A non-neutralizing glycoprotein B monoclonal antibody protects against herpes simplex virus disease in mice
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:133 |
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| Enthalten in: |
The Journal of clinical investigation - 133(2023), 3 vom: 01. Feb. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kuraoka, Masayuki [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 02.02.2023 Date Revised 01.04.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/JCI161968 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM349672806 |
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| 100 | 1 | |a Kuraoka, Masayuki |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A non-neutralizing glycoprotein B monoclonal antibody protects against herpes simplex virus disease in mice |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 02.02.2023 | ||
| 500 | |a Date Revised 01.04.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Antigen | |
| 650 | 4 | |a Immunoglobulins | |
| 650 | 4 | |a Infectious disease | |
| 650 | 4 | |a Vaccines | |
| 650 | 7 | |a Antibodies, Neutralizing |2 NLM | |
| 650 | 7 | |a Antibodies, Viral |2 NLM | |
| 650 | 7 | |a Glycoproteins |2 NLM | |
| 650 | 7 | |a Antibodies, Monoclonal |2 NLM | |
| 650 | 7 | |a Viral Envelope Proteins |2 NLM | |
| 700 | 1 | |a Aschner, Clare Burn |e verfasserin |4 aut | |
| 700 | 1 | |a Windsor, Ian W |e verfasserin |4 aut | |
| 700 | 1 | |a Mahant, Aakash Mahant |e verfasserin |4 aut | |
| 700 | 1 | |a Garforth, Scott J |e verfasserin |4 aut | |
| 700 | 1 | |a Kong, Susan Luozheng |e verfasserin |4 aut | |
| 700 | 1 | |a Achkar, Jacqueline M |e verfasserin |4 aut | |
| 700 | 1 | |a Almo, Steven C |e verfasserin |4 aut | |
| 700 | 1 | |a Kelsoe, Garnett |e verfasserin |4 aut | |
| 700 | 1 | |a Herold, Betsy C |e verfasserin |4 aut | |
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| 856 | 4 | 0 | |u http://dx.doi.org/10.1172/JCI161968 |3 Volltext |
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