性和安全性良好, 在剂量递增阶段患者ORR为33%, 在剂量扩展阶段ORR为50%^[89]。2024年ESMO大会上发布的一项Ⅱ期临床试验(NCT04811027) 数据表明, 在一线治疗中使用IMP321联合Keytruda, PD-L1阴性的复发或转移性头颈部鳞状细胞癌患者ORR为35.5%, DCR为58.1%^[90]。先前的临床试验数据显示, 这类患者在接受PD-1抗体单药治疗时的ORR仅为5.4%。联合疗法加化疗(卡铂/培美曲塞) 三联疗法作为转移性或晚期非鳞状NSCLC一线疗法时(NCT03252938), 患者ORR为67%, DCR达91%。目前, 该三联疗法的Ⅲ期临床试验正在积极推进。此外, IMP321联合紫杉醇治疗转移性乳腺癌Ⅲ期临床试验(NCT05747794) 也正在进行中。最新公布的安全性引导(safety lead-in) 部分的数据显示, 患者ORR为50%, DCR为100%, 且未观察到患者出现剂量限制性毒性。值得一提的是, 一名曾经接受CDK4/6抑制剂治疗的三阴乳腺癌患者在接受IMP321和紫杉醇联合治疗后达成完全缓解(complete response, CR), 并在紫杉醇停药仅接受IMP321单药治疗持续保持CR。

5.4 LAG-3多肽及小分子抑制剂

多肽和小分子药物具有分子量小、易修饰、免疫原性低等优点, 它们在肿瘤免疫治疗中具有独特的优势。Zhai等^[91]开发了一种环肽C25, C25与人LAG-3具有相对较高的亲和力, 并能够干扰LAG-3-MHC-Ⅱ的相互作用。C25能显著刺激人外周血单个核细胞(peripheral blood mononuclear cell, PBMC) 中CD8⁺ T细胞的活化。在小鼠体内肿瘤模型中, C25能显著抑制肿瘤生长, 肿瘤组织中CD8⁺ T细胞浸润和IFN-γ分泌增加。Qian等^[92]通过采用噬菌体展示肽库筛选和D-氨基酸修饰, 获得了能够结合LAG-3的抗蛋白酶解多肽LFP-D1。该多肽能选择性阻断LAG-3-FGL1, 而不阻断LAG-3-MHC-Ⅱ的相互作用。LFP-D1在体外能够恢复T细胞的功能, 并在体内促进肿瘤组织中CD8⁺ T细胞的浸润, 抑制肿瘤生长。此外, 研究人员通过将LFP-D1与PD-1/PD-L1阻断肽OPBP-1偶联成功设计了靶向PD-1/PD-L1和LAG-3/FGL1的双特异性肽LFOP。与LFP-D1相比, LFOP具有更强的抗肿瘤作用, 且与放疗联用能够显著改善肿瘤中T细胞浸润, 增强抗肿瘤免疫反应。此外, Abdel-Rahman等^[93]通过化合物库筛选得到了能够同时抑制LAG-3-MHC-Ⅱ和LAG-3-FGL1的小分子化合物SA-15-P, 其抑制相互作用的IC₅₀值分别为4.21 ± 0.84和6.52 ± 0.47 μmol·L^-1。研究人员希望通过对SA-15-P进行进一步的结构修饰来评价其在小鼠体内肿瘤模型中的抗肿瘤作用。目前, LAG-3多肽和小分子药物的研发均处于临床前阶段, 其有效性和安全性还需要进一步评价。

除了与ICIs和化疗联用外, LAG-3药物与靶向药物联用也在临床前研究中展现出了潜在的协同作用。如糖原合成酶激酶3 (glycogen synthase kinase-3, GSK-3) 抑制剂SB415286和LAG-3抗体联用能够减缓小鼠黑色素瘤生长, CD8⁺ T淋巴细胞中颗粒酶B和IFN-γ水平升高^[94]。磷酸肌醇-3激酶(phosphoinositide 3-kinase, PI3K) δ抑制剂PI-3065和LAG-3抗体联合治疗可显著降低小鼠乳腺癌和结肠癌的肿瘤负荷^[95]。组蛋白去乙酰化酶(histone deacetylase, HDAC) 抑制剂domatinostat与LAG-3和PD-1抗体的联合治疗显著增加了抗肿瘤作用^[96]。此外, Gulhati等^[97]采用LAG-3抗体+41BB激动剂+CXCR1/2抑制剂的联合方案治疗小鼠原位iKRAS胰腺癌, 大部分小鼠肿瘤完全消退, 且90%的小鼠在停止治疗18个月后仍然存活。

6 总结与展望

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从20世纪90年代LAG-3首次报道, 经历了大约30年的研发历程, 靶向LAG-3的联合药物终于获准上市。综合现有临床试验结果, 靶向LAG-3药物在ICIs敏感的肿瘤患者(如黑色素瘤) 上具有较好的抗肿瘤活性。LAG-3抗体单用或与其他免疫疗法/化疗等联用在PD-1抗体不敏感或PD-L1阴性的头颈部鳞状细胞癌、NSCLC、转移性乳腺癌等肿瘤患者中具有独特的治疗优势。同时临床前研究也表明, LAG-3抗体对于ICIs原发耐药的胰腺癌也有显著效果。LAG-3作为第三个应用于临床的ICPs, 给肿瘤患者带来了新的治疗希望。

然而, 研究人员对LAG-3的了解还远远不够。首先, LAG-3的结构和功能尚未完全阐明, 由于LAG-3缺乏典型的抑制基序, 其介导的下游确切信号通路仍未被发现, 这限制了靶向LAG-3药物的研发; 其次, 在肿瘤微环境中, LAG-3的配体多样, 这些配体除了与LAG-3相互作用外, 还可参与其他受体传递信号转导; 再者, LAG-3与其他免疫检查点蛋白的相互作用复杂, 除PD-1之外, LAG-3还与CTLA-4、TIM-3等其他免疫检查点蛋白存在相互作用, 这些相互作用在肿瘤免疫逃逸和免疫治疗中的作用尚需进一步研究。此外, LAG-3靶向药物在不同肿瘤类型、不同分期患者中的治疗效果还需进一步明确。综上, 未来LAG-3的研究方向将聚焦于深入解析LAG-3的结构及信号转导机制、寻找可用于预测LAG-3靶向药物疗效的生物标志物, 以及探索靶向LAG-3的联合治疗策略, 以期更有效地提升患者的抗肿瘤免疫应答。

尽管目前关于LAG-3的研究仍有许多未知之处, 但鉴于其作用形式的多样性和在多种免疫细胞上所发挥的调节功能, 相信靶向LAG-3的药物将拥有更加广阔的应用前景。靶向LAG-3药物与化疗、靶向药物及ICIs的联用将为肿瘤患者提供更多样化的治疗选择。

作者贡献: 弓航负责文献收集和文章的撰写; 赵鑫和陈文霞负责文章格式的修订; 薛妮娜负责文章的立题和修改。

利益冲突: 所有作者均声明不存在利益冲突。

基金

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国家自然科学基金资助项目(81703566)

参考文献

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2025年第60卷第5期

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doi: 10.16438/j.0513-4870.2024-1290

接收时间：2024-12-25
首发时间：2025-10-29
出版时间：2025-05-12

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收稿日期：2024-12-25
修回日期：2025-02-09

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国家自然科学基金资助项目(81703566)

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^*薛妮娜, Tel: 86-10-63165207, E-mail: angelnina@imm.ac.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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