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Antibody-Dependent Enhancement (ADE) of SARS-CoV-2 Infection Requires FcγRIIB and Virus-Antibody Complex With Bivalent Interaction

33 Pages Posted: 9 Jul 2021 Publication Status: Under Review

See all articles by Shuang Wang

Shuang Wang

Mabwell (Shanghai) Bioscience Co., Ltd.

Junchao Wang

Anhui University - School of Life Sciences

Xiaojuan Yu

National Institutes for Food and Drug Control - Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products

Wen Jiang

Mabwell (Shanghai) Bioscience Co., Ltd.

Shuo Chen

University of Oxford - Ludwig Cancer Research

Rongjuan Wang

Mabwell (Shanghai) Bioscience Co., Ltd.

Mingzhu Wang

Anhui University - School of Life Sciences

Shasha Jiao

Mabwell (Shanghai) Bioscience Co., Ltd.

Yingying Yang

Mabwell (Shanghai) Bioscience Co., Ltd.

Wenbo Wang

National Institutes for Food and Drug Control - Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products

Huilin Chen

Mabwell (Shanghai) Bioscience Co., Ltd.

Ben Chen

Mabwell (Shanghai) Bioscience Co., Ltd.

Chunying Gu

Mabwell (Shanghai) Bioscience Co., Ltd.

Chuang Liu

Mabwell (Shanghai) Bioscience Co., Ltd.

An Wang

Mabwell (Shanghai) Bioscience Co., Ltd.

Min Wang

Mabwell (Shanghai) Bioscience Co., Ltd.

Gang Li

Mabwell (Shanghai) Bioscience Co., Ltd.

Cuicui Guo

Mabwell (Shanghai) Bioscience Co., Ltd.

Datao Liu

Mabwell (Shanghai) Bioscience Co., Ltd.

Jinchao Zhang

Mabwell (Shanghai) Bioscience Co., Ltd.

Min Zhang

Anhui University - School of Life Sciences

Lan Wang

National Institutes for Food and Drug Control - Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products

Xun Gui

Mabwell (Shanghai) Bioscience Co., Ltd.

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Abstract

Antibody-dependent enhancement (ADE) has been reported for SARS-CoV and MERS-CoV, suggesting the risk of ADE for antibody-based SARS-CoV-2 vaccines and therapeutics. Understanding the underlying molecular mechanisms behind ADE of SARS-CoV-2 is critical for development of safe and effective therapies. Here, we report that two neutralizing mAbs MW01 and MW05 could enhance the infection of SARS-CoV-2 on FcγRIIB-expressing B cells. Enhancing the interaction of Fc with FcγRIIB could increase the ADE activity mediated by MW01 and MW05. Expression of other FcγRs, such as FcγRIA and FcγRIIA, could decrease ADE activity of these two mAbs by competing with FcγRIIB. X-ray crystal structure determination and S trimer-binding modeling showed that MW01 and MW05 can bind to RBDs in S trimer with both “up” and “down” states. While, the neutralizing mAb MW07, which has no ADE activity only binds to RBD in S trimer with “up” state. Monovalent MW01 and MW05 completely diminished the ADE activity compared with their bivalent counterparts. Moreover, both macropinocytosis and endocytosis are confirmed involving in ADE of SARS-CoV-2 infection. Blocking endosome transportation and lysosome acidification could inhibit the ADE activity mediated by MW05. Together, our results identified a novel ADE mechanism of SARS-CoV-2, FcγRIIB-mediated uptake of SARS-CoV-2/mAb complex with bivalent interaction. These findings provide a novel perspective on the mechanism of ADE of SARS-CoV-2, which is informative to the development of safer therapeutics and vaccines.

Funding Information: This work was supported by National Key R&D Program (2020YFC0848600 to S.W. and 2020YFC0860700 to L.W.).

Declaration of Interests: X.G., S.W., S.J., W.J. and C.G. are listed as inventors on the licensed patents for MW05 and MW07. S.W., S.J., W.J., M.W., Z.L., C.G., B.C., H.C., A.W., G.L., C.G., X.G., J.Z. and D.L. are employees of Mabwell (Shanghai) Bioscience Co., Ltd. and may hold shares in Mabwell (Shanghai) Bioscience Co., Ltd. The other authors declare no competing interests.

Keywords: SARS-CoV-2, Neutralization, Spike trimer, ADE, FcγRIIB

Suggested Citation

Wang, Shuang and Wang, Junchao and Yu, Xiaojuan and Jiang, Wen and Chen, Shuo and Wang, Rongjuan and Wang, Mingzhu and Jiao, Shasha and Yang, Yingying and Wang, Wenbo and Chen, Huilin and Chen, Ben and Gu, Chunying and Liu, Chuang and Wang, An and Wang, Min and Li, Gang and Guo, Cuicui and Liu, Datao and Zhang, Jinchao and Zhang, Min and Wang, Lan and Gui, Xun, Antibody-Dependent Enhancement (ADE) of SARS-CoV-2 Infection Requires FcγRIIB and Virus-Antibody Complex With Bivalent Interaction. Available at SSRN: https://ssrn.com/abstract=3883634 or http://dx.doi.org/10.2139/ssrn.3883634
This version of the paper has not been formally peer reviewed.

Shuang Wang

Mabwell (Shanghai) Bioscience Co., Ltd. ( email )

Shanghai
China

Junchao Wang

Anhui University - School of Life Sciences

China

Xiaojuan Yu

National Institutes for Food and Drug Control - Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products ( email )

Beijing
China

Wen Jiang

Mabwell (Shanghai) Bioscience Co., Ltd. ( email )

Shanghai
China

Shuo Chen

University of Oxford - Ludwig Cancer Research ( email )

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

Rongjuan Wang

Mabwell (Shanghai) Bioscience Co., Ltd. ( email )

Shanghai
China

Mingzhu Wang

Anhui University - School of Life Sciences

China

Shasha Jiao

Mabwell (Shanghai) Bioscience Co., Ltd. ( email )

Shanghai
China

Yingying Yang

Mabwell (Shanghai) Bioscience Co., Ltd. ( email )

Shanghai
China

Wenbo Wang

National Institutes for Food and Drug Control - Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products ( email )

Beijing
China

Huilin Chen

Mabwell (Shanghai) Bioscience Co., Ltd. ( email )

Shanghai
China

Ben Chen

Mabwell (Shanghai) Bioscience Co., Ltd. ( email )

Shanghai
China

Chunying Gu

Mabwell (Shanghai) Bioscience Co., Ltd. ( email )

Shanghai
China

Chuang Liu

Mabwell (Shanghai) Bioscience Co., Ltd. ( email )

Shanghai
China

An Wang

Mabwell (Shanghai) Bioscience Co., Ltd. ( email )

Shanghai
China

Min Wang

Mabwell (Shanghai) Bioscience Co., Ltd. ( email )

Shanghai
China

Gang Li

Mabwell (Shanghai) Bioscience Co., Ltd. ( email )

Shanghai
China

Cuicui Guo

Mabwell (Shanghai) Bioscience Co., Ltd. ( email )

Shanghai
China

Datao Liu

Mabwell (Shanghai) Bioscience Co., Ltd. ( email )

Shanghai
China

Jinchao Zhang

Mabwell (Shanghai) Bioscience Co., Ltd. ( email )

Shanghai
China

Min Zhang

Anhui University - School of Life Sciences ( email )

Hefei
China

Lan Wang

National Institutes for Food and Drug Control - Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products ( email )

Beijing
China

Xun Gui (Contact Author)

Mabwell (Shanghai) Bioscience Co., Ltd. ( email )

Shanghai
China

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