Mabwell (Shanghai) Bioscience Co., Ltd, Shanghai, 201210, China.
Beijing Kohnoor Science & Technology Co., Ltd, Beijing, 102206, China.
Commun Biol. 2022 Mar 24;5(1):262. doi: 10.1038/s42003-022-03207-0.
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 pseudovirus on FcγRIIB-expressing B cells. X-ray crystal structure determination and S trimer-binding modeling showed that MW01 and MW05 could 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 pseudoviral 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 pseudovirus in vitro, FcγRIIB-mediated uptake of SARS-CoV-2/mAb complex with bivalent interaction.
了解 SARS-CoV-2 的抗体依赖性增强 (ADE) 的潜在分子机制对于开发安全有效的治疗方法至关重要。在这里，我们报告说，两种中和单克隆抗体 MW01 和 MW05 可以增强 SARS-CoV-2 假病毒在表达 FcγRIIB 的 B 细胞上的感染。X 射线晶体结构测定和三聚体结合建模表明，MW01 和 MW05 可以与三聚体中的 RBD 以“向上”和“向下”状态结合。而没有 ADE 活性的中和单克隆抗体 MW07 仅与三聚体中的 RBD 以“向上”状态结合。单价 MW01 和 MW05 与它们的二价对应物相比，完全消除了 ADE 活性。此外，巨胞饮作用和内吞作用都被证实涉及 SARS-CoV-2 假病毒感染的 ADE。阻断内体运输和溶酶体酸化可以抑制 MW05 介导的 ADE 活性。总之，我们的研究结果在体外鉴定了 SARS-CoV-2 假病毒的一种新的 ADE 机制，即 FcγRIIB 介导的 SARS-CoV-2/mAb 复合物的摄取与二价相互作用。
