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

Abstract

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.

Pathogenesis of human cytomegalovirus in the immunocompromised host

“…Antibodies, natural killer cells and macrophages may theoretically contribute to a protective immune response and are expected to interact and cooperate with T cells to control HCMV replication. A very recent paper has reported some of the immune functions that require collaborative contributions from more than one component of the immune system by studying viral proteins expressed at the surface of the infected cell and determining which could mediate antibody-dependent cellular cytotoxicity 100 . Remarkably, these targets were not the major structural glycoproteins of the virus but the proteins it deploys as immune evasins 100 .…”

“…A very recent paper has reported some of the immune functions that require collaborative contributions from more than one component of the immune system by studying viral proteins expressed at the surface of the infected cell and determining which could mediate antibody-dependent cellular cytotoxicity 100 . Remarkably, these targets were not the major structural glycoproteins of the virus but the proteins it deploys as immune evasins 100 . Future studies of this kind have the potential to give a more sophisticated assessment of the immune capability of individual patients at risk of HCMV infection.…”

Antiviral strategies targeting host factors and mechanisms obliging +ssRNA viral pathogens

“…These antibodies exhibit therapeutic effects with the help of antigen-binding fragment (Fab) and can be used against particular disease targets such as HCMV. 245 mAb therapy is just like passive immunotherapy which targets direct and rapid viral agent instead of developing a long-term immune response against that viral pathogen. In contrary, vaccine stimulates the host’s endogenous cellular and humoral immune responses to deliver sustained defensive immunity.…”

Playing chess with human cytomegalovirus

“…The diverse components of the immune system do not work in isolation; in the intact human, they may interact and cooperate to partially control HCMV replication, but we have little detailed knowledge about this. In a recent paper, authors with a strong background in examining many of these functions individually, assembled together some of the immune functions that require collaborative contributions from more than one component of the immune system 17 . Specifically, they studied viral proteins expressed at the surface of the infected cell and determined when antibody plus NK cells could mediate ADCC.…”

“…Specifically, they studied viral proteins expressed at the surface of the infected cell and determined when antibody plus NK cells could mediate ADCC. Remarkably, these targets were not the major structural glycoproteins of the virus, but the proteins it deploys as immune evasins 17 …”