Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Nat Immunol. 2021 Dec;22(12):1503-1514. doi: 10.1038/s41590-021-01068-z. Epub 2021 Oct 29.
Prevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Here we identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance.
预防病毒逃逸和增加对严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）关切变异株的覆盖范围，需要针对冠状病毒刺突糖蛋白多个脆弱部位的治疗性单克隆抗体（mAb）。在这里，我们鉴定了几种针对刺突蛋白的 N 端结构域（NTD）或受体结合域（RBD）的强效中和抗体。这些 mAb 以组合形式给药，通过中和和 Fc 效应抗体功能，在 K18-人血管紧张素转换酶 2 小鼠模型中提供了针对 SARS-CoV-2 感染的低剂量保护。靶向残基 F486 的 RBD mAb WRAIR-2125 通过独特的重链和轻链配对，对所有主要的 SARS-CoV-2 关切变异株均表现出强大的中和活性。与 NTD 和其他 RBD mAb 联合使用时，WRAIR-2125 还能防止病毒逃逸。这些数据表明，NTD/RBD mAb 组合提供了强大的保护作用，可能利用了病毒失活和清除的互补机制。
