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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2023, Vol. 43 Issue (1): 59-70    DOI: 10.13523/j.cb.2208017
综述     
不同给药途径的治疗性纳米抗体研究进展
吴悦1,2,孙白荷1,2,赵芮3,李延飞2,*(),马琳琳2,*()
1 上海理工大学健康科学与工程学院 上海 200093
2 上海健康医学院医学技术学院 上海 201318
3 上海市东海老年护理医院 上海 201303
Research Progress of Therapeutic Nanobodies with Different Routes of Administration
WU Yue1,2,SUN Bai-he1,2,ZHAO Rui3,LI Yan-fei2,*(),MA Lin-lin2,*()
1 School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
2 School of Medical Technology, Shanghai University of Medicine & Health Sciences, Shanghai 201318, China
3 Shanghai Donghai Geriatric Nursing Hospital, Shanghai 201303, China
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摘要：

骆驼科及鲨鱼科动物血清中天然存在的纳米抗体具有不同于传统单克隆抗体的独特结构和分子量,这为抗体药物开发提供了全新的思路。纳米抗体较小的分子量和优异的稳定性使其在给药方面具有更大的灵活性,可以在一定程度上克服传统单克隆抗体在给药途径方面存在的局限性。同时,较小的分子量使纳米抗体具有双重药代动力学特征,既有优异的组织渗透性,又表现出快速的血液清除。重点介绍纳米抗体的药物代谢动力学特征和进一步改善药代动力学的方法,综述不同给药途径的纳米抗体药物研究进展,对其治疗特定疾病的可行性、安全性以及治疗效果进行分析,以期为纳米抗体药物研发中给药途径的选择提供参考。
关键词： 纳米抗体;  生物学特性;  药代动力学;  给药途径    
Abstract:

The nanobodies naturally existing in the sera of camels and Sharks provide a new idea for the development of antibody drugs because of their unique structural characteristics and molecular weight different from traditional monoclonal antibodies. In particular, the small molecular weight and excellent stability of nanobodies enable them to have greater flexibility in drug delivery. They can withstand harsh biophysical environments and are developed into oral preparations and aerosolized inhalants, which to some extent solves the challenges and limitations of traditional monoclonal antibodies in drug delivery routes. However, the small molecular weight also makes the nanobody have dual pharmacokinetic characteristics after administration, both excellent tissue penetration and rapid blood clearance. Improving the pharmacokinetic characteristics of nanobodies is of great significance to reduce the frequency of drug delivery and drug efficacy. In this review, the biological characteristics of nanobodies were first described, and then the pharmacokinetic characteristics of nanobodies and the methods to further improve the pharmacokinetics were emphatically introduced. On this basis, the research progress of nanobody drugs used for intravenous, subcutaneous, oral and inhalation drug delivery routes was reviewed, the feasibility, safety and therapeutic effect of different drug delivery routes for the treatment of specific diseases were evaluated, and the possible drug delivery routes of nanobodies were also analyzed, so as to provide a reference for the selection of drug delivery routes in the follow-up research and development of nanobody drugs.
Key words: Nanobody    Biological characteristics    Pharmacokinetics    Route of administration
收稿日期: 2022-08-15 出版日期: 2023-02-14
ZTFLH:  Q819  
通讯作者: *李延飞 电子信箱:liyf@sumhs.edu.cn,马琳琳 mall@sumhs.edu.cn   
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引用本文:

吴悦, 孙白荷, 赵芮, 李延飞, 马琳琳. 不同给药途径的治疗性纳米抗体研究进展[J]. 中国生物工程杂志, 2023, 43(1): 59-70.

WU Yue, SUN Bai-he, ZHAO Rui, LI Yan-fei, MA Lin-lin. Research Progress of Therapeutic Nanobodies with Different Routes of Administration. China Biotechnology, 2023, 43(1): 59-70.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2208017    或    https://manu60.magtech.com.cn/biotech/CN/Y2023/V43/I1/59

