Immune therapies Laboratory, Burnet Institute, Melbourne, VIC, Australia.
Life Sciences, Burnet Institute, Melbourne, VIC, Australia.
Front Immunol. 2022 Jul 28;13:889372. doi: 10.3389/fimmu.2022.889372. eCollection 2022.
Joining a function-enhanced Fc-portion of human IgG to the SARS-CoV-2 entry receptor ACE2 produces an antiviral decoy with strain transcending virus neutralizing activity. SARS-CoV-2 neutralization and Fc-effector functions of ACE2-Fc decoy proteins, formatted with or without the ACE2 collectrin domain, were optimized by Fc-modification. The different Fc-modifications resulted in distinct effects on neutralization and effector functions. H429Y, a point mutation outside the binding sites for FcγRs or complement caused non-covalent oligomerization of the ACE2-Fc decoy proteins, abrogated FcγR interaction and enhanced SARS-CoV-2 neutralization. Another Fc mutation, H429F did not improve virus neutralization but resulted in increased C5b-C9 fixation and transformed ACE2-Fc to a potent mediator of complement-dependent cytotoxicity (CDC) against SARS-CoV-2 spike (S) expressing cells. Furthermore, modification of the Fc-glycan enhanced cell activation FcγRIIIa. These different immune profiles demonstrate the capacity of Fc-based agents to be engineered to optimize different mechanisms of protection for SARS-CoV-2 and potentially other viral pathogens.
将人类 IgG 的功能增强 Fc 部分与 SARS-CoV-2 进入受体 ACE2 结合，产生一种具有超越病毒中和活性的抗病毒诱饵。通过 Fc 修饰优化了 ACE2-Fc 诱饵蛋白的 SARS-CoV-2 中和和 Fc 效应子功能，这些诱饵蛋白具有或不具有 ACE2 集萃结构域。不同的 Fc 修饰对中和和效应子功能产生了不同的影响。H429Y 是结合 FcγRs 或补体的位点之外的一个点突变，导致 ACE2-Fc 诱饵蛋白的非共价寡聚化，消除了 FcγR 相互作用并增强了 SARS-CoV-2 的中和作用。另一种 Fc 突变 H429F 虽然不能提高病毒的中和作用，但导致 C5b-C9 的固定增加，并将 ACE2-Fc 转化为 SARS-CoV-2 刺突（S）表达细胞中补体依赖性细胞毒性（CDC）的有效介质。此外，Fc 聚糖的修饰增强了细胞激活 FcγRIIIa。这些不同的免疫特征表明，基于 Fc 的制剂有能力被设计为优化 SARS-CoV-2 和潜在其他病毒病原体的不同保护机制。
