A glycoengineered therapeutic anti-HBV antibody that allows increased HBsAg immunoclearance improves HBV suppression in vivo

Min You; Fentian Chen; Chao Yu; Yuanzhi Chen; Yue Wang; Xue Liu; Xueran Guo; Bing Zhou; Xin Wang; Boya Zhang; Mujin Fang; Tianying Zhang; Ping Yue; Yingbin Wang; Quan Yuan; Wenxin Luo

doi:10.3389/fphar.2023.1213726

A glycoengineered therapeutic anti-HBV antibody that allows increased HBsAg immunoclearance improves HBV suppression in vivo

Front Pharmacol. 2023 Dec 27:14:1213726. doi: 10.3389/fphar.2023.1213726. eCollection 2023.

Authors

Min You^#¹, Fentian Chen^#¹, Chao Yu^#¹, Yuanzhi Chen¹, Yue Wang¹, Xue Liu¹, Xueran Guo¹, Bing Zhou^{1

2}, Xin Wang^{1

2}, Boya Zhang¹, Mujin Fang^{1

3}, Tianying Zhang^{1

3}, Ping Yue⁴, Yingbin Wang^{1

3}, Quan Yuan^{1

3}, Wenxin Luo^{1

3}

Affiliations

¹ State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, School of Life Science, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, China.
² The 2nd Affiliated Hospital, South University of Science and Technology, Shenzhen, China.
³ Xiang An Biomedicine Laboratory, Xiamen, China.
⁴ School of Biology and Engineering (School of Health Medicine Modern Industry), Immune Cells and Antibody Engineering Research Center in University of Guizhou Province, Guizhou Medical University, Guiyang, China.

^# Contributed equally.

Abstract

Introduction: The effective and persistent suppression of hepatitis B surface antigen (HBsAg) in patients with chronic HBV infection (CHB) is considered to be a promising approach to achieve a functional cure of hepatitis B. In our previous study, we found that the antibody E6F6 can clear HBsAg through FcγR-mediated phagocytosis, and its humanized form (huE6F6 antibody) is expected to be a new tool for the treatment of CHB. Previous studies have shown that the glycosylation of Fc segments affects the binding of antibodies to FcγR and thus affects the biological activity of antibodies in vivo. Methods: To further improve the therapeutic potential of huE6F6, in this study, we defucosylated huE6F6 (huE6F6-fuc-), preliminarily explored the developability of this molecule, and studied the therapeutic potential of this molecule and its underlying mechanism in vitro and in vivo models. Results: huE6F6-fuc- has desirable physicochemical properties. Compared with huE6F6-wt, huE6F6-fuc- administration resulted in a stronger viral clearance in vivo. Meanwhile, huE6F6-fuc- keep a similar neutralization activity and binding activity to huE6F6-wt in vitro. Immunological analyses suggested that huE6F6-fuc- exhibited enhanced binding to hCD32b and hCD16b, which mainly contributed to its enhanced therapeutic activity in vivo. Conclusions: In summary, the huE6F6-fuc- molecule that was developed in this study, which has desirable developability, can clear HBsAg more efficiently in vivo, providing a promising treatment for CHB patients. Our study provides new guidance for antibody engineering in other disease fields.

Keywords: HBsAg; chronic hepatitis B infection; defucosylation; neutralization; phagocytosis; therapeutic antibody.

Grants and funding

This work was supported by the National Natural Science Foundation of China (31900675, U1905205, 32070940, 82202500, and 32170943), the Youth Innovation Fund of Xiamen (3502Z20206060), the China Postdoctoral Science Foundation (2021M700115), and the Guizhou Provincial Science and Technology Project (ZK 2022-397).