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

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.