Bispecific VH/Fab antibodies targeting neutralizing and non-neutralizing Spike epitopes demonstrate enhanced potency against SARS-CoV-2.
Bispecific VH/Fab antibodies targeting neutralizing and non-neutralizing Spike epitopes demonstrate enhanced potency against SARS-CoV-2.
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DOI：
10.1080/19420862.2021.1893426
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发表时间：
2021-01
期刊：
影响因子：
5.3
通讯作者：
Wells JA
中科院分区：
文献类型：
--
作者：
Lim SA;Gramespacher JA;Pance K;Rettko NJ;Solomon P;Jin J;Lui I;Elledge SK;Liu J;Bracken CJ;Simmons G;Zhou XX;Leung KK;Wells JA
许多针对SARS-CoV-2的中和抗体已被报道，其中最直接的是阻断病毒刺突受体结合域(RBD)与血管紧张素转换酶II(ACE2)的结合。在这里，我们故意利用非中和RBD抗体，表明当与中和结合物联系在一起时，它们可以极大地帮助中和。我们通过噬菌体展示鉴定了与RBD结合的抗原结合片段，但不能阻断ACE2或以免疫球蛋白的形式中和病毒。当这些非中和Fb被组装成具有中和VH结构域的双特异性VH/Fab Igs时，我们观察到与单特异性双价VH-Fc或VH-Fc和Ig G的混合物相比，中和SARS-CoV-2的效力提高了约25倍。这种效应是表位依赖的，反映了针对Spike的双特异性抗体的独特几何构型。我们的结果表明，结合了Spike-RBD上的中和表位和非中和表位的双特异性抗体是一种有希望的快速工程策略，可以提高SARS-CoV-2抗体的效力。
Numerous neutralizing antibodies that target SARS-CoV-2 have been reported, and most directly block binding of the viral Spike receptor-binding domain (RBD) to angiotensin-converting enzyme II (ACE2). Here, we deliberately exploit non-neutralizing RBD antibodies, showing they can dramatically assist in neutralization when linked to neutralizing binders. We identified antigen-binding fragments (Fabs) by phage display that bind RBD, but do not block ACE2 or neutralize virus as IgGs. When these non-neutralizing Fabs were assembled into bispecific VH/Fab IgGs with a neutralizing VH domain, we observed a ~ 25-fold potency improvement in neutralizing SARS-CoV-2 compared to the mono-specific bi-valent VH-Fc alone or the cocktail of the VH-Fc and IgG. This effect was epitope-dependent, reflecting the unique geometry of the bispecific antibody toward Spike. Our results show that a bispecific antibody that combines both neutralizing and non-neutralizing epitopes on Spike-RBD is a promising and rapid engineering strategy to improve the potency of SARS-CoV-2 antibodies.
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影响因子：
64.8
作者：
Ke, Zunlong;Oton, Joaquin;Briggs, John A. G.
通讯作者：
Briggs, John A. G.
影响因子：
56.9
作者：
Lv, Zhe;Deng, Yong-Qiang;Wang, Xiangxi
通讯作者：
Wang, Xiangxi
影响因子：
16.8
作者：
Huo, Jiangdong;Le Bas, Audrey;Naismith, James H.
通讯作者：
Naismith, James H.
影响因子：
4.8
作者：
Byrnes, James R.;Zhou, Xin X.;Wells, James A.
通讯作者：
Wells, James A.
DOI：
10.1093/protein/11.9.825
发表时间：
1998-09-01
期刊：
PROTEIN ENGINEERING
影响因子：
--
作者：
Daugherty, PS;Chen, G;Georgiou, G
通讯作者：
Georgiou, G