DataSheet_1_Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2.docx

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 via 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.

将功能优化的人免疫球蛋白G（IgG）Fc段（Fc portion）与新型冠状病毒（SARS-CoV-2）进入受体血管紧张素转换酶2（ACE2）结合，可获得具有跨毒株病毒中和活性的抗病毒诱饵蛋白。针对带有或缺失ACE2 collectrin结构域的ACE2-Fc诱饵蛋白，其新冠病毒中和活性与Fc效应功能均可通过Fc修饰得到优化。不同的Fc修饰方式对中和活性与效应功能产生了截然不同的影响。H429Y是位于Fcγ受体（FcγR）或补体结合位点之外的点突变，可诱导ACE2-Fc诱饵蛋白发生非共价寡聚化，消除FcγR结合并增强新冠病毒中和活性。另一项Fc突变H429F未提升病毒中和活性，但可增强C5b-C9补体复合物的结合，并将ACE2-Fc转化为针对表达新冠病毒刺突（S）蛋白细胞的强效补体依赖细胞毒性（CDC）介导因子。此外，Fc糖基化修饰可通过Fcγ受体IIIa（FcγRIIIa）增强细胞活化。上述多样的免疫特征表明，基于Fc的制剂可通过工程化改造优化针对新冠病毒乃至其他病毒病原体的不同保护机制。