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Monoclonal antibodies targeting nonstructural viral antigens can activate ADCC against human cytomegalovirus

Vlachava, Virginia-Maria ORCID:, Murrell, Isa, Zhuang, Lihui, Aicheler, Rebecca J., Lim, Eleanor, Miners, Kelly L., Ladell, Kristin ORCID:, Suárez, Nicolás M., Price, David A. ORCID:, Davison, Andrew J., Wilkinson, Gavin W.G., Wills, Mark R., Weekes, Michael P., Wang, Eddie C.Y. ORCID: and Stanton, Richard J. ORCID: 2021. Monoclonal antibodies targeting nonstructural viral antigens can activate ADCC against human cytomegalovirus. Journal of Clinical Investigation 131 (4) , e139296. 10.1172/JCI139296

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Human cytomegalovirus (HCMV) is a ubiquitous pathogen that causes severe disease following congenital infection and in immunocompromised individuals. No vaccines are licensed, and there are limited treatment options. We now show that the addition of anti-HCMV antibodies (Abs) can activate NK cells prior to the production of new virions, through Ab-dependent cellular cytotoxicity (ADCC), overcoming viral immune evasins. Quantitative proteomics defined the most abundant HCMV proteins on the cell surface, and we screened these targets to identify the viral antigens responsible for activating ADCC. Surprisingly, these were not structural glycoproteins; instead, the immune evasins US28, RL11, UL5, UL141, and UL16 each individually primed ADCC. We isolated human monoclonal Abs (mAbs) specific for UL16 or UL141 from a seropositive donor and optimized them for ADCC. Cloned Abs targeting a single antigen (UL141) were sufficient to mediate ADCC against HCMV-infected cells, even at low concentrations. Collectively, these findings validated an unbiased methodological approach to the identification of immunodominant viral antigens, providing a pathway toward an immunotherapeutic strategy against HCMV and potentially other pathogens.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License
Publisher: American Society for Clinical Investigation
ISSN: 0021-9738
Funders: MRC
Date of First Compliant Deposit: 16 February 2021
Date of Acceptance: 16 September 2020
Last Modified: 11 Oct 2023 17:08

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