A 33-residue peptide tag increases solubility and stability of Escherichia coli produced single-chain antibody fragments

Yang Wang, Wenjie Yuan, Siqi Guo, Qiqi Li, Xiaomei Chen, Cheng Li, Qianying Liu, Lei Sun, Zhenguo Chen, Zhenghong Yuan, Cheng Luo, Shijie Chen (), Shuping Tong, Michael Nassal, Yu-Mei Wen and Yong-Xiang Wang ()
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Yang Wang: Fudan University
Wenjie Yuan: Fudan University
Siqi Guo: Chinese Academy of Sciences
Qiqi Li: Fudan University
Xiaomei Chen: Fudan University
Cheng Li: Fudan University
Qianying Liu: Fudan University
Lei Sun: Fudan University
Zhenguo Chen: Fudan University
Zhenghong Yuan: Fudan University
Cheng Luo: Chinese Academy of Sciences
Shijie Chen: Chinese Academy of Sciences
Shuping Tong: Fudan University
Michael Nassal: Department of Internal Medicine II/Molecular Biology, University Hospital Freiburg
Yu-Mei Wen: Fudan University
Yong-Xiang Wang: Fudan University

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Single-chain variable fragments (scFvs), composed of variable domains of heavy and light chains of an antibody joined by a linker, share antigen binding capacity with their parental antibody. Due to intrinsically low solubility and stability, only two Escherichia coli-produced scFvs have been approved for therapy. Here we report that a 33-residue peptide, termed P17 tag, increases the solubility of multiple scFvs produced in Escherichia coli SHuffle strain by up to 11.6 fold. Hydrophilic sequence, especially charged residues, but not the predicted α-helical secondary structure of P17 tag, contribute to the solubility enhancement. Notably, the P17 tag elevates the thermostability of scFv as efficiently as intra-domain disulfide bonds. Moreover, a P17-tagged scFv targeting hepatitis B virus surface proteins shows over two-fold higher antigen-binding affinity and virus-neutralizing activity than the untagged version. These data strongly suggest a type I intramolecular chaperone-like activity of the P17 tag. Hence, the P17 tag could benefit the research, production, and application of scFv.

Date: 2022
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DOI: 10.1038/s41467-022-32423-9

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