https://orcid.org/0000-0003-0621-5320
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ABSTRACT
The development of specific, safe, and potent monoclonal antibodies (Abs) has led to novel therapeutic options for infectious disease. In addition to preventing viral infection through neutralization, Abs can clear infected cells and induce immunomodulatory functions through engagement of their crystallizable fragment (Fc) with complement proteins and Fc receptors on immune cells. Little is known about the role of Fc effector functions of neutralizing Abs in the context of encephalitic alphavirus infection. To determine the role of Fc effector function in therapeutic efficacy against Venezuelan equine encephalitis virus (VEEV), we compared the potently neutralizing anti-VEEV human IgG F5 (hF5) Ab with intact Fc function (hF5-WT) or containing the loss of function Fc mutations L234A and L235A (hF5-LALA) in the context of VEEV infection. We observed significantly reduced binding to complement and Fc receptors, as well as differential in vitro kinetics of Fc-mediated cytotoxicity for hF5-LALA compared to hF5-WT. The in vivo efficacy of hF5-LALA was comparable to hF5-WT at −24 and + 24 h post infection, with both Abs providing high levels of protection. However, when hF5-WT and hF5-LALA were administered + 48 h post infection, there was a significant decrease in the therapeutic efficacy of hF5-LALA. Together these results demonstrate that optimal therapeutic Ab treatment of VEEV, and possibly other encephalitic alphaviruses, requires neutralization paired with engagement of immune effectors via the Fc region.
Abbreviations
| Ab | = | Antibody |
| ADCC | = | Antibody-dependent cell-mediated cytotoxicity, |
| ADCP | = | Antibody-dependent cellular phagocytosis |
| BSA | = | Bovine serum albumin |
| CDC | = | Complement-dependent cytotoxicity |
| Fc | = | Crystallizable fragment |
| FcγRs | = | Fc gamma receptors |
| GFP | = | Green fluorescent protein |
| hF5 | = | VEEV-neutralizing human IgG1 antibody F5 |
| hF5-LALA | = | Human antibody hF5 with loss of function Fc mutations L234A and L235A |
| hF5-WT | = | Wildtype human antibody F5 with intact Fc function |
| hpi | = | hours post infection |
| HRP | = | Horseradish peroxidase |
| IgG | = | Immunoglobulin G |
| NHS | = | normal human serum |
| NMS | = | normal mouse serum |
| PFA | = | paraformaldehyde |
| VEEV | = | Venezuelan Equine Encephalitis Virus |
Acknowledgments
This work was supported by the Defense Threat Reduction Agency [contract HDTRA140027, project CB10489, PI: Harmon]. Sandia National Laboratories is a multimission laboratory managed and operated by National Technology & Engineering Solutions of Sandia, LLC, a wholly owned subsidiary of Honeywell International Inc., for the U.S. Department of Energy’s National Nuclear Security Administration under contract DE-NA0003525. All work performed at Lawrence Livermore National Laboratory is performed under the auspices of the U.S. Department of Energy under Contract DE-AC52-07NA27344. This paper describes objective technical results and analysis. Any subjective views or opinions that might be expressed in the paper do not necessarily represent the views of the U.S. Department of Energy or the United States Government.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/19420862.2023.2297451
Correction Statement
This article was originally published with errors, which have now been corrected in the online version. Please see Correction (http://dx.doi.org/10.1080/19420862.2024.2312050)