2025-12-15 テキサス大学オースチン校(UT Austin)
<関連情報>
- https://news.utexas.edu/2025/12/15/cytomegalovirus-breakthrough-could-lead-to-new-treatments/
- https://www.cell.com/cell-reports/fulltext/S2211-1247(25)01365-8
IgG1のウイルスFc受容体への結合を選択的に分離することで、HCMVに対する抗体を介したNK細胞の活性化が回復する Selective decoupling of IgG1 binding to viral Fc receptors restores antibody-mediated NK cell activation against HCMV
Ahlam N. Qerqez ∙ Katja Hoffmann ∙ Alison G. Lee, ∙ … ∙ Richard J. Stanton ∙ Annalee W. Nguyen ∙ Jennifer A. Maynard
Cell Reports Published:December 3, 2025
DOI:https://doi.org/10.1016/j.celrep.2025.116593
Graphical abstract
Highlights
- Host and HCMV FcR compete for IgG1 binding but engage different residues
- Fc-engineering abrogates viral FcR antagonism while retaining CD16A activation
- Antibodies that resist vFcγR capture promote superior ADCC against infected cells
- Designer Fc domains complement Fabs to create enhanced disease-specific therapies
Summary
Antibodies binding cell-surface antigens to activate cellular immunity are an important mechanism of anti-viral protection, yet antibodies targeting cells infected by human cytomegalovirus (HCMV) exhibit limited efficacy. This is due to HCMV immune evasion mechanisms, including viral receptors (vFcγRs) that bind human immunoglobulin G Fc domains to inhibit host Fcγ receptor activation and impair Fc-mediated immune functions. Here, we biochemically characterize two conserved vFcγRs, gp34 and gp68, and map their Fc binding sites. We then engineer Fc variants to retain binding to host Fc receptors CD16A and FcRn but exhibit markedly reduced gp34/gp68 interactions. Antibodies targeting the gB fusogen with engineered Fc domains are not internalized by infected cells, mediate enhanced immune cell activation, and limit viral spread in HCMV-infected fibroblasts more effectively than antibodies with wild-type Fc. This work demonstrates a strategy to enhance therapeutic antibody control of HCMV infections and other herpesvirus infections with similar immune-evasion mechanisms.
