A non-neutralizing glycoprotein B monoclonal antibody protects against herpes simplex virus disease in mice
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
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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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 6

Isolation and characterization of gB-specific BCRs from GC B cells.

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Isolation and characterization of gB-specific BCRs from GC B cells. HSV ...
HSV gB-specific GC B cells were identified by screening of HSV-reactive Nojima culture samples by a Luminex assay. Inhibition of BMPC-23 by gB-specific rAbs was assessed in a multiplex binding assay as described in Methods. The gB-specific rAbs (filled symbols) were grouped by their inhibitory capacity: strong (HSV010-4, -7, and -34; left), weak (HSV010-6, -9, -13, -14, and -28; middle), and no inhibition (HSV010-20; right). Inhibition by self (BMPC-23, open circles) and an irrelevant, hapten-specific mAb (H33Lγ1, open squares) is coplotted in each panel. The y axis indicates MFI percentage of maximal binding, determined as the mean MFI in the presence of H33Lγ1. Dotted lines indicate MFI values corresponding to 50%, 90%, and 99% inhibition, respectively.