图1  源自人和骆驼科动物的抗体及其可变区结构
图2  用于减少给药频率的不同结构纳米抗体、药物递送载体及药物控释系统
给药方式 疾病名称 药物名称 靶点 研究阶段 临床试验编号 参考文献
静脉+皮下给药 获得性血栓血小板减少性紫癜 Caplacizumab(ALX-0081) vWF 上市 - [3]
静脉给药 类风湿性关节炎 Vobanlizumab(ALX-0061) IL-6R IIb期临床 NCT02287922 [39]
癌症(G protein coupled
receptor, GPCR)		 ALX-0651 CXCR4 I期临床停止 NCT01374503 -
局部晚期/转移性实体瘤 KN044 CTLA-4 I期临床 NCT04126590 -
实体瘤 TAS266 DR5 I期临床停止 NCT01529307 [42]
鳞状非小细胞肺癌 KN046 PD-L1/CTLA-4 Ⅲ期临床 NCT04474119 -
胸腺癌 KN046 - II期临床 NCT04925947 -
实体瘤 11A4-ABD-AF HER2 临床前 - [40]
神经退行性疾病 BI1034020 Aβ I期临床停止 NCT01958060 -
实体瘤 BI836880 VEGF/Ang2 I期临床 NCT02689505 -
实体瘤 S7 ADC EGFR 临床前 - [73]
晚期癌症 JS014 IL-21 I期临床 NCT05296772 -
实体瘤 αPD1-MSLN-CAR T PD-1 I期临床 NCT05373147 -
急性髓性白血病 BissCAR T CD13、TIM3 临床前 - [74]
复发难治多发性骨髓瘤 LCAR-B38M BCMA II期临床 NCT03758417 -
多发性骨髓瘤 JNJ-68284528 BCMA II期临床 NCT04133636 -
多发性骨髓瘤 Ciltacabtagene autoleucel
(cilta-cel)		 BCMA IV期临床 NCT05201781 [6,41]
复发/难治性B细胞淋巴瘤 CD19/CD20 bispecific CAR-T CD19/CD20 I期临床 NCT03881761 -
皮下给药 类风湿性关节炎 Ozoralizumab(ATN-103) TNFα Ⅲ期临床 NCT04077567 [48]
斑块型银屑病 Sonelokimab(M1095) IL-17A/IL-17F IIb期临床 NCT03384745 [46]
化脓性汗腺炎 Sonelokimab(M1095) - II期临床 NCT05322473 -
dMMR/MSI-H晚期实体瘤 Envafolimab(KN035) PD-L1 II期临床 NCT03667170 [27,34]
2型糖尿病 Everestmab GLP-1R 临床前 - [47]
骨关节炎 M6495 ADAMTS-5 I期临床 NCT03583346 [45]
慢性乙型肝炎 ASC22 PD-L1 IIb期临床 NCT04465890 [49]
系统性红斑狼疮 Vobarilizumab(ALX-0061) - II期临床 NCT02437890 [39]
口服给药 炎症性肠病(克罗恩病) V565 TNFα II期临床 NCT02976129 [54,56]
炎症性肠病 V56B2 TNF-α/IL-23 临床前 - [57]
儿童腹泻 VHH batch 203027 (ARP1) RV病毒 II期临床 NCT01259765 [58]
腹泻 ARP3-ARP1 RV病毒 临床前 - [60]
腹泻 MucoRice-ARP1 RV病毒 临床前 - [59]
霍乱 Anti-LPS nanobody 霍乱弧菌O1 LPS 临床前 - [75]
空肠弯曲杆菌感染 LMN-101 鞭毛蛋白FlaA II期临床 NCT04182490 -
吸入给药 COVID-19 PiN21 SARS-CoV-2-RBD 临床前 - [63]
COVID-19 K-874A SARS-CoV-2-S1 临床前 - [62]
COVID-19 Nb11-59 SARS-CoV-
2RBD/ACE2		 临床前 - [21]
给药方式 疾病名称 药物名称 靶点 研究阶段 临床试验编号 参考文献
COVID-19 Nb15-NbH-Nb15 SARS-CoV-2-RBD 临床前 - [76]
COVID-19 Nb91-Nb3-hFc SARS-CoV-2-RBD 临床前 - [77]
COVID-19 Nb1-Nb2-Fc SARS-CoV-2-RBD 临床前 - [64]
呼吸道肺炎 m17 /m35 RSV F蛋白 临床前 - [78]
呼吸道感染 ALX-0171 RSV病毒 II期临床停止 NCT03418571 [65]
哮喘 LQ036 IL-4Rα I期临床 NCT04993443 -
肌肉注射 流感 R1a-B6-Fc 流感病毒 临床前 - [66]
动脉注射 神经系统疾病/脑恶性肿瘤 NB11 - 临床前 - [67]
眼部给药 视网膜新生血管疾病 BI-X VEGF、Ang-2 临床前 - [70]
腹腔注射(小鼠模型) 发热伴血小板减少综合征 SNB02 SFTSV病毒 临床前 - [69]
狂犬病 Rab-E8/H7 狂犬病病毒 临床前 - [68]
黑色素瘤 2.17-mAlb LepR 临床前 - [79]
表1  不同给药途径的治疗性纳米抗体药物研究进展
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