A non-neutralizing glycoprotein B monoclonal antibody protects against herpes simplex virus disease in mice
Masayuki Kuraoka, … , Garnett Kelsoe, Betsy C. Herold
Masayuki Kuraoka, … , Garnett Kelsoe, Betsy C. Herold
Published December 1, 2022
Citation Information: J Clin Invest. 2023;133(3):e161968. https://doi.org/10.1172/JCI161968.
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Research Article Infectious disease

A non-neutralizing glycoprotein B monoclonal antibody protects against herpes simplex virus disease in mice

Abstract

There is an unmet need for monoclonal antibodies (mAbs) for prevention or as adjunctive treatment of herpes simplex virus (HSV) disease. Most vaccine and mAb efforts focus on neutralizing antibodies, but for HSV this strategy has proven ineffective. Preclinical studies with a candidate HSV vaccine strain, ΔgD-2, demonstrated that non-neutralizing antibodies that activate Fcγ receptors (FcγRs) to mediate antibody-dependent cellular cytotoxicity (ADCC) provide active and passive protection against HSV-1 and HSV-2. We hypothesized that this vaccine provides a tool to identify and characterize protective mAbs. We isolated HSV-specific mAbs from germinal center and memory B cells and bone marrow plasmacytes of ΔgD-2–vaccinated mice and evaluated these mAbs for binding, neutralizing, and FcγR-activating activity and for protective efficacy in mice. The most potent protective mAb, BMPC-23, was not neutralizing but activated murine FcγRIV, a biomarker of ADCC. The cryo–electron microscopic structure of the Fab–glycoprotein B (gB) assembly identified domain IV of gB as the epitope. A single dose of BMPC-23 administered 24 hours before or after viral challenge provided significant protection when configured as mouse IgG2c and protected mice expressing human FcγRIII when engineered as a human IgG1. These results highlight the importance of FcR-activating antibodies in protecting against HSV.

Authors

Masayuki Kuraoka, Clare Burn Aschner, Ian W. Windsor, Aakash Mahant Mahant, Scott J. Garforth, Susan Luozheng Kong, Jacqueline M. Achkar, Steven C. Almo, Garnett Kelsoe, Betsy C. Herold

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Figure 3

Functional characteristics of HSV-specific rAbs.

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Functional characteristics of HSV-specific rAbs. (A) mAbs with a murine ...
(A) mAbs with a murine IgG1 (open symbols) or IgG2c (filled symbols) Fc (1 mg/mL) were tested for their ability to induce FcγRIV activation when incubated with HSV-2–infected Vero cells. Each antibody was tested at least twice in duplicate, and mean results are shown (P = 0.03 comparing the fold induction elicited by IgG2c vs. IgG1 for the subset of 18G4, 19G7, 22D10, 33B8, 35H7, and BMPC-23; Wilcoxon’s matched-pairs signed rank test). (B) A subset of antibodies was tested for their ability to neutralize HSV in the absence (left) or presence (right) of complement. Results are shown as percent neutralization relative to control and are the mean of duplicate wells at each concentration. (C) Female C57BL/6 mice received 750 μg of the IgG1 or the IgG2c version of indicated antibody 1 day before an LD90 challenge (5 × 104 PFU/mouse) with HSV-2(4674). Percentage survival is shown; n = 10 mice per group, 2 independent experiments. (D) Mice were treated i.p. with 250 or 500 μg of BMPC-23 or equivalent concentration of control (VD60 lysate–vaccinated) immune serum 24 hours after an LD90 skin challenge (n = 5 mice per group with 2 independent experiments for VD60 and 250 μg BMPC-23 and 1 experiment with 500 μg BMPC-23). In C and D, each group is compared with the VD60 control–treated mice by Gehan-Breslow-Wilcoxon test, **P < 0.01, ****P < 0.0001.