Monoclonal antibodies targeting nonstructural viral antigens can activate ADCC against human cytomegalovirus
Miners, Kelly L.
Suárez, Nicolás M.
Price, David A.
Davison, Andrew J.
Wilkinson, Gavin W.G
Wills, Mark R.
Weekes, Michael P.
Wang, Eddie C.Y.
Stanton, Richard J.
American Society for Clinical Investigation
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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.
Journal of Clinical Investigation;
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., Wills, M.R., Weekes, M.P., Wang, E.C., Stanton, R.J.(2021) 'Monoclonal antibodies targeting nonstructural viral antigens can activate ADCC against human cytomegalovirus', The Journal of Clinical Investigation, 131(4) doi: 10.1172/JCI139296
Article published in Journal of Clinical Investigation available open access at https://doi.org/10.1172/JCI139296
This work was supported by funding from the Wellcome Trust (100326/Z/12/Z, 204870/Z/16/Z, 108070/Z/15/Z) and the Medical Research Council (MRC) (MR/S00971X/1, MR/L008734/1, MR/P001602/1, MC_UU_12014/3, MR/S00081X/1. LZ was funded by a grant from Kymab, however, Kymab had no part in the design, execution, or analysis of the experiments reported in this study.