One-step synthesis of site-specific antibody-drug conjugates by reprograming IgG glycoengineering with LacNAc-based substrates
文献类型:期刊论文
作者 | Shi, Wei3,4,5; Li, Wanzhen2; Zhang, Jianxin2; Li, Tiehai5; Song, Yakai5; Zeng, Yue5; Dong, Qian5; Lin, Zeng5; Gong, Likun5; Fan, Shuquan1 |
刊名 | ACTA PHARMACEUTICA SINICA B |
出版日期 | 2022-05-01 |
卷号 | 12期号:5页码:2417-2428 |
ISSN号 | 2211-3835 |
关键词 | Site-specific ADCs ENGase LacNAc One-step assembly Potent in vivo efficacy |
DOI | 10.1016/j.apsb.2021.12.0132211-3835 |
通讯作者 | Tang, Feng(tangfeng2013@simm.ac.cn) ; Huang, Wei(huangwei@simm.ac.cn) |
英文摘要 | Glycosite-specific antibody???drug conjugatess (gsADCs), harnessing Asn297 N-glycan of IgG Fc as the conjugation site for drug payloads, usually require multi-step glycoengineering with two or more enzymes, which limits the substrate diversification and complicates the preparation process. Herein, we report a series of novel disaccharide-based substrates, which reprogram the IgG glycoengineering to one-step synthesis of gsADCs, catalyzed by an endo-N-acetylglucosaminidase (ENGase) of Endo-S2. IgG glycoengineering via ENGases usually has two steps: deglycosylation by wild-type (WT) ENGases and transglycosylation by mutated ENGases. But in the current method, we have found that disaccharide LacNAc oxazoline can be efficiently assembled onto IgG by WT Endo-S2 without hydrolysis of the product, which enables the one-step glycoengineering directly from native antibodies. Further studies on substrate specificity revealed that this approach has excellent tolerance on various modification of 6-Gal motif of LacNAc. Within 1 h, one-step synthesis of gsADC was achieved using the LacNAc-toxin substrates including structures free of bioorthogonal groups. These gsADCs demonstrated good homogeneity, buffer stability, in vitro and in vivo anti-tumor activity. This work presents a novel strategy using LacNAc-based substrates to reprogram the multi-step IgG glycoengineering to a one-step manner for highly efficient synthesis of gsADCs. 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
WOS关键词 | BETA-N-ACETYLGLUCOSAMINIDASE ; TRANSGLYCOSYLATION ACTIVITY ; CHEMOENZYMATIC SYNTHESIS ; GLYCOSYNTHASE MUTANTS ; GLYCOSYLATION ; ENDOGLYCOSIDASE ; GENERATION ; IMPROVES |
资助项目 | National Natural Science Foundation of China (NSFC)[2187116] ; National Natural Science Foundation of China (NSFC)[82003574] ; Shanghai Municipal Science and Technology Major Project ; Shanghai Sail Program[19YF1457100] ; Special Research Assistant Program (Chinese Academy of Sciences, CAS) ; Natural Science Foundation of Shandong Province[ZR2017BC062] |
WOS研究方向 | Pharmacology & Pharmacy |
语种 | 英语 |
出版者 | INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES |
WOS记录号 | WOS:000810964300009 |
源URL | [http://119.78.100.183/handle/2S10ELR8/301489] |
专题 | 中国科学院上海药物研究所 |
通讯作者 | Tang, Feng; Huang, Wei |
作者单位 | 1.Liaocheng Univ, Sch Life Sci, Liaocheng 252059, Shandong, Peoples R China 2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Biotherapeut Discovery Res, CAS Key Lab Receptor Res,CAS Ctr Excellence Mol C, Shanghai 201203, Peoples R China |
推荐引用方式 GB/T 7714 | Shi, Wei,Li, Wanzhen,Zhang, Jianxin,et al. One-step synthesis of site-specific antibody-drug conjugates by reprograming IgG glycoengineering with LacNAc-based substrates[J]. ACTA PHARMACEUTICA SINICA B,2022,12(5):2417-2428. |
APA | Shi, Wei.,Li, Wanzhen.,Zhang, Jianxin.,Li, Tiehai.,Song, Yakai.,...&Huang, Wei.(2022).One-step synthesis of site-specific antibody-drug conjugates by reprograming IgG glycoengineering with LacNAc-based substrates.ACTA PHARMACEUTICA SINICA B,12(5),2417-2428. |
MLA | Shi, Wei,et al."One-step synthesis of site-specific antibody-drug conjugates by reprograming IgG glycoengineering with LacNAc-based substrates".ACTA PHARMACEUTICA SINICA B 12.5(2022):2417-2428. |
入库方式: OAI收割
来源:上海药物研究所
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