人源抗体制备及临床应用研究进展 <sup>*</sup>

doi:10.13523/j.cb.20191011

中国生物工程杂志

2019, Vol. 39

Issue (10): 90-96 DOI: 10.13523/j.cb.20191011

综述

人源抗体制备及临床应用研究进展 ^*

陈秀秀^1,²,吴成林²,周丽君^1,^2,^**(

)

1 安徽医科大学海军临床学院北京 100048
2 中国人民解放军总医院第六医学中心中心实验室北京 100048

Research Progress in Preparation and Clinical Application of Therapeutic Human Antibodies

CHEN Xiu-xiu^1,²,WU Cheng-lin²,ZHOU Li-jun^1,^2,^**(

)

1 Department of Naval Clinical Medicine, Anhui Medical University, Beijing 100048, China
2 Central Laboratory of the Sixth Medical Center, General Hospital of the Chinese People’s Liberation Army, Beijing 100048, China;

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摘要：

与常规治疗药物相比,抗体药物具有靶向性强、特异性好等优点,其作为一类重要的治疗性药物,近年来在临床中的应用逐渐增多,为疾病的治疗提供了新的选择,应用范围逐渐从肿瘤、自身免疫性疾病及慢性炎症扩展到心血管和感染性等疾病中。人源抗体的全部结构是由人类抗体基因所编码的,因此避免了异种蛋白长期应用引起的不良反应,加之人源抗体制备技术的不断发展完善,使其逐渐成为治疗性抗体研发的首要选择。综述了近年来治疗性人源抗体的主要制备技术及其在临床中应用的最新进展,同时探讨了人源抗体制备技术的不足之处,以期为人源抗体的发展提供借鉴和思路。

关键词： 人源抗体; 噬菌体展示技术; 转基因鼠技术; 临床应用

Abstract:

As important therapeutic drugs, human antibodies have been widely applied in clinical therapy in recent years. At present, the range of clinical application has gradually expanded from tumors, autoimmune diseases and chronic inflammation to cardiovascular diseases and infection, Compared with conventional therapy, the advantages of antibody therapy are specificity and high efficiency, which provides a new choice for the treatment of diseases. The entire structure of the human antibody is encoded by the human antibody gene, the human antibody gradually becomes the first choice for the development of therapeutic antibodies for avoiding the adverse reactions caused by the long-term application of the heterologous protein. The main preparation techniques and clinical application progress of therapeutic human antibodies are reviewed. At the same time, the disadvantages of human antibody preparation technology are also discussed to provide references and ideas for the development of human antibodies.

Key words: Human antibody Phage display technology Transgenic mouse technology Clinical application

收稿日期: 2019-01-30 出版日期: 2019-11-12

ZTFLH:

R392

基金资助: * 国家自然科学基金资助项目(31470897、81602457)

通讯作者: 周丽君 E-mail: hzzhoulj@126.com

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引用本文:

陈秀秀,吴成林,周丽君. 人源抗体制备及临床应用研究进展 ^*[J]. 中国生物工程杂志, 2019, 39(10): 90-96.

CHEN Xiu-xiu,WU Cheng-lin,ZHOU Li-jun. Research Progress in Preparation and Clinical Application of Therapeutic Human Antibodies. China Biotechnology, 2019, 39(10): 90-96.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.20191011 或 https://manu60.magtech.com.cn/biotech/CN/Y2019/V39/I10/90

名称	形式	制备方法	靶点	所治疾病	上市时间
Adalimumab	IgG1κ	噬菌体抗体库	TNF-α	类风湿性关节炎、克罗恩病	2002
Panitumumab	IgG2κ	转基因鼠	EGFR	结直肠癌	2006
Golimumab	IgG1κ	转基因鼠	TNF-α	类风湿性关节炎、溃疡性结肠炎	2009
Ustekinumab	IgG1κ	转基因鼠	IL-12;IL-23	银屑病、银屑病关节炎、克罗恩病	2009
Canakinumab	IgG1κ	转基因鼠	IL-1β	周期性发热、幼年特发性关节炎	2009
Ofatumumab	IgG1κ	转基因鼠	CD20	慢性淋巴细胞白血病	2009
Denosumab	IgG2κ	转基因鼠	RANK-L	骨质疏松症、实体瘤骨转移	2010
Belimumab	IgG1λ	噬菌体抗体库	BAFF	系统性红斑狼疮	2011
Ipilimumab	IgG1κ	转基因鼠	CTLA4	黑色素瘤	2011
Raxibacumab	IgG1λ	噬菌体抗体库	炭疽杆菌P84抗原	吸入性炭疽	2012
Nivolumab	IgG4κ	转基因鼠	PD1	黑色素瘤、非小细胞肺癌、霍奇金淋巴瘤	2014
Daratumumab	IgG1κ	转基因鼠	CD38	多发性骨髓瘤	2015
Necitumumab	IgG1κ	噬菌体抗体库	EGFR	鳞状非小细胞肺癌	2015
Alirocumab	IgG1λ	转基因鼠	PCSK9	高胆固醇血症	2015
Evolocumab	IgG2λ	转基因鼠	PCSK9	高胆固醇血症	2015
Olaratumab	IgG1κ	转基因鼠	PDGFRα	软组织肉瘤	2016
Ramucirumab	IgG1κ	噬菌体抗体库	VEGFR2	晚期胃癌、胃食管结合部腺癌	2014
Secukinumab	IgG1κ	转基因鼠	IL-17A	斑块状银屑病、强直性脊柱炎	2015
Bezlotoxumab	IgG2κ	转基因鼠	梭状芽孢杆菌毒素B	预防艰难梭菌感染复发	2016
Dupilumab	IgG4κ	转基因鼠	IL-4Rα	特应性皮炎	2017
Durvalumab	IgG1κ	转基因鼠	PD-L1	尿路上皮癌	2017
Sarilumab	IgG1κ	转基因鼠	IL-6R	类风湿性关节炎	2017
Avelumab	IgG1κ	噬菌体抗体库	PD-L1	默克细胞癌、尿路上皮癌	2017
Guselkumab	IgG1λ	噬菌体抗体库	IL-23	中重度斑块状银屑病	2017
Brodalumab	IgG1κ	转基因鼠	IL-17RA	中重度斑块状银屑病	2017
Erenumab	IgG2λ	转基因鼠	CGRPR	预防成人偏头痛	2018
Burosumab	IgG1κ	转基因鼠	FGF23	X连锁低磷血症	2018
Cemiplimab	IgG4κ	转基因鼠	PD-1	皮肤鳞状细胞癌、局部晚期皮肤鳞状细胞癌	2018
Lanadelumab	IgG1κ	噬菌体抗体库	Plasma kallikrein	遗传性血管性水肿	2018
Emapalumab	IgG1λ	转基因鼠	IFNγ	原发性噬血细胞性淋巴组织细胞增多症	2018

表1 截至2018年美国FDA批准上市的人源抗体[2, 13-17]

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