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PEGylation of Dipeptide Linker Improves Therapeutic Index and Pharmacokinetics of Antibody-Drug Conjugates

文献类型：期刊论文

作者Long, Jing7,8; Shao, Ting8; Wang, Yongmei7,8; Chen, Tianzhi8; Chen, Yuning7,8; Chen, Yi-Li6,8; Wang, Qi8; Yu, Xiong4,5; Yu, Jinghua5; He, Kaifeng3,8
刊名BIOCONJUGATE CHEMISTRY
出版日期2025-01-20
页码11
ISSN号1043-1802
DOI10.1021/acs.bioconjchem.4c00392
通讯作者Wang, Guifeng(gfwang@simm.ac.cn) ; Wang, Chunhe(wangc@simm.ac.cn)
英文摘要Hydrophobic payloads incorporated into antibody-drug conjugates (ADCs) typically are superior to hydrophilic ones in tumor penetration and "bystander killing" upon release from ADCs. However, they are prone to aggregation and accelerated plasma clearance, which lead to reduced efficacies and increased toxicities of ADC molecules. Shielding the hydrophobicity of payloads by incorporating polyethylene glycol (PEG) elements or sugar groups into the ADC linkers has emerged as a viable alternative to directly adopting hydrophilic payloads. In this study, ADC linkers incorporating PEG or sugar groups were synthesized by modifying dipeptide linkers, with hydrophobic monomethyl auristatin E (MMAE) serving as an exemplary hydrophobic payload. All drug-linkers (DLs) were conjugated to RS7, a humanized antibody targeting Trop-2, with drug-to-antibody ratio (DAR) values set at 4 or 8. Among these, the ADC molecule RS7-DL 11, featuring a methyl-PEG24 (mPEG24) moiety as a side chain to the Valine-Lysine-PAB (VK) linker, demonstrated maximum hydrophilicity, biophysical stability, and tumor suppression, along with prolonged half-life and enhanced animal tolerability. In conclusion, through PEGylation of the traditional dipeptide linker, we have demonstrated an optimized ADC conjugation technology that can be employed for conjugating ultrahydrophobic payloads, thus enhancing both the therapeutic index and pharmacokinetics profile.
WOS关键词CANCER ; TUMORS ; DS-8201A ; EXPRESSION
资助项目National Natural Science Foundation of China[2022B1111070007] ; Key-Area Research and Development Program of Guangdong Province[81872785] ; Key-Area Research and Development Program of Guangdong Province[32370958] ; National Natural Science Foundation of China[21S11904500] ; Shanghai Municipal Commission of Science and Technology of China[210205143867019] ; Major Scientific and Technological Special Project of Zhongshan City[LX211005] ; CAS Bohai Rim Advanced Research Institute for Drug Discovery Project
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
WOS记录号WOS:001400743600001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/315914]  
专题中国科学院上海药物研究所
通讯作者Wang, Guifeng; Wang, Chunhe
作者单位1.Dartsbio Pharmaceut Ltd, Zhongshan 528400, Guangdong, Peoples R China
2.Chinese Acad Sci, SIMM, Zhongshan Inst Drug Discovery, Zhongshan 528400, Guangdong, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
4.Ocean Univ China, Sch Med & Pharm, Qingdao 266005, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201210, Peoples R China
6.Shanghai Mabstone Biotechnol Ltd, Shanghai 201203, Peoples R China
7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
8.Chinese Acad Sci, Shanghai Inst Mat Med, Biotherapeut Discovery Res Ctr, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Long, Jing,Shao, Ting,Wang, Yongmei,et al. PEGylation of Dipeptide Linker Improves Therapeutic Index and Pharmacokinetics of Antibody-Drug Conjugates[J]. BIOCONJUGATE CHEMISTRY,2025:11.
APA Long, Jing.,Shao, Ting.,Wang, Yongmei.,Chen, Tianzhi.,Chen, Yuning.,...&Wang, Chunhe.(2025).PEGylation of Dipeptide Linker Improves Therapeutic Index and Pharmacokinetics of Antibody-Drug Conjugates.BIOCONJUGATE CHEMISTRY,11.
MLA Long, Jing,et al."PEGylation of Dipeptide Linker Improves Therapeutic Index and Pharmacokinetics of Antibody-Drug Conjugates".BIOCONJUGATE CHEMISTRY (2025):11.

入库方式： OAI收割

来源：上海药物研究所

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