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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志  2021, Vol. 41 Issue (2/3): 78-88    DOI: 10.13523/j.cb.2011027
综述     
双特异性纳米抗体的研究进展及其应用 *
原博1,2,王杰文1,2,康广博1,2,黄鹤1,2,***()
1 天津大学生物化学工程系 化学工程学院 天津 300350
2 天津大学 系统生物工程教育部重点实验室 天津 300072
Research Progress and Application of Bispecific Nanobody
YUAN Bo1,2,WANG Jie-wen1,2,KANG Guang-bo1,2,HUANG He1,2,***()
1 Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China
2 Key Laboratory of Systems Bioengineering of Ministry of Education, Tianjin University, Tianjin 300072, China
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摘要:

从纳米抗体的研究进展,双特异性纳米抗体在感染类疾病、肿瘤以及免疫系统疾病治疗领域的研究成果、研究热点及发展前景等方面综述了双特异性纳米抗体的研究进展并分析了未来可能的发展方向。首先比较了纳米抗体与全长单克隆抗体之间的差异并阐述了双特异性纳米抗体具备的独特优势;继而概括了双特异性纳米抗体的发展历程,并对新冠病毒的中和性抗体、CAR-T细胞治疗和免疫检查点治疗抗体等研究热点进行了深入分析;最后对双特异性纳米抗体的应用前景进行分析,指出双特异性纳米抗体能够克服目前全长抗体治疗过程中存在的缺陷,成为一种极具发展潜力的抗体形式。

关键词: 纳米抗体双特异性抗体感染性疾病肿瘤治疗免疫性疾病    
Abstract:

This article reviews the application and advances of bispecific nanobodies from the research progress of nanobodies and studies of bispecific nanobodies in treating infectious diseases, cancer, and immune system diseases. Moreover, it highlights the research hotspots and potential research areas at this current stage. For in-depth analysis, the differences between nanobodies and full-length monoclonal antibodies are compared and the unique advantages of bispecific nanobodies are demonstrated. The research progress of nanobodies has been summarized, while emphasizing the research hot spots of neutralizing nanobodies of the COVID-19, CAR-T cell therapy, and immune checkpoint therapy antibodies. In conclusion, a prospect analysis of the application prospects of bispecific nanobodies is carried out. It is pointed out that bispecific nanobodies are able to overcome the shortcomings of full-length antibody and become a form of the antibody with great druggability.

Key words: Nanobody    Bispecific antibody    Infectious diseases    Tumor therapy    Immune diseases
收稿日期: 2020-11-16 出版日期: 2021-04-08
ZTFLH:  Q51  
基金资助: * 国家重点研发计划(2019YFA0905600);天津科技计划资助项目(19YFSLQY00110)
通讯作者: 黄鹤     E-mail: huang@tju.edu.cn
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引用本文:

原博,王杰文,康广博,黄鹤. 双特异性纳米抗体的研究进展及其应用 *[J]. 中国生物工程杂志, 2021, 41(2/3): 78-88.

YUAN Bo,WANG Jie-wen,KANG Guang-bo,HUANG He. Research Progress and Application of Bispecific Nanobody. China Biotechnology, 2021, 41(2/3): 78-88.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2011027        https://manu60.magtech.com.cn/biotech/CN/Y2021/V41/I2/3/78

图1  不同类型双特异性抗体示意图
图2  双特异性纳米抗体在不同治疗领域中的应用
抗体名称 靶标 治疗疾病 年份 参考文献
NbF12-10 AahI型毒素/AahII型毒素 Aah蝎子毒素 2010 [17]
ABA TcdA/TcdB 艰难梭状芽孢杆菌(CDI)感染 2014 [18]
T5-V36 TerC/Mac-1 破伤风毒素 2015 [19]
RTA-VHH-RTB-VHHs RTA/ RTB 蓖麻毒素 2015 [20]
JMN-D10-JMO-G1 水肿因子/致死因子 炭疽杆菌毒素感染 2016 [21]
Ad/VNA2-PA 水肿因子/致死因子 炭疽杆菌毒素感染 2016 [22]
NbF12-10 AahI型毒素/AahII型毒素 澳大利亚海蛇毒毒素 2018 [23]
ACE-Anti-CD16 VHH sACE22/CD16 新冠状病毒 2020 [24]
H11-D4/HH11-H4 RBD /ACE2 新冠状病毒 2020 [25]
NbPCV2 -NbcRBC PCV2/cRBCs 猪圆环2型病毒 2020 [26]
表1  抗感染类双特异性纳米抗体
抗体名称 靶标 治疗疾病 年份 参考文献
IE2-AIb8/6E10-AIb8 HGF/HSA HGF表达肿瘤,如胶质瘤 2012 [32]
MaAbNA HER2/EGFR1 乳腺癌 2015 [33]
ttα GFP-α CEA
ttα GFP-α EGFR-α CEA
CEA/GFP/EGFR 人表皮样癌 2016 [34]
VHH EGFR-VHH GFP GFP/EGFR EGFR阳性肿瘤 2017 [35]
VHH CD3ε- VHH CD19 CD3ε/CD19 特异性表达CD19的肿瘤 2017 [36]
7D12-5GS-6H4 Vγ9Vδ2-T cells/EGFR Vγ9Vδ2-T cells的肿瘤
EGFR相关肿瘤
2017 [37]
ENb-TRAIL DR/EGFR 大肠癌、肺癌和胶质瘤 2017 [38]
RR2-H-RR4-Lip HER2表位1/ HER2表位2 乳腺癌 2018 [39]
Muc1-Bi-1 Muc1/CD16 Muc1细胞异常表达引发的多种癌症 2018 [40]
NanoCAR HER2/CD20 B细胞白血病和淋巴瘤 2018 [41]
PEG-S-Fab CEA/CD3 人结肠腺癌细胞治疗 2018 [42]
SBC77 CEA/CD16a CEA在不同恶性肿瘤中过度表达的治疗
(包括结肠直肠癌、胃癌、乳腺癌等)
2019 [43]
STAR-isolated Nb157 CD13/TIM3 急性髓系白血病 2020 [44]
Bi1/Bi2 FP/EGFR 肺癌、头颈癌和结肠癌等高表达EGFR的恶性肿瘤 2020 [45]
TSsdAb CD16/EGFR EGFR阳性肿瘤 2020 [46]
表2  抗肿瘤双特异性纳米抗体
抗体名称 靶标 治疗疾病 年份 参考文献
Ozoralizumab(ATN-103) TNF-α/HSA 类风湿关节炎(RA) 2012 [15]
FAF Nb2-MSA21 Furin/MT1-MMP 胶溶蛋白淀粉样病变 2014 [68]
ALX-0061 IL-6/HSA 类风湿关节炎(RA) 2015 [16]
TROS TNFR/HSA 类风湿关节炎(RA)、克罗恩病(CD) 2015 [69]
AAV9-Nb11-FAF1 Furin/MT1-MMP 胶溶蛋白淀粉样病变 2017 [70]
M1095 IL-17A/IL-17F 银屑病 2017 [71]
Nb 70-alb-14 MMP8/hTNFR1 急性炎症和败血症 2018 [72]
VHH (J3/3E3)-VHH (2E7) gp41/gp120 获得性免疫缺陷综合征 2019 [73]
Everestmab GLP-1/GLP-1R T2DM(2型糖尿病) 2020 [74]
表3  免疫类疾病双特异性纳米抗体
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