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

Ahlam N Qerqez¹, Katja Hoffmann², Alison G Lee³, Sumit Pareek⁴, Kelli Hager³, Akaash K Mishra³, George Delidakis⁴, Kirsten Bentley⁵, Lauren Kerr-Jones⁵, Mica Cabrera³, Truong Nguyen³, Rebecca L Göttler⁶, Amjad Chowdhury⁴, Philipp L Kolb⁶, Hartmut Hengel⁶, George Georgiou⁷, Jason S McLellan⁸, Richard J Stanton⁵, Annalee W Nguyen⁴, Jennifer A Maynard⁹

Affiliations

¹ Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA. Electronic address: ahlam.qerqez@gmail.com.
² Institute of Virology, University Medical Center, and Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany. Electronic address: katja.hoffmann@uniklinik-freiburg.de.
³ Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
⁴ Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
⁵ Division of Infection and Immunology, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
⁶ Institute of Virology, University Medical Center, and Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.
⁷ Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA; LaMontaigne Center for Infectious Diseases, University of Texas at Austin, Austin, TX 78712, USA.
⁸ Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA; LaMontaigne Center for Infectious Diseases, University of Texas at Austin, Austin, TX 78712, USA.
⁹ Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA; LaMontaigne Center for Infectious Diseases, University of Texas at Austin, Austin, TX 78712, USA. Electronic address: maynard@che.utexas.edu.

PMID: 41343276
DOI: 10.1016/j.celrep.2025.116593

Free article

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

Ahlam N Qerqez et al. Cell Rep. 2025.

Free article

. 2025 Dec 3;44(12):116593.

doi: 10.1016/j.celrep.2025.116593. Online ahead of print.

Authors

Affiliations

¹ Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA. Electronic address: ahlam.qerqez@gmail.com.
² Institute of Virology, University Medical Center, and Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany. Electronic address: katja.hoffmann@uniklinik-freiburg.de.
³ Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
⁴ Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
⁵ Division of Infection and Immunology, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
⁶ Institute of Virology, University Medical Center, and Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.
⁷ Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA; LaMontaigne Center for Infectious Diseases, University of Texas at Austin, Austin, TX 78712, USA.
⁸ Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA; LaMontaigne Center for Infectious Diseases, University of Texas at Austin, Austin, TX 78712, USA.
⁹ Department of Chemical Engineering, University of Texas at Austin, Austin, TX 78712, USA; LaMontaigne Center for Infectious Diseases, University of Texas at Austin, Austin, TX 78712, USA. Electronic address: maynard@che.utexas.edu.

PMID: 41343276
DOI: 10.1016/j.celrep.2025.116593

Abstract

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.

Keywords: CP: immunology.

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Conflict of interest statement

Declaration of interests A.N.Q., A.G.L., S.P., and J.A.M. are inventors on WO2023108117A2 (“Engineered Fc Domains and Engineered HCMV Viral Fc Receptors”). P.K. was funded by Biotest AG, who produces Cytotect (2022–2024), and serves as a consultant for Oak Hill Bio. R.J.S. has been a paid consultant for Vaccitech and Moderna on HCMV vaccines. J.S.M. and J.A.M. received funding from Dynavax to evaluate stabilized HCMV gB immunogens. These activities had no impact on this study.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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