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

Vlahava, V.-M. et al. (2021) Monoclonal antibodies targeting nonstructural viral antigens can activate ADCC against human cytomegalovirus. Journal of Clinical Investigation, 131(4), e139296. (doi: 10.1172/JCI139296) (PMID:33586678) (PMCID:PMC7880312)

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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:Articles
Glasgow Author(s) Enlighten ID:Suarez, Dr Nicolas and Davison, Professor Andrew
Authors: Vlahava, V.-M., Murrell, I., Zhuang, L., Aicheler, R. J., Lim, E., Miners, K. L., Ladell, K., Suárez, N. M., Price, D. A., Davison, A. J., Wilkinson, G. W.G., Wills, M. R., Weekes, M. P., Wang, E. C.Y., and Stanton, R. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Clinical Investigation
Publisher:American Society for Clinical Investigation
ISSN (Online):1558-8238
Published Online:15 February 2021
Copyright Holders:Copyright © 2021 Vlahava et al.
First Published:First published in Journal of Clinical Investigation 131(4): e139296
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
174258Exploiting a human challenge model to understand the pathogenesis of cytomegalovirusAndrew DavisonWellcome Trust (WELLCOTR)204870/Z/16/Z (17/0008)III-MRC-GU Centre for Virus Research
656321Genomics of human cytomegalovirusAndrew DavisonMedical Research Council (MRC)MC_UU_12014/3MVLS III - CENTRE FOR VIRUS RESEARCH