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Hiding Payload Inside the IgG Fc Cavity Significantly Enhances the Therapeutic Index of Antibody-Drug Conjugates

文献类型：期刊论文

作者Shi, Wei2,4,5; Zhang, Jianxin3,5; Liu, Liya1,5; Li, Wanzhen3,5; Liu, Zhi3; Ren, Anni2; Wang, Jie2; Tang, Caihong5; Yang, Yang2; Xu, Dandan2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-12-30
页码16
ISSN号0022-2623
DOI10.1021/acs.jmedchem.2c01812
通讯作者Huang, Wei(huangwei@simm.ac.cn) ; Tang, Feng(tangfeng2013@simm.ac.cn)
英文摘要The inadequate understanding of the structure- activity relationship (SAR) of glycosite-specific antibody-drug conjugates (ADCs) hinders its design and development. Herein, we revealed the systemic SAR and structure-toxicity relationship (STR) of gsADCs by constructing 50 gsADC structures bearing three glycan subtypes and diverse linker-drug combinations. According to the results, extra hydrophilic linkers are indispensable for the intact glycan-based gsADCs to achieve better in vivo efficacy. Meanwhile, the gsADCs that conjugate linker-drug complexes onto the terminal sialic acid are more stable and potent than the ones conjugated onto the terminal galactose in vivo. Notably, the LacNAc-based gsADCs, which shortened the spacer and located the linker-drug more inside the immunoglobulin class G (IgG) Fc cavity, showed excellent hydrophilicity, in vivo activity, pharmacokinetics, and safety. Conclusively, we found that hiding the linker-toxin into the Fc cavity can significantly enhance the therapeutic index of LacNAc-based gsADCs, which will benefit the further design of ADCs with optimal druggability.
WOS关键词ANTITUMOR-ACTIVITY ; SITE ; STABILITY ; PHARMACOKINETICS ; OPTIMIZATION ; STRATEGIES ; PROTEINS ; IMPROVES ; LINKER
资助项目Natural Science Foundation of China (NSFC)[21877116] ; Natural Science Foundation of China (NSFC)[92153301] ; Natural Science Foundation of China (NSFC)[82003574] ; Shanghai Sail Program[22YF1457400] ; Special Research Assistant Program (Chinese Academy of Sciences, CAS) ; Shanghai Municipal Science and Technology Major Project ; Hangzhou innovation and entrepreneurship leading team project[TD2020005] ; China Postdoctoral Science Foundation[2021M700158] ; National Key Research and Development Plan grants[2021YEE0200500] ; Lingang Laboratory[LG-QS-202206-03] ; SANOFI Scholarship Program
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000907825400001
源URL[http://119.78.100.183/handle/2S10ELR8/303905]  
专题中国科学院上海药物研究所
通讯作者Huang, Wei; Tang, Feng
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
4.Shanghai GlycanLink Biotech Co Ltd, Shanghai 201203, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Ctr Excellence Mol Cell Sci, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Shi, Wei,Zhang, Jianxin,Liu, Liya,et al. Hiding Payload Inside the IgG Fc Cavity Significantly Enhances the Therapeutic Index of Antibody-Drug Conjugates[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022:16.
APA Shi, Wei.,Zhang, Jianxin.,Liu, Liya.,Li, Wanzhen.,Liu, Zhi.,...&Tang, Feng.(2022).Hiding Payload Inside the IgG Fc Cavity Significantly Enhances the Therapeutic Index of Antibody-Drug Conjugates.JOURNAL OF MEDICINAL CHEMISTRY,16.
MLA Shi, Wei,et al."Hiding Payload Inside the IgG Fc Cavity Significantly Enhances the Therapeutic Index of Antibody-Drug Conjugates".JOURNAL OF MEDICINAL CHEMISTRY (2022):16.

入库方式： OAI收割

来源：上海药物研究所

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