Selective decoupling of IgG1 binding to viral Fc receptors restores antibody-mediated NK cell activation against HCMV

A key mechanism of antiviral antibodies is to bind cell-surface viral antigens and activate cellular immunity to clear infected cells, yet antibodies targeting human cytomegalovirus (HCMV) have exhibited limited efficacy. This appears due to HCMV’s multiple immune evasion mechanisms, including viral receptors (vFcγRs) which bind human IgG Fc domains to co-operatively inhibit Fc activation of host Fcγ receptors and impair Fc-mediated effector functions. We biochemically characterized and evaluated the functions of two highly conserved vFcγRs, gp34 and gp68, and mapped their binding epitopes on the Fc domain. Based on this information, we then engineered Fc variants that retain binding to CD16A, which is essential for NK activation, and to FcRn but have markedly attenuated binding to gp34 and gp68. IgG1 antibodies targeting the gB fusogen with engineered Fc domains were not internalized by infected cells, mediated enhanced CD16A activation and limited viral spread in HCMV-infected fibroblasts more effectively than wild-type Fc. Together, this work demonstrates a strategy to enhance the efficacy of antibody therapies to clear HCMV infections.