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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志  2022, Vol. 42 Issue (4): 58-67    DOI: 10.13523/j.cb.2111018
综述     
靶向人白介素-6蛋白的治疗性单克隆抗体研究进展*
李开通1**,刘金青2**,蔡望伟2,肖曼2,沈倍奋1,王晶1,***(),冯健男1,***()
1 军事科学院军事医学研究院毒物药物研究所 抗毒药物与毒理学国家重点实验室 北京 100850
2 海南医学院基础医学系 海口 570102
Advances of Therapeutic Monoclonal Antibodies Targeting Human Interleukin-6 Protein
LI Kai-tong1,LIU Jin-qing2,CAI Wang-wei2,XIAO Man2,SHEN Bei-fen1,WANG Jing1,***(),FENG Jian-nan1,***()
1 State key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
2 School of Basic Medicine, Hainan Medical College, Haikou 570102, China
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摘要:

白介素-6(interleukin-6,IL-6)作为一种多效的细胞因子,参与机体内众多生理与病理过程。研究表明,IL-6首先与自身受体(IL-6R、gp130)形成异源六聚体复合物,进而激活下游信号转导通路,最终发挥生物学功能。 IL-6信号通路异常活化及功能失调与多种疾病密切相关,如自身免疫疾病、慢性炎症、恶性肿瘤等。另外IL-6的异常表达在新型冠状病毒肺炎(COVID-19)细胞因子风暴综合征(CSS)中也扮演重要角色。一般而言,阻断IL-6信号通路上的各关键节点,均可用于IL-6相关疾病的治疗。有别于阻断IL-6R或gp130等公共受体分子,阻断IL-6蛋白的治疗性单克隆抗体特异性更高,在临床研究中,部分品种显示出其独有的治疗特点及有益的疗效。现阶段只有1个靶向IL-6蛋白的单克隆抗体药物获美国FDA批准上市,以及超过8个治疗性单克隆抗体在临床研究阶段。重点对国内外靶向人IL-6蛋白的治疗性单克隆抗体及其临床应用进行综述。

关键词: IL-6IL-6/IL-6R信号通路单克隆抗体抗体表位临床应用    
Abstract:

Interleukin-6 (IL-6) is a pleiotropic cytokine, which participates in many physiological and pathological functions. Studies have shown that IL-6 first forms a heterohexameric complex with its own receptors (IL-6R, gp130), which further activate downstream signal transduction pathways, and finally exerts biological functions. However, abnormal activation and dysfunction of IL-6 signaling pathway are closely related to a variety of diseases, such as autoimmune diseases, chronic inflammation, and malignant tumors. In addition, the abnormal expression of IL-6 also plays an important role in COVID-19’s cytokine storm syndrome (CSS). In general, treatments that block key molecules in the IL-6 signaling pathway can be used for IL-6-related diseases. Different from blocking shared receptor molecules such as IL-6R or gp130, therapeutic monoclonal antibodies that block IL-6 protein are more specific. In clinical research, some antibodies targeting IL-6 show their unique therapeutic characteristics and beneficial effects. At present, only one monoclonal antibody drug targeting IL-6 protein has been approved by the US FDA for marketing, and more than 8 therapeutic monoclonal antibodies are in the clinical research. This article focuses on a brief review of therapeutic monoclonal antibodies targeting human IL-6 protein around world and their clinical applications.

Key words: IL-6    IL-6/IL-6R signal pathway    Monoclonal antibody    Epitope    Clinical application
收稿日期: 2021-11-06 出版日期: 2022-05-05
ZTFLH:  Q816  
基金资助: * 国家自然科学基金面上项目(31771010);国家自然科学基金面上项目(81672368)
通讯作者: 王晶,冯健男     E-mail: Jingw_biomed@163.com;fengjiannan1970@qq.com
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引用本文:

李开通, 刘金青, 蔡望伟, 肖曼, 沈倍奋, 王晶, 冯健男. 靶向人白介素-6蛋白的治疗性单克隆抗体研究进展*[J]. 中国生物工程杂志, 2022, 42(4): 58-67.

LI Kai-tong, LIU Jin-qing, CAI Wang-wei, XIAO Man, SHEN Bei-fen, WANG Jing, FENG Jian-nan. Advances of Therapeutic Monoclonal Antibodies Targeting Human Interleukin-6 Protein. China Biotechnology, 2022, 42(4): 58-67.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2111018        https://manu60.magtech.com.cn/biotech/CN/Y2022/V42/I4/58

图1  IL-6信号转导通路及靶向IL-6蛋白的治疗性单克隆抗体示意图
英文名称
(代号)
中文
名称
研制公司 研发
国家
人源化
程度
适应证与临床进展 参考文献
Siltuximab
(CNTO 328)
司妥昔
单抗
Centocor/
Johnson &
Johnson
美国 人鼠嵌合单
克隆抗体
HIV和HHV-8阴性的多中心性卡斯尔曼病病(2014 年FDA/EMA批准; NMPA上市许可申请,并纳入优先审评);复发/难治性多发性骨髓瘤(II期);冒烟型多发性骨髓瘤(SMM)(II期);COVID-19(III期);精神分裂症辅助治疗(I期);转移性胰腺癌(Ib/II) [2,48-51]
Sirukumab
(CNTO 136)
西鲁库
单抗
Johnson &
Johnson/GSK
美国/
英国
全人源单
克隆抗体
一种或多种DMARD 应答不足或不耐受的中重度活动性RA成人患者,单药或与非生物 DMARD联合治疗(2017年FDA驳回BLA);严重抑郁症(II期);COVID-19(II期) [1,48-49]
Clazakizumab
(BMS-945429,
ALD518)
克拉扎珠
单抗
Alder/ BMS 美国 人源化单
克隆抗体
肾移植患者的慢性活性抗体介导的排斥反应(III期);中度至重度RA(IIB期);COVID-19(II期) [2,52]
Olokizumab 奥洛吉
珠单抗
UCB Pharma/
R-Pharm
比利时/
俄罗斯
人源化单克
隆抗体
(大鼠来源)
对甲氨蝶呤反应不足的RA(III期);对甲氨蝶呤反应不足的RA (与阿达木单抗比较,III期);TNF-α抑制剂反应不足的RA(III期);COVID-19(III期);2020年俄罗斯上市 [53-56]
MEDI5117
(WBP216)
N/A 药明
利康
中国 全人源单
克隆抗体
2016.12 NMPA IND;RA(I期) N/A
GB224 杰瑞
单抗
嘉和生物
(Genor
Biopharma)
中国 N/A 2016.12 NMPA IND; RA(I期) N/A
Ziltivekimab 泽韦奇
单抗
Novo Nordisk 丹麦 全人源单
克隆抗体
心血管疾病慢性肾病炎症患者(III期);晚期慢性肾病患者炎症(II期);2021.11 NMPA IND [57]
PF-04236921 N/A Pfizer 美国 全人源单
克隆抗体
克罗恩病(II期);广泛性红斑狼疮(II期);RA(I期) [58]
FB704A N/A Fountain/
Oneness
中国
台湾
全人源单
克隆抗体
严重哮喘(II期);RA(I期) N/A
EBI-031 N/A Eleven
Biotherapeutics/
Roche
美国/瑞士 人源单克
隆抗体
糖尿病黄斑水肿(I期撤回) [2]
表1  靶向IL-6蛋白的治疗性单克隆抗体及其临床进展
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