Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
Department of Chemistry, Stanford University, Stanford, CA, USA.
Nat Chem Biol. 2022 Nov;18(11):1270-1276. doi: 10.1038/s41589-022-01140-1. Epub 2022 Sep 8.
Omicron and its subvariants have rendered most authorized monoclonal antibody-based treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ineffective, highlighting the need for biologics capable of overcoming SARS-CoV-2 evolution. These mostly ineffective antibodies target variable epitopes. Here we describe broad-spectrum SARS-CoV-2 inhibitors developed by tethering the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), to known non-neutralizing antibodies that target highly conserved epitopes in the viral spike protein. These inhibitors, called receptor-blocking conserved non-neutralizing antibodies (ReconnAbs), potently neutralize all SARS-CoV-2 variants of concern (VOCs), including Omicron. Neutralization potency is lost when the linker joining the binding and inhibitory ReconnAb components is severed. In addition, a bi-functional ReconnAb, made by linking ACE2 to a bi-specific antibody targeting two non-overlapping conserved epitopes, defined here, shows sub-nanomolar neutralizing activity against all VOCs, including Omicron and BA.2. Given their conserved targets and modular nature, ReconnAbs have the potential to act as broad-spectrum therapeutics against SARS-CoV-2 and other emerging pandemic diseases.
奥密克戎及其亚型变体使大多数经授权的用于治疗严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的单克隆抗体疗法失效，这凸显了需要能够克服 SARS-CoV-2 进化的生物制剂。这些大多数无效的抗体针对可变表位。在这里，我们描述了通过将 SARS-CoV-2 受体血管紧张素转换酶 2（ACE2）与靶向病毒刺突蛋白中高度保守表位的已知非中和抗体连接来开发的广谱 SARS-CoV-2 抑制剂。这些抑制剂称为受体阻断保守非中和抗体（ReconnAbs），能够强烈中和所有关注的 SARS-CoV-2 变体（VOCs），包括奥密克戎。当连接结合和抑制性 ReconnAb 成分的接头被切断时，中和效力就会丧失。此外，通过将 ACE2 与靶向两个非重叠保守表位的双特异性抗体连接制成的双功能 ReconnAb，针对所有 VOCs（包括奥密克戎和 BA.2）显示出亚纳摩尔级的中和活性。鉴于它们的保守靶标和模块化性质，ReconnAbs 有可能成为针对 SARS-CoV-2 和其他新发流行疾病的广谱治疗药物。
