Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10029, USA.
Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10029, USA; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
Structure. 2021 Jul 1;29(7):655-663.e4. doi: 10.1016/j.str.2021.05.014. Epub 2021 Jun 9.
Emerging SARS-CoV-2 strains, B.1.1.7 and B.1.351, from the UK and South Africa, respectively, show decreased neutralization by monoclonal antibodies and convalescent or vaccinee sera raised against the original wild-type virus, and are thus of clinical concern. However, the neutralization potency of two antibodies, 1-57 and 2-7, which target the receptor-binding domain (RBD) of the spike, was unaffected by these emerging strains. Here, we report cryo-EM structures of 1-57 and 2-7 in complex with spike, revealing each of these antibodies to utilize a distinct mechanism to bypass or accommodate RBD mutations. Notably, each antibody represented an immune response with recognition distinct from those of frequent antibody classes. Moreover, many epitope residues recognized by 1-57 and 2-7 were outside hotspots of evolutionary pressure for ACE2 binding and neutralizing antibody escape. We suggest the therapeutic use of antibodies, such as 1-57 and 2-7, which target less prevalent epitopes, could ameliorate issues of monoclonal antibody escape.
分别来自英国和南非的新兴 SARS-CoV-2 菌株 B.1.1.7 和 B.1.351 对针对原始野生型病毒产生的单克隆抗体和恢复期或疫苗接种者血清的中和作用降低，因此具有临床关注性。然而，两种靶向刺突受体结合域（RBD）的抗体 1-57 和 2-7 的中和效力不受这些新兴株的影响。在这里，我们报告了 1-57 和 2-7 与 Spike 复合物的冷冻电镜结构，揭示了这两种抗体都利用了不同的机制来绕过或适应 RBD 突变。值得注意的是，每种抗体所代表的免疫反应的识别特征都与常见的抗体类别不同。此外，1-57 和 2-7 识别的许多表位残基都不在 ACE2 结合和中和抗体逃逸的进化压力热点之外。我们建议使用靶向不太常见表位的抗体（如 1-57 和 2-7）进行治疗，这可能会改善单克隆抗体逃逸的问题。
