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中华肾病研究电子杂志 ›› 2025, Vol. 14 ›› Issue (01) : 53 -56. doi: 10.3877/cma.j.issn.2095-3216.2025.01.009

综述

膜性肾病的靶抗原发现及靶向治疗研究进展
沈小芳1, 赵娜1, 李克佳1, 肖跃飞1,()   
  1. 1. 100049 北京,航天中心医院肾内科
  • 收稿日期:2024-11-21 出版日期:2025-02-28
  • 通信作者: 肖跃飞

Research progress on target antigen discovery and targeted therapy of membranous nephropathy

Xiaofang Shen1, Na Zhao1, Kejia Li1, Yuefei Xiao1,()   

  1. 1. Department of Nephrology, Aerospace Center Hospital,Beijing 100049, China
  • Received:2024-11-21 Published:2025-02-28
  • Corresponding author: Yuefei Xiao
引用本文:

沈小芳, 赵娜, 李克佳, 肖跃飞. 膜性肾病的靶抗原发现及靶向治疗研究进展[J/OL]. 中华肾病研究电子杂志, 2025, 14(01): 53-56.

Xiaofang Shen, Na Zhao, Kejia Li, Yuefei Xiao. Research progress on target antigen discovery and targeted therapy of membranous nephropathy[J/OL]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2025, 14(01): 53-56.

近年来对膜性肾病(MN)病理生理机制研究不断深入,逐步揭示出MN 发病的关键机制是自身抗体与足细胞靶抗原的相互作用。 与此同时,MN 的流行病学特征显示出地域差异和不断变化的趋势,为疾病防控和诊疗提供了新的视角。 本综述系统梳理了MN 的最新研究进展,重点关注靶抗原发现以及以靶向治疗为代表的创新治疗策略,包括抗CD20 单克隆抗体、抗补体药物、蛋白酶体抑制剂等,旨在为膜性肾病后续的研究工作以及临床诊疗提供参考。

In recent years, significant advances in understanding the pathophysiological mechanisms of membranous nephropathy (MN) have revealed its underlying pathogenesis, primarily characterized by the interaction between autoantibodies and podocyte target antigens.Concurrently, the epidemiological features of MN have demonstrated regional variations and dynamic trends, offering novel insights for disease prevention and clinical management.This review systematically summarizes the latest progress in MN research, with a particular focus on the discovery of target antigens and innovative therapeutic approaches represented by targeted therapy,including anti-CD20 monoclonal antibodies, complement inhibitors, and proteasome inhibitors, in order to provide reference for the follow-up research and clinical diagnosis and treatment of membranous nephropathy.

图1 膜性肾病靶抗原的发现时间分布图 注:NEP:neutral endopeptidase,中性肽链内切酶;PLA2R:血清M 型磷脂酶A2 受体;C-BSA:cationic bovine serum albumin,阳离子化牛血清白蛋白;THSD7A:thrombospondin type-1 domain-containing 7A,1 型血小板反应蛋白7A 域;NELL-1:neural epidermal growth factor-like 1 protein,神经表皮生长因子样蛋白-1;EXT1/EXT2:exostosin l/ exostosin 2,外泌素1/和外泌素2;Sema3B:semaphorin 3B,信号素3B;CNTN1:contactin 1,接触蛋白1;HTRA1:high-temperature requirement A serine peptidase 1,高温型丝氨酸蛋白酶A1;NCAM1:neural cell adhesion molecule 1,神经细胞黏附分子1;PCDH7:protocadherin 7,原钙黏蛋白7;TGFBR3:transforming growth factor β receptor 3,转化生长因子β 受体3;FAT1:原钙黏蛋白FAT1;NTNG1:netrin G1,Netrin G1 蛋白;CD206:cluster of differentiation 206,分化簇206;EEA1:early endosome antigen 1,早期内吞体抗原;FCN3:ficolin 3,纤维胶凝蛋白3;MST1:macrophage stimulating 1,巨噬细胞刺激因子 1;NDNF:neuron-derived neurotrophic factor,神经元衍生神经营养因子;NPR3:natriuretic peptide receptor 3,利钠肽受体3;PCSK6:proprotein convertase subtilisin,前蛋白转化酶枯草溶菌素/Kexin 6 型;SEZ6L2:seizure-related 6 homolog like 2,癫痫相关6同源物样蛋白2;VASN:Vasorin 蛋白
表1 膜性肾病靶向治疗的对比
靶向治疗 代表药物 作用机制 疗效 主要副作用
抗CD20 单克隆抗体 利妥昔单抗 靶向CD20, 耗竭B 细胞, 减少抗PLA2R 抗体生成 完全缓解率和部分缓解率达50%80%;对PLA2R 阳性患者疗效显著 感染、输注反应、骨髓抑制
奥妥珠单抗 靶向CD20, 诱导B 细胞凋亡, 增强ADCC 作用 在利妥昔单抗耐药患者中展现潜力;可能延长缓解时间并减少输注相关反应 输注反应较少,但长期安全性仍需验证
抗CD38 单克隆抗体 达雷妥尤单抗 靶向CD38,清除浆细胞,减少自身抗体生成 对利妥昔单抗无效的患者可能有效;初步研究显示可降低抗PLA2R 抗体水平 感染风险增加;输注反应
Felzartamab单抗 靶向CD38,减少浆细胞生成 在PLA2R 相关MN 中显示剂量依赖性降低血清抗PLA2R 抗体 数据有限,需更多研究支持
补体抑制剂 Iptacopan Narsoplimab单抗 因子B 抑制剂,阻断替代补体途径
甘露糖结合凝集素相关丝氨酸蛋白酶-2 抑制剂,阻断甘露糖结合凝集素途径
临床试验中显示可减少肾小球损伤
初步研究显示对改善蛋白尿和肾功能有潜力
尚无明确不良反应数据
数据有限,需进一步研究
其他新兴疗法 硼替佐米 蛋白酶体抑制剂,诱导浆细胞凋亡 可快速降低PLA2R抗体水平并改善蛋白尿 感染风险、神经毒性
Belimumab单抗 抗BLyS 单克隆抗体,抑制自反应性B细胞 可降低PLA2R 抗体滴度并达到部分或完全缓解 数据有限;可能增加感染风险
CAR-T 疗法 靶向特定B 细胞或浆细胞,通过基因改造T 细胞清除致病细胞 初步研究显示对难治性MN 患者有潜力 潜在严重副作用,包括细胞因子释放综合征
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